case study on pulmonary embolism

Pulmonary Embolism Case Study: Diagnosis and Treatment

by John Landry, BS, RRT | Updated: Apr 19, 2024

A pulmonary embolism is a blockage in the pulmonary artery caused by a blood clot in the lungs. This is a life-threatening condition and results in symptoms that respiratory therapists and medical professionals must be able to identify.

This case study will explore the events leading up to a patient being diagnosed with a pulmonary embolism, as well as the treatment and management of this condition.

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Pulmonary Embolism Clinical Scenario

You are called to the emergency room to treat a 25-year-old, 67 kg female patient. She is experiencing new onset chest pain and shortness of breath. She describes her chest pain as a stabbing sensation that radiates down to her left arm and gets worse during periods of exertion. She also feels lightheaded and highly anxious. In addition, the patient has a history of allergic asthma. Her only home medications are Microgestin Fe 1/20 (i.e., birth control) and albuterol PRN. She has no history of smoking or vaping.

Patient Assessment

The patient’s pupils are round and reactive.
She is mildly diaphoretic.
She is showing signs of nasal flaring without pursed-lip breathing.
Her trachea is located in the midline.
She has no jugular venous distention.
She has been coughing up small amounts of blood-tinged sputum.
She has bilateral, decreased chest rise.
Auscultation reveals crackles and a third heart sound.
Palpation reveals normal tactile fremitus.
Her percussion findings are normal at the apexes and decreased at the bases.
She has a normal anterior-posterior chest diameter.
Her chest is not tender to the touch.
Her abdomen is soft and not distended.

Extremities:

She shows no sign of digital clubbing.
Her capillary refill time is 4 seconds.
Her fingertips are slightly cyanotic and cool to the touch.
She shows no signs of pedal edema.
She has a moderately sized bruise on her right leg that is tender and warm to the touch.

Vital Signs:

Respiratory rate: 30 breaths/min
Heart rate: 120 beats/min
Blood pressure: 100/75 mmHg
Chest x-ray: Consolidation in both lung bases

Diagnosis and Treatment

Based on the patient’s assessment , history, and vital signs, what condition does the patient have, and why?

The patient is presenting with a pulmonary embolism (PE).

Key Components:

The use of oral contraceptives is important for the diagnosis because one common side effect is hyper-coagulation.
A bruise that is accompanied by tenderness and warmth in her leg is a sign of deep vein thrombosis (i.e., blood clot). This is important because blood clots can travel from the legs to the lungs, resulting in a pulmonary embolism.
Other important signs include hypoxemia (i.e., low SpO2), increased capillary refill, cyanosis, and coolness to the touch. This could be caused by decreased perfusion and/or atelectasis .
Diaphoresis and anxiety
The patient has decreased percussion and crackles in the lung bases, which indicates atelectasis. Atelectasis can occur in patients who experience pulmonary infarction due to a pulmonary embolism.
A third heart sound is sometimes heard in patients with a pulmonary embolism.
Another important finding is the patient’s chest x-ray, which only shows atelectasis. A pulmonary embolism will not show up on a chest x-ray, but sometimes a wedge-shaped inflate will appear if pulmonary infarction has occurred as a result.

Bonus Point: You should have been able to recognize that, while the patient had a history of allergic asthma , their current presentation did not align with that of an asthma exacerbation. Remember that additional information may be given to you in scenario-based testing. When this happens, take note of the information in case it becomes important later on, but don’t let it distract you from the task at hand.

What tests can confirm the presence of a pulmonary embolism?

Computed tomography pulmonary angiogram (CTPA): This is the preferred test for confirming a pulmonary embolism. The presence of a blood clot will show as a darkened area.
V/Q scan: This is the second most preferred radiological test for a suspected pulmonary embolism. It will show a disturbance in gas distribution in the patient’s lungs when a thrombus is present.
Pulmonary angiogram: This is the least preferred test because it is the most invasive. It involves the insertion of a catheter while dye is injected into the pulmonary artery, which will reveal the presence of an embolism.

You may also wish to recommend specific blood tests, such as D-dimer and platelet count. These will give you clues about the patient’s clotting status. D-dimer is most often used to look for the presence of a blood clot, as it will be increased if a clot is present.

It is important to remember that other factors can cause a patient’s d-dimer and clotting factors to increase; therefore, you should not rely on this test solely to confirm that a pulmonary embolism is present.

Additional Treatment

Let’s assume that you initiated the patient on oxygen therapy via nasal cannula at 2 L/min to try and correct their hypoxemia. After 20 minutes, you decided to incrementally increase the flow to 5 L/min, but there was no improvement in their oxygenation status.

Why is the patient’s SpO2 and PaO2 unresponsive to receiving supplemental oxygen?

This occurs because blood clots reduce or entirely prevent blood from flowing past a clot. Therefore, any alveoli distal to the clot will receive little to no perfusion. This decrease in perfusion prevents carbon dioxide and oxygen from effectively being exchanged at the alveolar-capillary membrane, even when the patient is ventilating normally.

This prevention of effective gas exchange due to low perfusion is part of what causes patients with a pulmonary embolism to be unresponsive to supplemental oxygen. The development of atelectasis due to pulmonary infarction secondary to a pulmonary embolism can further reduce the patient’s responsiveness to oxygen.

What other treatment methods would you recommend?

Anticoagulants: The administration of a fast-acting anticoagulant, like heparin, and a slow-acting anticoagulant, like Warfarin should be recommended. This can help stop the existing clot from growing and to prevent new clots from forming. Patients who are prescribed Warfarin will need to have their other medications, dietary supplements, and nutrition plan reviewed. That is because medications, supplements, or food can impact the blood’s ability to clot while potentially negatively impacting the drug.
Thrombolytic agents: The administration of thrombolytic drugs, such as altepase, streptokinase, or urokinase, can help break down the embolism. Patients who are prescribed a thrombolytic should be monitored for an increased risk of bleeding. This is especially true when prescribed heparin alongside a thrombolytic agent.
Analgesics: These drugs can be administered for any pain the patient may be experiencing.
Preventative actions: Ensuring the patient stays active, moves their limbs, is well-hydrated, and wears compression socks can help prevent another clot from forming.
Pneumatic compression cuffs: These should be placed on the patient’s legs while they’re bedridden to decrease the risk of more blood clots forming.
Surgical interventions: A pulmonary embolectomy can be performed to remove an existing clot that is not dissolved by medications. The placement of an inferior vena cava filter can also be used to prevent future clots from reaching the patient’s lungs. These filters are usually reserved for patients who are at high risk for developing further embolisms despite receiving pharmaceutical interventions.

Final Thoughts

A pulmonary embolism is a serious medical condition that can be difficult to diagnose. Respiratory therapists must be aware of the risk factors and symptoms to properly assess and treat their patients. A few key things to remember about patients with a pulmonary embolism include:

They often present with radiating chest pain.
They need radiological testing that is more extensive than a simple chest x-ray.
They are often unresponsive to supplemental oxygen.

Treatment for a pulmonary embolism should be aimed at dissolving existing clots while preventing future clots from forming. Thanks for reading, and, as always, breathe easy, my friend.

Written by:

John Landry is a registered respiratory therapist from Memphis, TN, and has a bachelor's degree in kinesiology. He enjoys using evidence-based research to help others breathe easier and live a healthier life.

Egan’s Fundamentals of Respiratory Care. 12th ed., Mosby, 2020.
Wilkins’ Clinical Assessment in Respiratory Care. 8th ed., Mosby, 2017.
Clinical Manifestations and Assessment of Respiratory Disease. 8th ed., Mosby, 2019.
Tarbox, Abigail K., and Mamta Swaroop. “Pulmonary Embolism.” National Library of Medicine, Int J Crit Illn Inj Sci, Jan. 2013, www.ncbi.nlm.nih.gov/pmc/articles/PMC3665123 .
Turetz, Meredith, et al. “Epidemiology, Pathophysiology, and Natural History of Pulmonary Embolism.” National Library of Medicine, Semin Intervent Radiol, Jan. 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC5986574 .
Morrone, Doralisa, and Vincenzo Morrone. “Acute Pulmonary Embolism: Focus on the Clinical Picture.” National Library of Medicine, Korean Circ J., May 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC5940642 .
Lavorini, Federico, et al. “Diagnosis and Treatment of Pulmonary Embolism: A Multidisciplinary Approach.” National Library of Medicine, Multidiscip Respir Med, 2013, www.ncbi.nlm.nih.gov/pmc/articles/PMC3878229 .

Pulmonary Embolism: Clinical Case

The following are key points to remember about this clinical case on pulmonary embolism (PE):

Although approximately 20% of patients who are treated for PE die within 90 days, true short-term mortality attributed to PE is estimated to be <5%. Approximately 50% of the patients who receive a diagnosis of PE have functional and exercise limitations 1 year later (known as post–PE syndrome), and the health-related quality of life for patients with a history of PE is diminished as compared with that of matched controls.
Newer approaches such as YEARS algorithm and age adjustment for D-dimer thresholds for ruling out PE are recommended.
Diagnostic chest imaging is reserved for patients in whom PE cannot be ruled out based on clinical decision making.
After initial diagnosis, clinical risk stratification into high, intermediate high risk, intermediate low risk, and low risk is recommended next. The nomenclature of “massive” and “submassive” in describing PE is confusing, given that clot size does not dictate therapy.
High risk: Intravenous systemic thrombolysis is the most readily available reperfusion option in high-risk PE patients. Alternative reperfusion approaches include surgical thrombectomy and catheter-directed thrombolysis (with or without thrombectomy). Additional supportive measures include the administration of inotropes and the use of extracorporeal life support.
Intermediate high risk: When available, catheter-directed thrombus removal remains an option for such. At this time, there is insufficient evidence to support catheter-directed thrombolysis over anticoagulation alone in these patients. Systemic thrombolysis is not typically recommended for these patients.
Intermediate low risk: Anticoagulation with low molecular weight heparin and close monitoring for 24-48 hours for clinical worsening is recommended.
Low risk: Outpatient management with direct oral anticoagulants is the preferred strategy.
All patients with acute PE should receive anticoagulant therapy for ≥3 months. The decision to continue treatment indefinitely depends on whether the associated reduction in the risk of recurrent venous thromboembolism outweighs the increased risk of bleeding and should take into account patient preferences.
Patients should be followed longitudinally after an acute PE to assess for dyspnea or functional limitation, which may indicate the development of post–PE syndrome or chronic thromboembolic pulmonary hypertension.

Clinical Topics: Anticoagulation Management, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Interventions and Imaging, Interventions and Vascular Medicine

Keywords: Anticoagulants, Diagnostic Imaging, Dyspnea, Extracorporeal Membrane Oxygenation, Heparin, Low-Molecular-Weight, Outpatients, Pulmonary Embolism, Quality of Life, Reperfusion, Risk Assessment, Secondary Prevention, Thrombectomy, Thrombolytic Therapy, Thrombosis, Vascular Diseases, Venous Thromboembolism

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Case report
Open access
Published: 15 September 2009

Pulmonary embolism presenting as syncope: a case report

Ahmet Demircan 1 ,
Gulbin Aygencel 2 ,
Ayfer Keles 1 ,
Ozgur Ozsoylar 3 &
Fikret Bildik 1

Journal of Medical Case Reports volume 3 , Article number: 7440 ( 2009 ) Cite this article

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Introduction

Despite the high incidence of pulmonary embolism its diagnosis continues to be difficult, primarily because of the vagaries of symptoms and signs in presentation. Conversely, syncope is a relatively easy clinical symptom to detect, but has varied etiologies that lead to a documented cause in only 58% of syncopal events. Syncope as the presenting symptom of pulmonary embolism has proven to be a difficult clinical correlation to make.

Case presentation

We present the case of a 26-year-old Caucasian man with pulmonary embolism induced-syncope and review the pathophysiology and diagnostic considerations.

Conclusions

Pulmonary embolism should be considered in the differential diagnosis of every syncopal event that presents at an emergency department.

Recognized venous thromboembolism (pulmonary embolism and deep venous thrombosis) is responsible for more than 250,000 hospitalizations and approximately 50,000 deaths per year in the United States. Because it is difficult to diagnose, the true incidence of pulmonary embolism is unknown, but it is estimated that approximately 650,000 cases occur annually [ 1 ].

Despite this high incidence, the diagnosis of pulmonary embolism continues to be difficult primarily because of the notorious vagaries of symptoms and signs in its presentation. Conversely, syncope is a relatively easy clinical symptom to detect, but has varied etiologies that lead to a documented cause in only 58% of syncopal events [ 2 ].

Syncope as the presenting symptom of pulmonary embolism has proven to be a difficult clinical correlation to make. We present the case of a patient with pulmonary embolism-induced syncope and review the pathophysiology and diagnostic considerations.

A 26-year-old Caucasian man with no history of disease was admitted to Gazi University Emergency Department after he had a syncopal episode in his home. The patient was in his usual good state of health until he suddenly collapsed while standing and lost consciousness for approximately five minutes. He recovered spontaneously but was extremely weak and dyspneic. He was also diaphoretic and tachypneic, but denied any associated chest pain or palpitations. No tonic-clonic activity was witnessed, and he experienced no incontinence.

The patient was a computer programmer and he had been working 18 hours a day without rest periods for a month. On admission, physical examination revealed a diaphoretic and dyspneic patient without focal neurologic findings. His heart rate was regular but tachycardic at 128 beats/minute, his blood pressure was 126/72 mmHg without orthostatic changes, and his respiratory rate was 32 breaths/minute. The room air oxygen saturation was 90%, and arterial blood gas analysis in room air revealed hypoxemia (PO 2 = 58 mmHg) with an elevated alveolo-arterial oxygen gradient (A-a O 2 gradient). Examination of his head and neck was normal. The results of chest wall examination revealed reduced breath sounds bilaterally at the lung bases. The findings of heart and abdominal examinations were unremarkable, but on examination of his legs, deep venous thrombosis (DVT) was noted in his left leg, with a positive Homans' sign in the left leg and the left calf measured 3 cm more than the right one.

Levels of serum electrolytes, glucose, blood urea and creatinine, and complete blood counts were normal. Results of a computed tomographic scan of his head were negative for bleeding, aneurysm or an embolic event. Chest X-ray was clear. An electrocardiogram showed a regular rhythm consistent with sinus tachycardia; there were Q and T waves in lead III and an S wave in lead I. A ventilation-perfusion scan demonstrated an unmatched segmental perfusion defect, indicating a high probability of the presence of a pulmonary thromboembolism (PTE) (Figures 1 and 2 ). A transthoracic echocardiogram revealed normal left ventricle function without a patent foramen ovale, an atrial septal defect or a ventricular septal defect, but with mild pulmonary hypertension (42 mmHg). A Doppler scan of the legs revealed an acute DVT in the patient's left leg, in the popliteal vein. Thrombolytic treatment was not given - the patient received standard anticoagulation treatment with unfractionated heparin and an oral anticoagulant. Before treatment, a blood sample was taken to examine the thrombophilia panel. After a 12-day course of hospital treatment, he was discharged on oral warfarin therapy. The patient's long-term follow-up was performed by the Department of Pulmonary Disease, and we learned that the patient was well for four months after that episode without any evidence of recurrent syncope or pulmonary embolism.

Decreased perfusion is seen to the right lung (particularly evident in the right lower lobe on the RPO image) in our case (perfusion scan was performed with Tc-99m MAA) .

There is no significant ventilation defect in our case (ventilation scan was performed with Xe-133 gas) .

Pulmonary embolism is a frequent cause of death in the United States. Nevertheless, it remains difficult to diagnose. Pulmonary emboli differ considerably in size and number, and the underlying disorders, including malignancy, trauma, and protein C or S deficiency, are numerous [ 1 ]. The classic triad of pleuritic chest pain, dyspnea, and hemoptysis is rare, and clinically apparent DVT is present in only 11% of confirmed cases of pulmonary embolism in patients without underlying cardiopulmonary disease [ 3 ].

However, the clinical picture of pulmonary embolism is variable and most patients suffering from acute pulmonary embolism present with one of three different clinical syndromes. These clinical syndromes are pulmonary infarction, acute unexplained dyspnea, and acute cor pulmonale. The pulmonary infarct syndrome usually occurs with a submassive embolism that completely occludes a distal branch of the pulmonary circulation. Patients with this condition have pleuritic chest pain, hemoptysis, rales, and abnormal findings on chest X-ray. The acute, unexplained dyspnea pattern may also be the result of submassive pulmonary embolism without pulmonary infarction. Results of a chest X-ray and electrocardiogram are usually normal, but pulse oxygen saturation is often depressed. The third pattern, acute cor pulmonale syndrome, is caused by the complete obstruction of 60 to 75% of pulmonary circulation. Patients with this pattern experience shock, syncope, or sudden death [ 4 , 5 ].

Syncope, in contrast to pulmonary embolism, is relatively easy to detect, but can be a difficult symptom from which to determine the etiology. In as many as 50% of patients with syncope, no specific cause is found despite extensive evaluation. Syncope has been classified as cardiovascular (reflex and cardiac syncope), noncardiovascular (including neurologic and metabolic disorders) and unexplained [ 2 , 6 ]. It occurs in approximately 10% of patients with acute pulmonary embolism and is commonly ascribed to a massive, hemodynamically unstable acute pulmonary embolism. Although the prognostic value of syncope has not been specifically addressed, it has generally been considered a poor indicator in diagnosing pulmonary embolism [ 7 ].

Syncope in the setting of pulmonary embolism can be the result of three possible mechanisms. First, greater than 50% occlusion of the pulmonary vascular tree causes right ventricular failure and impaired left ventricular filling, leading to a reduction in cardiac output, arterial hypotension, reduced cerebral blood flow, and ultimately syncope. The second mechanism of syncope associated with pulmonary embolism is the appearance of arrhythmias associated with right ventricular overload. In the third mechanism, the embolism can trigger a vasovagal reflex that leads to neurogenic syncope. However, the contribution of hypoxemia secondary to ventilation or perfusion abnormalities must also be considered and may play an important role in the development of syncope. Moreover, acute pulmonary hypertension may also lead to right-to-left flow across a patent foramen ovale, and thus exacerbate hypoxemia [ 8 , 9 ].

The clinician should seek the following clues to the diagnosis of pulmonary embolism in patients who have had a syncopal episode: (a) hypotension and tachycardia or transient bradyarrhythmia; (b) acute cor pulmonale according to electrocardiogram criteria or physical examination; and (c) other signs and symptoms indicative of pulmonary embolism. The presence of any of these findings without other obvious causes of syncope should lead to further work-up, including arterial blood gas analysis, ventilation-perfusion scanning, lower extremity duplex sonogram, echocardiography, multislice computed tomography and angiography, if necessary. Although oxygen saturation levels are inadequate for screening purposes, respiratory alkalosis with hypoxia and increased A-a O 2 gradient are typically seen. However, results of blood gas analysis are normal in 10% of cases [ 4 , 10 ].

In our case, the patient presented to the emergency department with complaints of dyspnea, tachypnea and tachycardia, following a syncopal episode. He had experienced immobilization for one month, hypoxemia in room air, and DVT according to the ultrasonographic results. PTE was initially considered and all of the diagnostic procedures were carried out to prove this presumptive diagnosis. Because DVT and PTE developed in this young patient with no history of any underlying diseases or disorders, he was referred for thrombophilia panel testing (including protein C or S deficiency and Factor V mutation) before treatment; however, as his long-term follow-up was performed by the Department of Pulmonary Diseases, we do not have any further detailed results from these examinations. This case is interesting because the patient did not experience a massive embolism but did develop syncope.

Pulmonary embolism presenting with syncope is difficult to diagnose. Physicians and other health care professionals must be vigilant with patients who have syncope, because this symptom may be a 'forgotten sign' of life-threatening pulmonary embolism.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

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Department of Emergency Medicine, Gazi University Faculty of Medicine, Ankara, Turkey

Ahmet Demircan, Ayfer Keles & Fikret Bildik

Department of Internal Medicine, Gazi University Faculty of Medicine, Ankara, Turkey

Gulbin Aygencel

Department of Anesthesiology and Reanimation, Gazi University Faculty of Medicine, Ankara, Turkey

Ozgur Ozsoylar

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Correspondence to Gulbin Aygencel .

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The authors declare that they have no competing interests.

Authors' contributions

AD, AK and FB analyzed and interpreted the patient data regarding the syncope and the pulmonary embolism. GA and OO performed the acute treatment of the patient, and were major contributors in writing the manuscript. All authors read and approved the final manuscript.

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Demircan, A., Aygencel, G., Keles, A. et al. Pulmonary embolism presenting as syncope: a case report. J Med Case Reports 3 , 7440 (2009). https://doi.org/10.4076/1752-1947-3-7440

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Received : 17 January 2008

Accepted : 06 March 2009

Published : 15 September 2009

DOI : https://doi.org/10.4076/1752-1947-3-7440

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Acute Pulmonary Embolism Presenting as Hypotension and Hypoxic Respiratory Failure

A discussion of percutaneous pulmonary embolism management.

By Bryan Kindya, MD , and Wissam A. Jaber, MD

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Pulmonary embolism (PE) is a commonly encountered inpatient hospital diagnosis with a severity that covers a wide spectrum—from small, distal thrombus of low hemodynamic consequence to central, life-threatening massive PE. With a reported incidence of about 112 per 100,000 cases, it accounts for approximately 100,000 deaths annually; however, the true number is likely higher given that PE is a potential cause of sudden cardiac death. 1 Thirty-day and 1-year mortality have been reported to be approximately 4% and 13%, 1 respectively, although the true risk varies with the size of the thrombus and patient comorbidities. In the past several years, there have been both technologic and procedural advancements as well as newly published data, allowing endovascular-based interventional techniques for patients at risk for deterioration. This article describes a patient who presented with hypotension and hypcoxic respiratory failure due to a large PE.

CASE PRESENTATION

A woman in her late 60s with a history of hypertension, chronic kidney disease, and Graves disease presented to the emergency department from the ophthalmology clinic after she was noted to be hypotensive and hypoxemic at her clinic appointment. On further questioning, she endorsed a 3-day history of fatigue and shortness of breath without chest pain. She denied any lower extremity swelling. For the 24 hours prior to presentation, she was feeling dizzy and having blurry vision. In clinic, her blood pressure (BP) was 79/50 mm Hg, and her oxygen saturation was 82% on room air.

On arrival to the emergency department, her BP improved to 100/85 mm Hg with intravenous fluids, her heart rate was 110 bpm, and oxygen saturation was 83% and improved to 96% on oxygen 6 L/min via nasal cannula. Her cardiopulmonary exam was unremarkable, and there was no peripheral edema in the lower extremities.

Results of initial laboratory tests were notable for creatinine of 2.9 mg/dL (glomerular filtration rate, 17 mL/min/1.73 m 2 ; baseline creatinine, 2.5 mg/dL), lactate of 2.5 mmol/L (mildly elevated), D-dimer of 10,261 ng/mL, troponin of 0.20 ng/mL (normal, < 0.04 ng/ml), and pro–B-type natriuretic peptide of 1,150 pg/mL. A chest x-ray was unremarkable.

Given the above, acute PE was highest on the differential diagnosis list. A pulmonary CT was deferred given her poor renal function, and she underwent urgent bilateral lower extremity venous imaging, which revealed an acute deep vein thrombosis (DVT) in the distal right common femoral vein, as well as a transthoracic echocardiogram, which was notable for a McConnell’s sign with a severely enlarged and severely dysfunctional right ventricle ( Figure 1 ).

Figure 1. Transthoracic echocardiogram with a severely enlarged right ventricle with severe systolic dysfunction and a McConnell’s sign. McConnell’s sign is an echocardiographic finding consistent of akinesis of the RV free wall with sparing and hyperdynamic contractility of the RV apex. Although not a sensitive finding in PE, its presence should raise the suspicion for a larger, more central PE.

1. Highlight Point

Although CT remains the most common modality of diagnosis, in patients who cannot undergo CT or when contrast needs to be deferred due to renal disease, ventilation/perfusion scanning is a good alternative that does not require contrast. However, in the appropriate clinical setting like in this case, the presence of acute right ventricular (RV) strain on echocardiography and acute DVT on ultrasound virtually establish the diagnosis of acute PE.

CASE CONTINUED

With the above history and workup, the pretest probability of PE was felt to be very high. The patient was thus started on a heparin infusion. Furthermore, with a presentation of hypotension and hypoxic respiratory failure and a McConnell’s sign on imaging with elevated cardiac biomarkers, it was felt likely that the suspected thrombus would warrant intervention, and the patient was taken to the cardiac catheterization laboratory for direct pulmonary angiography and mechanical thrombectomy if warranted.

2. Highlight Point

The patient could have been treated with anticoagulation alone given that her BP and oxygen saturation stabilized. Intervention such as systemic thrombolysis can then be administered in case of deterioration. This would be most consistent with the current guidelines. 2 However, the presence of each of the following findings is associated with increased PE-related mortality: tachycardia, hypoxemia, elevated cardiac biomarkers, elevated lactic acid, and RV dysfunction. These factors predict the presence of cardiogenic shock on invasive testing despite the presence of a “normal” BP. 3 Thus, it is frequently argued that such patients are best served by the addition of a thrombus reduction procedure on top of the anticoagulation. 4 Systemic thrombolytic are associated with an elevated risk of severe bleeding including up to 5% risk of intracranial hemorrhage, especially in patients aged > 65 years. 5 Given the availability of a potentially safer lytic-free intervention in the catheterization laboratory, and as the patient was stable enough to make the trip to a different suite, a percutaneous intervention was chosen in this case.

Right heart catheterization revealed the following findings:

Right atrium: 15 mm Hg
Right ventricle: 53/17 mm Hg
Pulmonary artery (PA): 52/27 (mean, 31) mm Hg
Pulmonary capillary wedge pressure: 12 mm Hg
PA saturation: 48%
Fick cardiac index: 1.9 L/min/m 2 (consistent with cardiogenic shock)

Selective left and right pulmonary angiography was performed, which revealed bilateral central thrombus in the lungs ( Figure 2 ). Digital subtraction angiography was performed with manual injection of contrast in each PA, utilizing < 20 mL of contrast in total. In patients with low cardiac output from acute PE, manual injection of < 10 mL of contrast in the branch PA is usually enough to establish the diagnosis. In patients with smaller PE and no hemodynamic derangement, power injection of at least 25 to 30 mL of contrast in each lung is usually needed to rule out acute PE. The case patient and most patients in need of intervention fall in the former category.

Figure 2. Angiograms of the lungs showing bilateral central thrombus burden.

3. Highlight Point

Options for interventional treatment include either mechanical thrombectomy or catheter-directed thrombolysis (lower dose and likely less risk of bleeding compared to systemic thrombolysis). The FDA-indicated devices for mechanical thrombectomy are the FlowTriever (Inari Medical), Indigo system (Penumbra, Inc.), and AlphaVac F1885 system (AngioDynamics), and the FDA-indicated devices for catheter-directed thrombolysis include the Ekos endovascular system (Boston Scientific Corporation) and the Bashir endovascular catheter (Thrombolex, Inc.). All have shown safety and effectiveness in interventional treatment of acute PE, but no comparative trials have yet been published.

We performed mechanical thrombectomy of the bilateral PAs using the FlowTriever device. After crossing the right heart with a balloon-tipped catheter, a 24-F FlowTriever catheter was advanced over an Amplatz Super Stiff guidewire (Boston Scientific Corporation) to the right PA, and thrombectomy was successful with aspiration of a large thrombus burden; however, the left-sided thrombus was large and relatively organized. On further interrogation, no blood or other substance was able to be aspirated from the device after several left-sided passes, leading to suspicion of either thrombus entrapped in the aspiration catheter or thrombus too large to enter the catheter and stuck on the tip of the device. We drew the catheter back to the infrarenal inferior vena cava (IVC) and stopped before the catheter entered the femoral venous sheath. We gained contralateral venous access above the level of the right femoral DVT, which was clearly visible on ultrasound, and performed venography, which showed the thrombus stuck to the tip of the catheter ( Figure 3 ).

Figure 3. Aspiration catheter in the IVC with large thrombus stuck to the tip.

If the catheter is pulled into the sheath, the thrombus will shear off and embolize. The sheath and catheter can alternatively be pulled as one unit over the wire and through the femoral venotomy site. With such a large thrombus, this will also likely result in embolization of part of the protruding thrombus. The ideal solution in this case is to intercept any embolus in the IVC above the visualized clot. This can be achieved by placing temporary filter-like material, such as the large FlowTriever disks or a retrievable IVC filter, in the suprarenal IVC. We elected to place a retrievable IVC filter. Through the contralateral venous access, we advanced a retrievable filter to the infrarenal IVC after dragging the clot further down to the iliac bifurcation. Removal of the sheath over the wire removed part of the thrombus, and as expected, a big part embolized and was found lodged in the IVC filter ( Figure 4 ). The same 24-F FlowTriever catheter was then used to aspirate the rest of the thrombus lodged in the filter. Figure 5 shows both parts of the extracted thrombus. Repeat PA catheterization showed an improvement in the mean PA pressure to 23 mm Hg and PA oxygen saturation to 55%.

Figure 4. Deployed IVC filter with captured thrombus.

Figure 5. Both parts of the thrombus dragged down to the IVC: One was removed in the initial externalization of the sheath (left side), and the rest of the thrombus was captured in the IVC filter (right side).

CASE CONCLUSION

Over the next 24 hours, the patient remained hemodynamically stable and felt much better. Her oxygen requirement was weaned, and she was transitioned to room air. Her heparin drip was transitioned the next day to a direct oral anticoagulant for continued anticoagulation. She was discharged on hospital day 3 to home. In follow-up, her RV size and function had significantly improved. She underwent IVC filter retrieval 2 months later, with a small amount of organized thrombus found in the filter.

Intermediate- and high-risk PE remain commonly encountered hospital diagnoses with high rates of in-hospital mortality. 6,7 Historically, management options included heparin infusion and systemic thrombolytics alone.

With advancements in technology, there now exist multiple endovascular treatment options for this patient population as an option between systemic anticoagulation, which may not be enough in these cases, and systemic thrombolysis, which carries increased inherent risk and patient candidacy concerns due to prohibitive comorbidities.

The case presented herein could have been treated with either catheter-based thrombectomy or catheter-directed thrombolysis. The choice of catheter is largely dependent on local practices and expertise.

Numerous studies and an increasing number of randomized trials are exploring the roles of these options in both intermediate- and high-risk PE. However, despite growing clinical experience and several single-arm studies and randomized trials showing good safety and efficacy of intervention in acute PE, level 1 data are still lacking overall. The results of currently enrolling trials are eagerly awaited.

1. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011;123:1788-1830. doi: 10.1161/CIR.0b013e318214914f

2. Konstantinides SV, Meyer G, Becattini C, et al. ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J. 2019;54:1901647. doi: 10.1183/13993003.01647-2019

3. Bangalore S, Horowitz JM, Beam D, et al. Prevalence and predictors of cardiogenic shock in intermediate-risk pulmonary embolism: insights from the FLASH registry. JACC Cardiovasc Interv. 2023;16:958-972. doi: 10.1016/j.jcin.2023.02.004

4. Jaber WA, Fong PP, Weisz G, et al. Acute pulmonary embolism: with an emphasis on an interventional approach. J Am Coll Cardiol. 2016;67:991-1002. doi: 10.1016/j.jacc.2015.12.024

5. Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014;311:2414-21. doi: 10.1001/jama.2014.5990

6. Secemsky E, Chang Y, Jain CC, et al. Contemporary management and outcomes of patients with massive and submassive pulmonary embolism. Am J Med. 2018;131:1506-1514.e0. doi: 10.1016/j.amjmed.2018.07.035

7. Sedhom R, Megaly M, Elbadawi A, et al. Contemporary national trends and outcomes of pulmonary embolism in the United States. Am J Cardiol. 2022;176:132-138. doi: 10.1016/j.amjcard.2022.03.060

8. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370:1402-1411. doi: 10.1056/NEJMoa1302097

Bryan Kindya, MD Division of Cardiology Emory University School of Medicine Atlanta, Georgia Disclosures: None.

Wissam A. Jaber, MD Division of Cardiology Emory University School of Medicine Atlanta, Georgia [email protected] Disclosures: Consultant to Inari Medical, Medtronic, Abbott, Thrombolex, and RapidAI.

Filter-Associated Inferior Vena Cava Thrombosis

By Sipan Mathevosian, MD, and Wendy Nelson, CNS, ACNP

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A 25 year old white female reports to the Emergency Room because of sharp left sided chest pain and shortness of breath of one day duration. The patient was in excellent health until yesterday. She was awakened from her sleep by sharp left sided chest pain. The pain worsened with motion and deep breathing. The pain has been progressively increasing in severity and she now has severe left shoulder pain. She complains of shortness of breath and is very apprehensive about dying. She denies any cough, fever, sputum production or hemoptysis.

She is married and had one normal delivery three years ago. She is currently on birth control pills. She has never been hospitalized except for labor and delivery. Review of systems are negative. She denies any past history of venous problems.

She reveals having a similar transitory minor episode of chest pain approximately one year ago while she was vacationing in Michigan.

She works as a computer programmer. She smokes one pack of cigarettes a day for the past eight years. She considers herself a social drinker.

1 She has pleuritic pain. What are the characteristics of pleuritic pain?

2 Is her pain due to visceral or parietal pleural inflammation?

3 What is the differential diagnosis of pleuritic pain?

4 List diagnoses that could fit the history of this patient as an etiology for pleuritic pain.

Physical Examination

Blood pressure 114/80; pulse 118; temperature 37.0 (oral)

She appears to be in moderate respiratory distress. She is well developed and nourished. Pertinent findings include a respiratory rate of 30 and shallow breathing. There is dullness, decreased chest expansion and decreased breath sounds in the left base. There is egophony in the left base. There were no rales or rubs.

Heart reveals PMI in the 5th intercostal space in MCL. The pulmonic component of the second sound is accentuated.

Abdomen, pelvic and rectal exams are normal.

The extremities reveal no evidence of edema, cyanosis or clubbing.

Patient has negative Homan's Sign.

Joint exam revealed shoulder movements complete in range. No warmth or tenderness noted. The rest of the patient's joints are normal.

5 Which of the diagnoses is supported by the physical exam.

6 What type of process is going on in the chest by evidence of exam.

7 What is Homan's Sign?

The Emergency Room physician orders the following tests:

CBC: Hgb 15.0; Hct 43; WBC 11,500; 83 polys, 1 band and 14 lymphs

SMA-12: Normal

Arterial blood gases: FI02 .21; pH 7.39; PCO2 30; HCO2 20; PO2 80 and SO2 95%

EKG reveals sinus tachycardia and non-specific S-T-T wave changes axis + 80.

CXR reveals a small pleural effusion in the left base. The left diaphragm is elevated.

Shoulder x-ray is normal.

Decubitus reveals a small amount of fluid in the left pleural space.

8 Does the CBC support your diagnosis?

9 Interpret the blood gases.

10 Calculate the A-a gradient.

11 Interpret the CXR.

12 Does the EKG findings support your diagnosis?

13 What is your explanation for her shoulder pain?

14 What is your working diagnosis now, after the screening lab tests?

15 What additional studies would you like to do?

Additional Studies

Lung scan revealed a defect corresponding to the area of pleural effusion.

Pleural tap revealed yellow fluid; protein 3.5 grams; glucose 64 and pH 7.4.

Doppler exam revealed deep vein thrombosis of the left lung.

16 Are you familiar with the way lung scans are reported from a diagnostic consideration of pulmonary embolism?

17 What are the characteristics of pleural effusion of a patient with pulmonary embolism?

18 Why did she develop deep vein thrombosis? Does she have a predisposing factor?

19 Are you surprised by the lack of physical findings for thrombophlebitis in this patient?

20 How often do we have physical findings of thrombophlebitis in patients with proven deep vein thrombosis?

21 Why did she develop deep vein thrombosis? Does she have a predisposing factor?

22 When do you consider pulmonary angiogram in the work-up of a patient suspected to have PE?

The Patient was admitted to the hospital. Repeat lung scan revealed multiple defects.

23 How will you treat her?

24 How long do you want to treat her in the hospital?

25 How long do you want to anticoagulate her as an outpatient and why?

26 Could this problem have been prevented?

Vol 11, No 8 (April 28, 2023) /

Acute pulmonary embolism with loss of consciousness as the first manifestation: a case report

Zhongyi Chai, Rong Hu, Changsheng Ma

Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University , National Clinical Research Center for Cardiovascular Diseases , Beijing , China

Contributions: (I) Conception and design: C Ma; (II) Administrative support: R Hu; (III) Provision of study materials or patients: Z Chai; (IV) Collection and assembly of data: Z Chai; (V) Data analysis and interpretation: Z Chai; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Background: The clinical manifestations of pulmonary embolism are varied, and atypical pulmonary embolism can easily be missed in some patients, resulting in serious clinical consequences and injuries.

Case Description: This report describes a rare case of acute pulmonary embolism with loss of consciousness as the first manifestation. A 50-year-old male was admitted with loss of consciousness and difficulty breathing. Acute coronary syndromes and neurological disorders such as seizures were excluded by clinical history and electrocardiogram dynamic changes. Multiple clues such as coagulation function and myocardial enzymes are highly suggestive of pulmonary embolism, after the completion of computed tomography pulmonary angiogram (CTPA) diagnosis, the severity of the acute pulmonary embolism was evaluated, after which the patient was given low-molecular-weight heparin sequentially overlapping with oral warfarin as the anticoagulation treatment. Following this, the life signs of the patient were stable, and there were no special complaints; thus, this patient was discharged smoothly. As of this writing, the patient is still being followed up clinically with no recurrent embolism or deterioration occurred.

Conclusions: This case is of guiding significance for the early detection and rapid diagnosis and treatment of such patients with pulmonary embolism. It is necessary to acquire the vital signs, including those related to heart rate, electrocardiography, respiration, and blood oxygen saturation in the first clinical contact for patients with syncope as soon as possible. Patients with problems related to the above-mentioned basic vital signs should be highly suspected of cardiopulmonary diseases, and CTPA should be performed as soon as possible after the evaluation of the clinical possibility of pulmonary embolism and D-dimer screening. Moreover, the critical degree of pulmonary embolism should be evaluated, and then reperfusion or anticoagulation treatment should be performed appropriately. This should be followed by etiology screening. To avoid recurrence or aggravation of pulmonary embolism, the cause of the disease should be determined and treated.

Keywords: Loss of consciousness; pulmonary embolism; clinical possibility; etiology screening; case report

Submitted Feb 02, 2023. Accepted for publication Apr 06, 2023. Published online Apr 17, 2023.

doi: 10.21037/atm-23-656

Highlight box

Key findings

• Patients admitted with the primary clinical presentation of loss of consciousness alone may have pulmonary embolism without the typical signs.

What is known and what is new?

• The clinical manifestations of pulmonary embolism are varied.

• Loss of consciousness may also be an atypical clinical manifestation of pulmonary embolism.

What is the implication, and what should change now?

• For patients admitted to hospital due to loss of consciousness, attention should be paid first to the exclusion of life-threatening diseases, as the clinical manifestations may be obscure and easily missed.

Introduction

Pulmonary embolism is a common thromboembolic disease in clinic. Its typical clinical manifestations include dyspnea (more than 50%), pleural pain (39%), cough (23%), retrosternal pain (15%), fever (10%), hemoptysis (8%), syncope (less than 5%), unilateral limb swelling (24%), and unilateral limb pain (6%) ( 1 ). Acute pulmonary embolism is a clinical and pathophysiological syndrome of pulmonary circulation obstruction caused by endogenous or exogenous emboli blocking the main artery or branches of the pulmonary artery. It is a critical and severe disease with a high mortality rate. However, due to the lack of sufficient attention to the prevention and treatment of the disease for a long time, doctors often miss the diagnosis. The vast majority of these patients have disease causes, such as lower limb or pelvic vein thrombosis, long-term bedridden or inactive, chronic cardiopulmonary disease, surgery, trauma, malignant tumors, pregnancy and oral contraceptives. Treatment methods include anticoagulation, thrombolysis and interventional therapy ( 2 ).

Syncope can be the only first symptom of pulmonary embolism, but fewer than 1% of patients with pulmonary embolism have syncope or loss of consciousness as the main symptom ( 2 ). Pulmonary embolism is not a routine screening item in the differential diagnosis of syncope in our region. The patient described in this report was a rare case of clearly diagnosed acute pulmonary embolism with loss of consciousness as the first manifestation. If such patients are not detected in time and continue to undergo a series of screening and examination on the cause of syncope in the outpatient clinic according to the general syncope patients, it will lead to a series of serious consequences such as deterioration of the condition of such patients and even death. We present the following article in accordance with the CARE reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-23-656/rc ).

Case presentation

The patient was 50-year-old male, who 2 days before admission, had difficulty breathing when standing at home after bending over and working, which was accompanied by shortness of breath and amaurosis. He subsequently fell to the ground unconsciousness, but experience no fall injuries. After being unconscious on the ground for 10 seconds, the patient regained consciousness and had experienced no convulsion when falling, no rolling up of the eyes, and no incontinence. There was no dizziness, headache, chest tightness, chest pain, nausea or vomiting, palpitation, or sweating before the onset of loss of consciousness. After waking up, the patient continued to have dyspnea, general fatigue, intermittent shortness of breath, and chest pain. After that, the patient developed intermittent dry cough but no fever or expectoration, no dizziness or headache, no palpitation or back pain, and no residual neurological symptoms and was able to walk. He complained that when he went up the stage, he had increased shortness of breath and amaurosis but no chest pain or fainting. Moreover, the patient had no history of chest distress, chest pain, or asthma. He could lie down quietly and sleep at night. For further diagnosis and treatment, he visited to the cardiology department of Beijing Anzhen Hospital. From the onset of the disease, the patient had a clear mind, good spirits, normal stool and urine, and no significant change in weight. He had a history of gout for about 3 years. Before admission, he had experienced gout attacks and swollen and painful feet. The patient had oral administration of Celebrex and sodium bicarbonate 1 month before admission which reduced the activity of both his lower limbs. He had a history of varicose veins of the lower limbs for 20 years and a history of fatty liver for 10 years. The patient underwent radiofrequency ablation for paroxysmal atrial fibrillation 3 years prior in our hospital, and there was no recurrence during postoperative follow-up. His father had a history of high blood pressure, diabetes, and pulmonary embolism, while his mother had coronary heart disease. Physical examination results on admission were the following: temperature, 36.5 ℃; pulse, 82 times/minute; respiration, 16 times/minute; and blood pressure, 131/74 mmHg. The superficial lymph nodes of the whole body were not palpable or swollen. The breath sounds in both lungs were clear, no dry or wet rales were heard, the heart boundary was normal, the heart rhythm was regular, and no pathological murmur could be heard in the auscultation area of each valve. P2 showed no hyperactivity, the abdomen was flat and soft with no tenderness, there was no rebound pain or muscle tension, and bowel sounds were normal. The patient had mild edema in both the lower limbs but was negative for gastrocnemius gripping pain. Other physical examinations showed no obvious abnormalities.

The complete results of laboratory examination after admission are described below. (I) The results of routine laboratory examinations were the following: blood gas analysis (without oxygen inhalation) indicated PH 7.442, CO 2 partial pressure 28.2 mmHg↓, O 2 partial pressure 95.4 mmHg, and oxygen saturation 98.1%; no abnormalities were found in routine blood or urine tests. Liver and kidney function results were the following: alanine aminotransferase, 8 U/L↓; aspartate aminotransferase, 16 U/L; α-hydroxybutyrate dehydrogenase; 205 U/L↑; albumin, 38.0 g/L↓; uric acid, 598 µmol/L↑; triglyceride, 1.84 mmol/L↑; creatinine, 75 µmol/L; estimated glomerular filtration rate (eGFR) 102 mL/min ×1.73 m 2 ; and blood electrolytes, normal. B-type natriuretic peptide (BNP) levels were 136 pg/mL↑. Myocardial injury marker results were as follows: troponin I (TNI), 0.053 ng/mL↑; tumor markers (−); and thyroid functions (−). (II) Results for coagulation markers were the following: fibrin degradation product, 49.3 ug/mL↑; and D-dimer, 5,366 ng/mL↑. (III) Screening results for pulmonary embolism etiology and thrombophilia were the following: lupus anticoagulant factor test, 1.33↑; β-2 determination of glycoprotein I, 34.16 RU/mL↑; autoantibody spectrum, antinuclear antibody negative; immune index: complement 3:1.540 G/L↑; no abnormality in immunoglobulin determination; protein C activity, 148.0%↑; protein S activity, negative; blood M protein, negative; antithrombin III activity measurement, (−); blood homocysteine (−); anticardiolipin antibody, 5.7 U/mL; anti-nucleosome antibody, 0.67 RU/mL; and anti-double-stranded DNA antibody, 7.3 IU/mL.

Other auxiliary examination results after admission were conducted. (I) Electrocardiogram (ECG) results were the following: sinus rhythm, typical SIQIIITIII manifestation on electrocardiogram, V1–V3 lead T wave inversion (in Figure 1 ), and no dynamic changes in the recheck. (II) Chest radiography revealed heavier bilateral lung markings and possibly a small amount of pleural effusion on the left side. (III) Echocardiogram indicated a slightly increased pulmonary artery systolic pressure (41 mmHg). The echocardiogram of this patient did not show the characteristic features of pulmonary embolism, and only mild to moderate tricuspid regurgitation was observed. (IV) Colored Doppler ultrasound of lower limb veins revealed no vein thrombosis in the left superficial femoral vein, popliteal vein, posterior tibial vein, or lower leg soleus muscle, but there was bilateral great saphenous vein inflow segment reflux (severe). (V) Computed tomography pulmonary angiogram (CTPA) revealed the following (see Figure 2 ): multiple pulmonary embolisms at the bifurcation of left and right pulmonary arteries and at each segment of the pulmonary artery, high density shadow at the dorsal side of the lower lobes of both lungs. Before discharge, CTPA reexamination showed that the multiple pulmonary embolism at the bifurcation of the left and right pulmonary arteries and at each segment of the pulmonary artery had basically disappeared, while a slight embolism might have remained at the residual left upper lobe and lower lingual segment of the pulmonary artery. (VI) Abdominal ultrasound showed no obvious abnormalities in liver, spleen, or kidney.

After admission, the relevant examinations were completed, the diagnosis of pulmonary embolism was confirmed. Since the patient’s vital signs were stable upon admission, no recurrent syncope episodes were observed, and no significant right ventricular dysfunction was observed on echocardiography, we chose conventional anticoagulant therapy over thrombolytic therapy. Immediate anticoagulation was administered with 6,000 IU q12h (based on the patient’s body weight (body weight ×100 U), this patient weighed about 60 kg) via a subcutaneous injection of enoxaparin sodium. After this, the patient did not complain of dyspnea, chest pain, or shortness of breath and did not experience a loss of consciousness. The current examination results of this patient could not confirm the diagnosis of thrombophilia, so the treatment plan after discharge was to review CTPA and other items after anticoagulation for 3–6 months to determine the discontinuation of medication and follow-up. We decided to use warfarin instead of the new oral anticoagulant for health insurance and financial reasons. Subsequently, administration for oral warfarin and heparin were overlapped for anticoagulation. The international normalized ratio (INR) was 1.22 on admission. After warfarin was added, the INR was 2.38 and heparin was stopped. After discharge, the CTPA reexamination showed that the multiple pulmonary embolisms at the left and right pulmonary artery bifurcation and at each segment of the pulmonary artery had basically disappeared. Therefore, the patient was arranged to leave the hospital, and the patient was ordered to have regular outpatient follow-up, monitor the INR, and be alert to bleeding. The patient was additionally instructed to adjust the dose of warfarin as appropriate. As of this writing, this patient is still in the process of clinical follow-up (see Figure 3 for a summary of the case).

The latest European guidelines classify syncope as reflex syncope, postural hypotension and cardiogenic syncope. Due to the clinical manifestations of the patient's characteristic dyspnea and a series of subsequent auxiliary examination results that clearly indicated embolism, the syncope was considered to be caused by acute pulmonary embolism and no further screening was conducted for other syncope causes.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

This patient was a middle-aged male who experienced a sudden loss of consciousness as the first symptom of pulmonary embolism, which was followed by continuous dyspnea, shortness of breath, and chest pain. After admission, ECG, echocardiography, D-dimer, blood gas analysis, BNP, TNI and other relevant examinations suggested the possibility of pulmonary thromboembolism. The patient had high blood pressure and normal oxygen saturation when he was admitted. After the diagnosis of pulmonary embolism was confirmed with CTPA, low-molecular-weight heparin overlapped with warfarin anticoagulantion therapy was administered to the patient. After anticoagulantion therapy, the patient did not complain of any dyspnea, shortness of breath, chest pain, or other discomfort, and thus warfarin was taken via oral administration, INR was monitored, and the patient was discharged according to the doctor’s advice.

In this case, the patient may have been bedridden for a short time due to recent gout attacks, and venous thrombosis was formed after lower limb immobility, which eventually led to the occurrence of pulmonary embolism. At the same time, the first clinical manifestation of pulmonary embolism in this patient was the transient disorder of cerebral blood supply resulting in loss of consciousness due to the sudden restricted pulmonary gas exchange.

Therefore, this is a rare case of acute pulmonary embolism with sudden loss of consciousness as the first symptom. The possibility of pulmonary embolism should be considered in patients with syncope and dyspnea. Examination should be improved in time to assist in the diagnosis, anticoagulation and reperfusion therapy should be given in time.

The pathophysiological mechanism of pulmonary embolism causing syncope

Acute pulmonary embolism can lead to increased pulmonary circulation resistance, increased pulmonary artery pressure, and decreased pulmonary vascular bed area. When the pulmonary vascular bed area is reduced by 30% to 40%, the mean pulmonary artery pressure can reach more than 30 mmHg; when the pulmonary vascular bed area is reduced by 40% to 50%, the mean pulmonary artery pressure can reach 40 mmHg; when the pulmonary vascular bed area is reduced by 50% to 70%, persistent pulmonary hypertension can occur; when the pulmonary vascular bed area is reduced by more than 85%, sudden death can occur ( 2 ). As pulmonary vascular resistance increases, the pressure and volume of the right ventricle increase, the right ventricle dilates, and wall tension increases to maintain blood flow in the blocked pulmonary vascular bed, while systemic vascular constriction stabilizes systemic blood pressure. However, the degree of this immediate compensation is limited, and right cardiac insufficiency eventually occurs, resulting in reduced left cardiac return blood volume and thus reduced cardiac output. The cerebral cortex is unable to meet the demand for blood supply, and hypoxemia caused by the imbalance of the ventilation: blood flow ratio in the clogged capillary bed also affects the oxygen demand of the cerebral cortex. The normal functioning of the higher nervous system mainly in the cerebral cortex depends on the continuous provision of a sufficiently large blood supply and oxygen demand. As the demand for adequate blood and oxygen supply cannot be met during acute pulmonary embolism, amaurosis, fainting, and loss of consciousness may result, which explains the patient’s clinical symptoms ( 2 ). However, our center has also admitted patients who were only clinically suspected of pulmonary embolism, but in whom timely CTPA examination and anticoagulation-related treatment were not implemented. The patients’ ischemic and anoxic state could not be corrected accordingly for a long period of time. During hospitalization, these patients might present various nonspecific clinical manifestations, such as continuous disturbance of consciousness and even shallow coma, compared with syncope alone. These patients could have acute chest pain with corresponding ST segment elevation in the thoracic leads, which is similar to the symptoms of acute myocardial infarction or variable angina pectoris.

Differential diagnosis of syncope or loss of consciousness in clinic

The diagnosis and differential diagnosis of syncope or loss of consciousness is an area of intense research focus. In the modern era, clinicians cardiology departments are required to quickly and accurately identify the causes of a patients’ loss of consciousness in order to quickly ascertain critical factors of this syncope. The causes of syncope can be divided into several categories: (I) hypotensive syncope; (II) hypoglycemia, in which, before the onset of hypoglycemic syncope, people usually experience hunger, sweating, and prolonged disturbance of consciousness, which can be significantly improved with eating; (III) hypoxia, which is more common in syncope caused by pulmonary embolism, such as the syncope in this case; (IV) cerebrovascular diseases, including transient ischemic attack of the vertebrobasilar artery system or severe stenosis of the corresponding vessels, subclavian steal syndrome, and rare cerebrovascular diseases (e.g., moyamoya disease); (V) abnormal electrical activity in the cerebral cortex, including seizures; and (VI) hystericus insultus, which includes states of anxiety and hysterical syncope. Among these, syncope caused by hypotension is still the most common ( 3 - 5 ). Syncope caused by hypotension can be subdivided into 5 types: (I) poor ventricular filling, including dehydration, bleeding, severe pulmonary hypertension, pericardial tamponade, and atrial myxoma; (II) poor ventricular emptying, including aortic coarctation, hypertrophic obstructive cardiomyopathy, and severe systolic heart failure; (III) abnormal heart rhythm, including various types of tachycardia and bradycardia, vasovagal syncope (cardiac inhibitory), and carotid sinus syncope (cardiac inhibitory); (IV) reduced peripheral resistance, including vasovagal syncope (vascular inhibitory type), postural hypotension, carotid sinus allergy (vascular inhibitory type), and drug-related hypotension (nitrates, alpha-blockers, tricyclic antidepressants, etc.); and (V) syncope with other specific causes, including cough-related syncope, urination-related syncope, etc. ( 6 ). Our center has a complete examination procedure for patients with loss of consciousness whose condition is stable. In addition to routine hospital-related examinations, routine blood tests (including myocardial injury markers, BNP, coagulation analysis and D-dimer, routine biochemical indicators and blood gas analysis, and long-term dynamic ECG monitoring for 24–72 hours), echocardiography, blood pressure detection in different positions, and ultrasonography of the carotid artery, subclavicular artery, and peripheral artery should be completed. The upright tilt test, head magnetic resonance imaging (MRI) and transcranial Doppler examination, and the further monitoring of the intracranial artery via magnetic resonance (MR) angiography and electroencephalogram are evaluated according to the consultation opinions of neurology department, and then a further examination and treatment plan are made according to the patient’s clinical data and the results of the corresponding examinations described above ( 7 ).

Screening of patients at risk for pulmonary embolism

The most common clinical manifestation in patients with pulmonary embolism is dyspnea, while the most common sign is increased respiratory rate (>20 beats/min). Dyspnea, syncope, cyanosis, and hypotension tend to indicate a large pulmonary embolism near the main pulmonary artery, whereas pleural pain, cough, and hemoptysis tend to indicate a small pulmonary embolism near the pleura. Therefore, routine D-dimer screening should be performed for a patient with loss of consciousness, and the possibility of pulmonary embolism should be vigilantly monitored for patients with dyspnea. For patients suspected of pulmonary embolism clinically, the following should be considered for clinical possibility assessment: (I) previous history of pulmonary embolism or lower limb venous thrombosis; (II) a heart rate increase of more than 20% compared with the normal base value; (III) history of surgery, fracture, or breaking within the last 1 month; (IV) hemoptysis; (V) tumor activity stage; (VI) age over 65 years; (VII) unilateral lower limb swelling and pain; and (VIII) gastrocnemius muscle grip pain, deep vein tenderness of lower limb, and unilateral swelling of lower limb. If 3 or more of the above 8 criteria are met, the possibility of pulmonary embolism is high. At this time, CTPA should be able to confirm or exclude the diagnosis of pulmonary embolism regardless of the results of D-dimer. If only 0–2 of the 8 criteria meet, D-dimer screening should be further improved; if D-dimer is elevated, further CTPA examination can be considered for definite diagnosis; if D-dimer is not high, pulmonary embolism can be basically excluded ( 7 ).

Formulation of the subsequent treatment plan after definite diagnosis

Risk stratification should be performed simultaneously for patients with suspected acute pulmonary embolism to guide the subsequent diagnosis and treatment measures. There are multiple different criteria and scores for the risk stratification of pulmonary embolism, and the clinical indicators observed by the corresponding criteria and scores are not the same. A comprehensive assessment of risk stratification as recommended by the earliest guidelines for the diagnosis, treatment, and prevention of pulmonary thromboembolism was previously performed ( 8 ), with patients being classified into a high-risk group (with shock or hypotension), middle-high-risk group (stable hemodynamics but positive laboratory indicators and imaging), medium-low risk group (stable hemodynamics, with single positive laboratory indicators or imaging), and low-risk group (stable hemodynamics but no laboratory indicators or imaging abnormalities). There are also several other kinds of complicated scores for assessment of pulmonary embolism used at present ( 9 , 10 ). The scoring indicators are as follows: older age (over 65-year-old), male sex, tumor presence, chronic heart failure, chronic lung disease, pulse greater than 110 beats/min, systolic blood pressure less than 100 mmHg, respiratory rate greater than 30 beats/min, arterial oxygen saturation less than 90%, new characteristic ECG changes, hypothermia and changes in mental state, ultrasound changes in right ventricular shape, positive findings of deep venous thrombosis of lower extremities, and abnormal increase of cardiac TNI and BNP, etc. However, in clinical practice, no significant clinical benefit has been observed when thrombolytic therapy is actively applied to certain patients with high risk scores or grades compared with conventional anticoagulant therapy. Pulmonary embolism patients with syncope as the first symptom are not necessarily high-risk patients, nor do they necessarily need reperfusion therapy, but the presence of shock or persistent hypotension is suspected to be high-risk acute pulmonary embolism. Shock or persistent hypotension refers to systolic blood pressure <90 mmHg and/or a decrease to >40 mmHg for more than 15 minutes, except in cases of new arrhythmias, decreased blood volume, sepsis, etc. ( 11 ). These patients can be directly treated with reperfusion. In the absence of shock or persistent hypotension, conventional anticoagulant therapy can be used, and remedial reperfusion therapy can be used as appropriate in patients with elevated troponin combined with changes in right ventricular morphology and function ( 12 , 13 ).

Etiology screening of pulmonary embolism

In view of the etiology of pulmonary embolism in this patient, relevant risk factors of pulmonary embolism should be identified first, including major trauma, surgery, lower limb fracture, spinal cord injury, autoimmune disease, hereditary hypercoagulability, thromboembolism, inflammatory bowel disease, tumor, oral contraceptives and hormone replacement therapy, arteriovenous catheterization, stroke paralysis, chronic heart failure and respiratory failure, pregnancy, long-term bed immobilization, sedentary, aging, varicose veins, risk factors associated with atherosclerosis, history of use of chemotherapy drugs [e.g., erythropoietin (EPO) (hemopoietin) and some non-steroid anti-inflammatory drugs (NSAIDs)] ( 14 - 17 ). This patient had a clear history of varicose veins of the lower limbs and a family history of pulmonary embolism. One month before admission, he had taken NSAIDs orally and had relative immobilization due to gout attack and increased bed rest and thus belonged to the population prone to pulmonary embolism. In addition, the improvement of the screening related to thrombolysis after admission was demonstrated by the following results: lupus anticoagulant factor test, 1.33↑; and β2 glycoprotein I, 34.16 RU/mL↑. The possibility of antiphospholipid antibody syndrome was not excluded. The patient was asked to undergo review for the indicators related to the thrombolysis in the outpatient department of rheumatology and immunology 2 months later to confirm whether the diagnosis of antiphospholipid antibody syndrome could be established and to continue to follow up.

Conclusions

The possibility of pulmonary embolism should be considered particularly in patients with syncope complicated with dyspnea. Vital signs, heart rate, electrocardiogram, respiration, and blood oxygen saturation of patients with syncope should be determined immediately, and appropriate respiratory support and blood pressure support should be given to high-risk patients as soon as is needed. Patients with the above basic vital signs should be highly suspected of loss of consciousness caused by cardiopulmonary diseases. After finishing the clinical possibility assessment for pulmonary embolism and D-dimer screening are completed, CTPA should be performed according to the circumstances to help clarify or exclude the diagnosis of pulmonary embolism. Meanwhile, the severity of pulmonary embolism should be evaluated, and then reperfusion or anticoagulation therapy should be administered accordingly. Following this, etiological screening and medical history should be conducted to identify the risk factors related to pulmonary embolism, and corresponding treatments and disease guidance should be provided accordingly to avoid recurrence or aggravation of pulmonary embolism.

Acknowledgments

Funding: None.

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Diagnosis of acute pulmonary embolism: when photon-counting-detector CT replaces energy-integrating-detector CT in daily routine

Published: 18 April 2024

Cite this article

Martine Remy-Jardin ORCID: orcid.org/0000-0003-1944-4288 1 , 2 , 3 ,
Idir Oufriche 3 ,
Lucas Guiffault 3 ,
Alain Duhamel 1 , 4 ,
Thomas Flohr 5 ,
Bernhard Schmidt 5 &
Jacques Remy 3 , 6

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To compare the diagnostic approach of acute pulmonary embolism (PE) with photon-counting-detector CT (PCD-CT) and energy-integrating-detector CT (EID-CT).

Materials and methods

Two cohorts underwent CT angiographic examinations with EID-CT (Group 1; n = 158) and PCD-CT (Group 2; n = 172), (b) with two options in Group 1, dual energy (Group 1a) or single energy (Group 1b) and a single option in Group 2 (spectral imaging with single source).

In Group 2, all patients benefited from spectral imaging, only accessible to 105 patients (66.5%) in Group 1, with a mean acquisition time significantly shorter (0.9 ± 0.1 s vs 4.0 ± 0 .3 s; p < 0.001) and mean values of CTDI vol and DLP reduced by 46.3% and 47.7%, respectively. Comparing the quality of 70 keV (Group 2) and averaged (Group 1a) images: (a) the mean attenuation within pulmonary arteries did not differ ( p = 0.13); (b) the image noise was significantly higher ( p < 0.001) in Group 2 with no difference in subjective image noise ( p = 0.29); and (c) 89% of examinations were devoid of artifacts in Group 2 vs 28.6% in Group 1a. The percentage of diagnostic examinations was 95.2% (100/105; Group 1a), 100% (53/53; Group 1b), and 95.3% (164/172; Group 2). There were 4.8% (5/105; Group 1a) and 4.7% (8/172; Group 2) of non-diagnostic examinations, mainly due to the suboptimal quality of vascular opacification with the restoration of a diagnostic image quality on low-energy images.

Compared to EID-CT, morphology and perfusion imaging were available in all patients scanned with PCD-CT, with the radiation dose reduced by 48%.

Clinical relevance statement

PCD-CT enables scanning patients with the advantages of both spectral imaging, including high-quality morphologic imaging and lung perfusion for all patients, and fast scanning—a combination that is not simultaneously accessible with EID-CT while reducing the radiation dose by almost 50%.

The complementarity between morphology and perfusion imaging is accessible in each PCD-CT examination.

High-quality images are obtained with PCD-CT in all categories of patients, including dyspneic patients.

PCD-CT enables about 50% radiation dose reduction compared with EID-CT.

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Photon-counting CT for diagnosis of acute pulmonary embolism: potential for contrast medium and radiation dose reduction

Pauline Pannenbecker, Henner Huflage, … Bernhard Petritsch

State-of-the-Art Imaging for the Evaluation of Pulmonary Embolism

Leonid Roshkovan & Harold Litt

Single- and dual-energy CT pulmonary angiography using second- and third-generation dual-source CT systems: comparison of radiation dose and image quality

Lukas Lenga, Franziska Trapp, … Simon S. Martin

Abbreviations

Contrast-to-noise ratio

CT angiography

Volume computed tomography dose index volume

Dual energy CT

Dose-length-product

Energy-integrating-detector CT
Photon-counting-detector CT
Acute pulmonary embolism

Signal-to-noise ratio

Virtual monoenergetic imaging

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Martine Remy-Jardin, Idir Oufriche, Lucas Guiffault & Jacques Remy

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Remy-Jardin, M., Oufriche, I., Guiffault, L. et al. Diagnosis of acute pulmonary embolism: when photon-counting-detector CT replaces energy-integrating-detector CT in daily routine. Eur Radiol (2024). https://doi.org/10.1007/s00330-024-10724-5

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Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration (2024)

Chapter: 6 vascular conditions and covid-19 vaccines: myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis and venous thromboembolism.

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism This chapter describes the potential relationship between COVID-19 vaccines and potential vascular-related harms: myocardial infarction, ischemic stroke, hemorrhagic stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and the composite venous thromboembolism (PE and/or DVT). Each outcome is addressed in a separate section in this chapter. Twelve scientific reports were selected for evaluation of the six clinical outcomes considered; these are summarized and referenced in Table 6-1. Many of these reports addressed more than one clinical outcome and more than one vaccine. Additionally, some of these reports included outcomes and vaccines that were addressed in other chapters of this report. The 12 reports in Table 6-1 generally represented large populations, with only one study from the United States, conducted on the Medicare populations (persons 65+), multiple studies from the United Kingdom, and Scandinavia, two from the French national health system (covering different age groups), and individual studies from Israel, Hong Kong, Japan, Spain, and Malaysia. These studies may in some sense represent broad global coverage, but many countries, cultures, and health systems were not covered, including most low- and middle-income countries. Although these studies applied standard epidemiological methods and analytical techniques overall, they did not appear to have followed a common or harmonized protocol. For example, they varied in how age groups were presented and the postimmunization exposure interval, although many centered on approximately 28 days. One study examined outcomes for weeks one and two separately, resulting in smaller sample sizes. None of the reports emphasized vaccine outcomes in children, which is unsurprising given the emphasis on the chronic vascular conditions of older persons. Only a minority of the studies adjusted their analytic models for a history of comorbid conditions. Several studies used patient self-controls, with a few employing case-control or cohort designs, including non-immunized comparator groups (Grosso et al., 2011). Further information can be found on the studies as part of the descriptions of the vaccineâdisease outcomes in the respective sections of this chapter. Some other general methodological issues of potential import to the reports were discussed sparingly or not at all, such as the potential health impact of multiple vaccines at the same time of administration (e.g., COVID-19 and influenza). A particularly interesting and difficult issue is possible exposure to SARS-CoV-2 simultaneously with vaccination, although some reports provided separate comparator groups of patients with documented, possibly making it more difficult to distinguish harms caused by vaccination from those caused by COVID-19 infection. The studies also varied in whether sources of patient data included both inpatient and ambulatory care, although all studies reported information on hospitalized patients. These and PREPUBLICATION COPYâUncorrected Proofs

158 VACCINE EVIDENCE REVIEW other issues should be the topic of more intensive research to better refine the evaluation of vaccine safety. The committee attempted to focus on the six thromboembolic outcomes from the first and/or second dose of the primary series. No studies of adverse outcomes from bivalent or monovalent updated booster vaccines were considered here, in part because few such studies were available, and a variety of important selective forces likely affected who received subsequent doses, such as variation in individual clinical circumstances. The studies had generally modest variations in analysis and presentation, such as differences in the post-immunization analytical intervals, age groups of the vaccinees, and clinical history of COVID-19 infection (see Table 6-1). All studies used in this chapter applied general administrative disease coding according to ICD-10 nosology. Importantly, some studies only included hospitalized patients, likely deterring identification of diseases and conditions that might be identified largely in ambulatory settings. Due to expected variation in cross-national medical care and coding practices, harmonization across disease rubrics and nosology could not be assured. Some studies reported diagnoses that could have been placed in alternative disease categories or classification codes. For example, âsubarachnoid hemorrhageâ may or may not be the same as âhemorrhagic stroke.â This was not unexpected, but it challenges the validity of disease classification. This is explained further in the subsections of this chapter. Studies were only included if the disease reports used identical terms to those requested in the Statement of Task. Only Shoaibi et al. (2023) provided a supplemental validation study of disease coding accuracy, using medical charts as the standard. For both MI and PE, the majority of diagnoses were consistent with this manual evaluation. No study reported an evaluation of the accuracy of population immunization registries used to link vaccine receipt data to the respective medical care systems. See Boxes 6-1 through 6-4 for all conclusions in this chapter. The following is a brief synopsis of the 12 studies contained in Table 6-1, in order to orient the reader to study characteristics and interpretation. They are presented in alphabetical order, as it appears also in the Table. Vaccines analyzed are identified throughout the table headings in this chapterâs subheadings. Clinical trial results submitted to FDA for Emergency Use Authorization and/or full approval do not indicate a signal regarding any of the outcomes reviewed in this chapter and any of the vaccines under study (FDA, 2021, 2023a, 2023b, 2023c). Ab Rahman et al. (2021) explored adverse events of special interest among patients admitted to major urban hospitals in Malaysia, during Feb. through September 2021. The basic analyses were conducted using a self-controlled case series, and outcomes were represented as Incidence Rate Ratios. Three vaccine platforms were evaluated, although as noted elsewhere in this report only those vaccines used in the United States were presented in our evaluations. Several but not all adverse events of special interest were analyzed relevant to this chapter, but only those occurring within 21 days after immunization were included. More than one vaccine dose may have been administered during the study window. Barda et al. (2021) conducted an analysis of adverse events after the first dose of BNT162b2 vaccine, in the setting of the largest health care organization in Israel, starting among persons with no medical history of any of the adverse events of interest. One person with a history of vaccine receipt was matched with another with no vaccine history, and with adjustment for various sociodemographic variables. Adverse everts in both groups were monitored using medical records were followed for an observation interval of 42 days using system medical records. Study participantsâ ages ranged from 16 years of age and above. Other PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 159 inclusion and exclusion were applied. In addition to the analysis of adverse events, a second, similarly matched analytical cohort was created using those with a history of COVID-19 infection, matched to similar persons with no history of infection at the same time; then, the clinical outcomes were followed in both groups to separately assess the role of general infection on these outcomes as a comparator. Other studies used in this chapter and in other chapters used similar methodology to contrast rates of adverse events following vaccination with similar rates of adverse events following infection. Botton et al. (2022) explored three adverse vascular effects, myocardial infarction, stroke, and pulmonary embolism, for three vaccines used also in the US: BNT162b2, mRNA1273 and Ad26.COV2.S, among persons ages 18â74 years. The study population included over 46 million adults using the French National Health System, using a self-controlled case series method adapted to the event-dependent exposure and overall high rate of general mortality characteristic of this large population size. The relative incidence of each clinical outcome of interest was determined for three, separately reported weeks after the recorded date of vaccine receipt, derived from separate population vaccine use files. Study data were separately reported for the first and second dose of the primary series for each of the vaccines. Of note, the same overall study methods were used for persons 75 years or older in the same geographic region but are reported separately by Jabagi et al. Burn et al (2022a) conducted a series of cohort studies from September 2020 through May 2021 in the United Kingdom, using a series of national clinical databases that included clinical characteristics of patients as well as vaccine receipt. Clinical outcomes included both vascular and hematological conditions, which also served to better understand pre-vaccination health status for a variety of comorbid conditions. Only data on the BNT162b2 were relevant to this chapter, and both first and second doses were considered, encompassing over 3 million doses distributed, who were 20 years of age and older. Additionally, a separate cohort of patients who sustained the COVID-19 infection was analyzed to use as a comparator to the vaccine receipt cohorts with regard to clinical outcomes. Adverse events were counted in the 28 days after vaccine receipt. Of note, this study used some of some of same clinical data resources as another study by Hippesley-Cox et al., but this was not deemed an important problem. Burn et al. (2022b) analyzed hospital and primary care data from the region of Catalonia, Spain, including the first and second dose of BNT162b2. Another vaccine was studied but not used in the United States. Over 3 million persons were reported to have used at least one dose of this vaccine and were available for study. The outcomes assessed relevant to this chapter were venous thromboembolism, myocardial infarction, and ischemic stroke, with results among vaccinated persons compared to an historical comparator group. However, several other comorbid conditions were studied as âpre-morbidâ risk factors, or as potential harms assessed in other chapters of this report (e.g., immune thrombocytopenia). As in other reports utilized in this chapter and others, a separate cohort of persons with the viral COVID-19 infection was identified as a separate comparator outcome events relative to those receiving the study vaccines. Chui et al. (2022) conducted a series of studies on the potential harms of the BNT162b2 vaccine in 2.9 million vaccinees in the period between February and September 2021, Data were obtained from Hong Kong (China) territory-wide electronic health and vaccination records. The basic analytical design was a âmodifiedâ self-controlled case series using a variety of preselected vascular and thromboembolic events and hemorrhagic stroke. The period of adverse event risk assessment was 27 days after vaccination, and first and second doses of the vaccine were considered separately. An additional cohort of patients acquiring COVID-19 infection was also PREPUBLICATION COPYâUncorrected Proofs

160 VACCINE EVIDENCE REVIEW analyzed as a separate comparator. Of note, this was one of the first studies to concede that citizens had the right to change the scheduling of the first and second primary series doses. Hippesley-Cox et al. (2021) conducted self-controlled case series analyses of thromboembolism and thrombocytopenia in over 9.5 million persons receiving the BNT162b2 vaccine in England, UK, between December 2020 and April 2021, among persons 16 years of age or older. All information was derived from national databases of mortality, hospitalization, and vaccinations. Only clinical outcomes after the first dose were considered by the authors. Important to this chapter, myocardial infarction, ischemic stroke, and venous thromboembolism outcomes were available, and were assessed in the 28 days after vaccination. Additionally, a separate cohort was analyzed using patients who were noted to be infected with COVID-19 virus, as a comparator for relevant clinical outcomes. As noted above, there may be a small amount of database overlap between this study and that of Burn et al. (2022a). Hviid et al. (2022) conducted a cohort study in Denmark of âfrontline workers,â who were among the first priority groups to receive COVID-19 vaccines when available in that country. These workers, born after 1957, were the only study group of its type to be evaluated in this chapter (the remainder were all from the general community). They were largely health care and institutional workers (n ~101,000) although some others were not further classified occupationally. Analytical information was obtained from national health and immunization registers. Only the BNT162b2 vaccine was assessed in this chapter, and the most important outcomes here were pulmonary embolism and deep vein thrombosis. The study sample size was more modest than most of the other studies considered in this chapter, limiting the statistical power of the analysis. The window of observation extended from December 2020 to April 2021. Jabagi et al. (2022) conducted a self-controlled case series analysis of persons from the French National Health Service linked to the National COVID-19 vaccination database and can be considered an âextensionâ of the report by Botton et al. (2021) (see above), except that it included only persons 75 years and older. The paper by Botton et al. (2021) only considered persons only up to 74 years of age. The separate reporting emphasis was deemed useful because older persons were priority vaccinees in many global communities. Main outcomes included in this paper were myocardial infarction, stroke, and pulmonary embolism. In this paper over 3.9 million persons were included and only the BNT162b2 vaccine findings were reported, perhaps in part because of the limited sample availability for other vaccines during the study interval. Data on first and second doses were reported separately, but only a two-week post vaccination interval was reported. Patone et al. (2021) conducted a study in England, UK, that was mostly devoted to identifying potential neurological harms of two COVID-19 vaccines; Only BNT162b2 was considered in this chapter because of relevance to U.S. vaccine exposures, as noted above, and over 12 million persons received this vaccine between December 2020 and May 2021. The study was considered for assessment in this chapter because hemorrhagic stroke (HS) was one of the prespecified safety outcomes. The study analysis was a self-controlled case series, and 811 HS events were detected among those who received BNT162b2 vaccine. The follow-up interval was weekly for 28 days after immunization, and only the first dose of vaccine and the first detected adverse event were considered in the analysis. Additional cohorts were developed among patients from Scottish data to serve as validation of the findings from England, and among those who were found to have a positive COVID-19 test for infection, to be used as a comparator for the core findings. PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 161 Shoaibi et al. (2023) studied two mRNA vaccines (BNT162b2 and mRNA-1273); this study differed in certain important ways from the other studies in this chapter. It was the only study reviewed in this section conducted on a U.S. population (the âMedicareâ population consisting of nearly all Americans 65 years and older). Vascular, coagulation and certain neurological outcomes were evaluated, but only those related to this chapter (see Background information section to this chapter) were included. The study design was also different from some of the others. The two mRNA vaccines were considered separately and assessed using self- controlled case series methods. However, after a pre-vaccination data collection period, where demographic and general clinical information on the study cohorts were collected, the selected outcomes were assessed in both ambulatory and hospital settings for 90 days after the vaccines became available. Thus, it was not possible to separate out first and second dose effects of the individual vaccines. Shoaibi et al. also conducted secondary and exploratory analyses, including a validation study of outcome codes using medical case record reviews. These findings strengthened the understanding and challenges of medical record data, even if the findings may not be similar in other reports reviewed in this chapter. Whiteley et al. (2022) examined the adult population of England, UK, using hospitalization and primary care data, comprising a total population of approximately 46 million persons observed between December 2020 and March 2021. Extensive clinical and demographic information were noted in the pre-vaccine period; a 28-day period of observation was used following the first immunization was employed; only the first dose was considered in the authorsâ analysis. Additionally, only the findings from the BNT162b2 vaccine were utilized in this chapter, as it was the only vaccine used in the United States. The clinical outcomes data in this report are specifically categorized two groupsâthose 69 years or younger and those 70 years and older. The authors noted two main limitations of their analyses: reliance on the accuracy of coded electronic health records and residual confounding within the adjusted models. Several of the hematological and coagulation findings from this report are contained in other chapters of this document. PREPUBLICATION COPYâUncorrected Proofs

162 VACCINE EVIDENCE REVIEW TABLE 6-1 Epidemiological Studies in the Vascular Conditions Evidence Review Study Design and Comparison Age Total Author Group Location Data Source Vaccine(s) Range Sample Size Ab Rahman Self-controlled Malaysia Malaysia Vaccine BNT162b2 18â60+ years 20 million et al. (2022) case series Administration System (myVAS) Barda et al. Cohort, Israel Clalit Health BNT162b2 16+ years 1.7 million (2021) unvaccinated Services individuals Botton et al. Self-controlled France French National BNT162b2, 18â74 years 46.5 million (2022) case series Health Data System mRNA-1273, Ad26.COV2.S Burn et al. Cohort, UK Electronic health BNT162b2 20+ years 5.6 million (2022a) historical records comparator Burn et al. Cohort, Spain Electronic health BNT162b2 20+ years 4.6 million (2022b) historical records comparator Chui et al. Self-controlled China Electronic health BNT162b2 16+ years 2.9 million (2022) case series records (BNT162b2 vaccinees) PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 163 TABLE 6-1 Continued Study Design and Comparison Author Group Location Data Source Vaccine(s) Age Range Total Sample Size Hippisley-Cox Self-controlled England National BNT162b2 16+ years 29 million et al. (2021) Immunization Management System data Hviid et al. Nationwide Denmark Danish Civil BNT162b2 16â64 years 355,209 (2022) exploratory Registration System retrospective cohort, unvaccinated comparison group Jabagi et al. Self-controlled France French National BNT162b2 75+ years 3.9 million (2022) case series Health System Patone et al. Self-controlled Scotland English National BNT162b2 16â90+ years 12.1 million (2021) case series Immunization Database Shoaibi et al. Self-controlled US Medicare claims BNT162b2, 65+ years 3.3 million (2023) case series mRNA-1273 (Doses 1 and 2) Whiteley et al. Cohort England English NHS, BNT162b2 >18 years 46 million (2022) General Practice Extraction Service Data for Pandemic Planning and Research NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name ComirnatyÂ®. mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name SpikevaxÂ®. Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen. SOURCES: Ab Rahman et al., 2022; Barda et al., 2021; Botton et al., 2022; Burn et al., 2022a, 2022b; Chui et al., 2022; Hippisley-Cox et al., 2021; Hviid et al., 2022; Jabagi et al., 2022; Patone et al., 2021; Shoaibi et al., 2023; Whiteley et al., 2022. PREPUBLICATION COPYâUncorrected Proofs

164 VACCINE EVIDENCE REVIEW MYOCARDIAL INFARCTION BOX 6-1 Conclusions for Myocardial Infarction Conclusion 6-1: The evidence favors rejection of a causal relationship between the BNT162b2 vaccine and myocardial infarction. Conclusion 6-2: The evidence favors rejection of a causal relationship between the mRNA-1273 vaccine and myocardial infarction. Conclusion 6-3: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and myocardial infarction. Conclusion 6-4: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and myocardial infarction. Background A heart attack (myocardial infarction [MI]) usually occurs when a blood clot blocks blood flow to the heart. Tissues, particularly heart muscle, lose oxygen and may die. Symptoms include tightness or pain in the chest, neck, back, or arms and fatigue, lightheadedness, abnormal heartbeat, and anxiety (Thygesen et al., 2018). MI is important and common; with other cardiovascular diseases, it is the leading cause of death in many developed countries. MI rates will vary among regional and national populations because of differences in risk factor levels and their management or medical treatment access to and use of health care resources and vary worldwide in part because of these differences in populations and communities. Sometimes a definitive diagnosis is difficult to make because of timing of clinical events, variation in symptom rates, premature death, or therapeutic interventions; this is likely to be a worldwide finding. The global epidemiology and occurrence have been reasonably well characterized (Salari et al., 2023). SARS-CoV-2 is believed to cause both MI and other vascular conditions (Siddiqi et al., 2021), due to a variety of mechanisms, including infection and inflammation of atherosclerotic plaques and coagulation abnormalities. In the studies evaluated in this section, MI was substantially more common among COVID-19âinfected persons than those who were uninfected but received any COVID-19 vaccine. Concordant exposure to both vaccine and infection during the pandemic can make it difficult to attribute MI to either potential cause. Mechanisms MI is primarily defined as the sudden ischemic death of myocardial tissue. This often occurs due to thrombotic blockage of a coronary vessel after a plaque ruptures. The lack of blood flow triggers significant metabolic and ionic disturbances in the myocardium, leading to rapid deterioration of systolic function (Prabhu and Frangogiannis, 2016). Prolonged lack of blood flow activates a âwavefrontâ of cardiomyocyte death, which progresses from the PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 165 subendocardium to the subepicardium. This process involves mitochondrial changes that are central to apoptosis and necrosis of cardiomyocytes (Davidson et al., 2020). Given the limited regenerative capacity of the adult mammalian heart, healing primarily occurs through scar formation. The immune system plays a significant role in both the homeostatic and perturbed conditions of the heart. Immune cells infiltrate the heart during gestation and persist in the myocardium throughout life, participating in essential housekeeping functions. After MI or in response to infection, large numbers of immune cells are recruited to the heart to remove dying tissue, scavenge pathogens, and promote healing (Prabhu and Frangogiannis, 2016). However, in some cases, these immune cells can cause irreversible damage, contributing to heart failure. Reports exist of vaccine-related MI cases, particularly after ChAdOx1-S, which were mostly characterized by ST-segment elevation and occurred after the first dose. However, no definitive mechanistic link is established in the literature between COVID-19 vaccination and MI. Furthermore, most cases occurred after the first dose, which suggests that the immune response elicited by the vaccine may play a minimal role in MI (Hana et al., 2022; Zafar et al., 2022); an overactive immune response would presumably lead to a higher incidence of MI after booster dose. The immune response to vaccination does not correlate with a single inflammatory biomarker associated with MI but shows a range of markers, including IL-6, C-reactive protein, and components of the interferon signaling pathway (HervÃ© et al., 2019). Epidemiological Evidence BNT162b2 and MI Table 6-2 presents eight studies that contributed to the causality assessment. PREPUBLICATION COPYâUncorrected Proofs

166 VACCINE EVIDENCE REVIEW TABLE 6-2 Epidemiological Studies in the BNT162b2âMyocardial Infarction Evidence Review Number Results Author N of Events (95% CI) Ab Rahman et al. (2022) Dose 1: 8.7 million vaccinees 409 IRR 0.97 (0.87â1.08) Dose 2: 6.7 million vaccinees 387 IRR 1.08 (0.97â1.21) Barda et al. (2021) Dose 1: 884,828 vaccinees 59 RR 1.07 (0.74â1.60) Botton et al. (2022) Dose 1: 16,728 vaccinees Week 1: 543 RI 0.91 (0.83â1.00) Week 2: 492 RI 0.86 (0.78â0.94) Dose 1: 14,004 vaccinees Week 1: 408 RI 0.89 (0.80â1.00) Week 2: 404 RI 0.95 (0.85â1.06) Burn et al. (2022a) Dose 1: 1.8 million vaccinees 442 SIR 0.88 (0.80â0.97) Dose 2: 1.3 million vaccinees 283 SIR 0.80 (0.71â0.89) Burn et al. (2022b) Dose 1: 2.0 million vaccinees 280 SIR 1.05 (0.93â1.18) Dose 2: 1.3 million vaccinees 272 SIR 1.10 (0.98â1.24) Jabagi et al. (2022) Dose 1: 3.9 million vaccinees 6,510 RI 0.97 (0.88â1.06) Dose 2: 3.2 million vaccinees 4,843 RI 1.04 (0.93â1.16) Shoaibi et al. (2023) Doses 1 and 2: 3.4 million vaccinees 2,783 IRR 1.04 (0.91â1.18) NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name ComirnatyÂ®. Shoaibi et al. (2023) combined the number of BNT162b2 and mRNA-1273 vaccinees. The primary series for BNT162b2 is two doses. Number of events refers to events in vaccinees only. CI: confidence interval; HR: hazard ratio; IR: incidence rate; IRR: incidence rate ratio; RI: relative incidence; RR: risk ratio; SIR: standardized incidence ratio. SOURCES: Ab Rahman et al., 2022; Barda et al., 2021; Botton et al., 2022; Burn et al., 2022a, 2022b; Jabagi et al., 2022; Shoaibi et al., 2023; Whiteley et al., 2022. PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 167 All studies have varying designs; the majority were self-controlled, and the remainder were cohort studies, except for a case-control study (Whiteley et al., 2022). The number of MI events after BNT162b2 1 was higher than the background rate, except for the Israeli study (n = 59) (Barda et al., 2021). Shoaibi et al. (2023) used the two-dose primary series as the âexposure,â without presenting the separate outcomes. This study was retained in the report, in part because it was the only U.S. study. The two studies from France are respectively the younger and older cohorts of patients from the same national health system (Botton et al., 2022; Jabagi et al., 2022); they reported MI outcomes only from a 2-week interval postimmunization. Whiteley et al. (2022) from England also presented data separately for two age categories (younger and older than 70). All the studies used a postimmunization analysis interval of 1 month or less, except Shoaibi et al. (2023), which used 90 days with appropriate adjustments. The findings were generally uniform across all eight studies. Seven of them showed no statistically significant increases in the risk of MI associated with BNT162b2. Shoaibi et al. (2023), in partially adjusted analyses, showed a modest increased risk: 1.17 (95% confidence interval [CI]: 1.08â1.28). However, these investigators included additional adjustments: current history of COVID-19 infection and seasonality. These factors were considered important; the latter was not explored in any other study contained in this chapter. After adjusting for these additional variables, the MIâBNT162b2 association was no longer significant: 1.04 (95% CI: 0.91â1.18). Shoaibi et al. (2023) also demonstrated that ICD codes for MI in their dataset were generally valid using medical chart reviews, with a positive predictive value of 80 percent. In summary, all the studies in Table 6-2 showed no significant association between immunization with BNT162b2 and MI. mRNA-1273 and MI Table 6-3 presents two studies that contributed to the causality assessment. TABLE 6-3 Epidemiological Studies in the mRNA-1273âMyocardial Infarction Evidence Review Number Author N Results (95% CI) of Events Week 1: 58 RI 0.78 (0.59â1.03) Dose 1: 2,435 vaccinees Botton et al. Week 2: 78 RI 1.06 (0.83â1.37) (2022) Week 1: 46 RI 0.85 (0.61â1.18) Dose 2: 1,831 vaccinees Week 2: 61 RI 1.21 (0.90â1.62) Shoaibi et al. Doses 1 and 2: 302 IRR 1.01 (0.82â1.26) (2023) 3.4 million vaccinees NOTES: mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name SpikevaxÂ®. Shoaibi et al. (2023) combined the number of BNT162b2 and mRNA-1273 vaccinees. The primary series for mRNA-1273 is two doses. Number of events refers to events in vaccinees only. CI: confidence interval; N/A: not applicable; IRR: incidence rate ratio; RI: relative incidence. SOURCES: Botton et al., 2022; Shoaibi et al., 2023. 1 The COVID-19 vaccine manufactured by Pfizer-BioNTech under the name ComirnatyÂ®. PREPUBLICATION COPYâUncorrected Proofs

168 VACCINE EVIDENCE REVIEW Two studies evaluated the association between mRNA-1273 2 and MI, one using data from the French national health service (Botton et al., 2022) and one using data from the U.S. Medicare system (Shoaibi et al., 2023) (see Tables 6-1 and 6-3.) Botton et al. (2022) covered adults under 75, and the vaccine was one of four evaluated in this report. A French companion report (Jabagi et al., 2022) showed data from the same study in persons 75+ but did not include mRNA-1273. Botton et al. (2022) used standard epidemiological methods but reported only on outcomes over a 2-week postimmunization interval, and each week was reported separately. Another study explored the association of mRNA-1273 with MI risk with data from the U.S. Medicare health system, representing persons in the U.S. 65+ years (Shoaibi et al., 2023). They used a 90-day post- vaccination interval and assessed MI outcome risk of the two-dose primary series. Despite these variations, the study results aligned well with others. Botton et al. (2022) found no increase in risk of MI with mRNA-1273 in the first (RI 0.78, 95% CI: 0.59â1.03) or second (RI 1.06, 95% CI: 0.83â1.37) outcome week (Botton et al., 2022). Shoaibi et al. (2023) showed no increased risk of MI: IRR 1.01 (95% CI: 0.82â1.26), after full adjustment for selected study variables. Ad26.COV2.S and MI Table 6-4 summarizes one study that contributed to the causality assessment. TABLE 6-4 Epidemiological Study in the Ad26.COV2.SâMyocardial Infarction Evidence Review Results Author N Number of Events (95% CI) Botton et al. Dose 1: Week 1: 33 RI 1.57 (1.02â2.44) (2022) 282 vaccinees Week 2: 34 RI 1.75 (1.16â2.62) NOTES: Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen. The primary series for Ad26.COV2.S is one dose. Number of events refers to events in vaccinees only. CI: confidence interval; N/A: not applicable; RI: relative incidence. SOURCE: Botton et al., 2022. As noted, this study from the French national health system, covering adults 18â74 years, evaluated four vaccines (Table 6-1). Ad26.COV2.S 3 was received by about 30,000 persons overall, and of those receiving the first dose, 282 MIs were identified. Data were presented separately for the first and second postimmunization weeks only. Outcomes were RI 1.57 (95% CI: 1.02â2.44) for the first week and RI 1.75 (95% CI: 1.16â2.62) for the second week. From Evidence to Conclusions Eight studies assessed the relationship between BNT162b2 and MI across different demographic groups and national populations on three continents. Despite some variation in the types of observational epidemiological study designs, all of these studies showed no important overall statistical evidence of increased risk of MI associated with either dose of BNT162b2 (Ab 2 Refers to the COVID-19 vaccine manufactured by Moderna under the name SpikevaxÂ®. 3 The COVID-19 vaccine manufactured by Janssen. PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 169 Rahman et al., 2022; Barda et al., 2021; Botton et al., 2022; Burn et al., 2022a, 2022b; Jabagi et al., 2022; Shoaibi et al., 2023; Whiteley et al., 2022). Conclusion 6-1: The evidence favors rejection of a causal relationship between the BNT162b2 vaccine and myocardial infarction. Only two studies evaluated the association between mRNA-1273 and MI; neither showed evidence of increased risk (Botton et al., 2022; Shoaibi et al. 2023), but the findings aligned with those for BNT162b2. Conclusion 6-2: The evidence favors rejection of a causal relationship between the mRNA-1273 vaccine and myocardial infarction. Only one study evaluated the relation between Ad26.COV2.S and MI, and the number of MI events was modest (Botton et al., 2022). Conclusion 6-3: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and myocardial infarction. No studies examined the relationship between NVX-CoV2373 4 and MI. Conclusion 6-4: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and myocardial infarction. 4 The COVID-19 vaccine manufactured by Novavax. PREPUBLICATION COPYâUncorrected Proofs

170 VACCINE EVIDENCE REVIEW ISCHEMIC STROKE BOX 6-2 Conclusions for Ischemic Stroke Conclusion 6-5: The evidence favors rejection of a causal relationship between the BNT162b2 vaccine and ischemic stroke. Conclusion 6-6: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and ischemic stroke. Conclusion 6-7: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and ischemic stroke. Conclusion 6-8: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and ischemic stroke. Background A stroke may occur due to either a blockage in blood flow to the brain or sudden bleeding within the brain. The primary form is known as an ischemic stroke, where the brain is deprived of necessary oxygen and nutrients due to a blockage in blood flow, leading to rapid cell death. The secondary type is termed a hemorrhagic stroke, characterized by blood leakage that applies pressure on brain cells, causing damage (NHLBI, 2023). Hemorrhagic strokes are discussed and evaluated in the next section. Ischemic strokes are usually caused by either atherosclerotic lesions in cerebral arteries or emboli, often blood clots, from the heart or other parts of the vascular tree. However, several other mechanisms are possible. Strokes can occur at any age but are most common in older people. In the United States, strokes are overall the fifth leading cause of death. Typically, strokes are acute and relatively sudden, often within hours or less, even though the lesions themselves may take a long time to develop. Sometimes, neurological manifestations occur intermittently and incompletely; these clinical events may be diagnosed as a âtransient ischemic attack,â which is often considered diagnostically separate from âcompletedâ strokes, which can be important in studies that assess stroke outcomes. The clinical presentation may also be modified by various medical interventions, leading to other diagnostic challenges. Stroke diagnoses may also vary by relative access to technology, such as imaging procedures, which can differ by country and within-country region. All of these factors can possibly affect apparent incidence rates across studies. To complicate matters further, persons with cardiovascular diseases are 2â4 times more likely to have a stroke (Robinson et al., 2023), raising issues of the underlying causes. These complex diagnostic challenges apply to all the thromboembolic outcomes assessed in this chapter, as discussed. However, in a comprehensive global review of ICD coding validity study, McCormick et al. (2015) found that the positive predictive value (PPV) was 82 and over 93 percent for ischemic and ICD-9 hemorrhagic stroke codes. For diagnosis, ischemic stroke is identified by the abrupt onset of focal neurologic deficits, with speech disturbance and weakness on one half of the body being the most common symptoms. Diagnostic studies are crucial to differentiate it from other conditions, such as PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 171 intracerebral hemorrhage, or entities mimicking it, such as seizures or hypoglycemia. Neuroimaging, particularly noncontrast computed tomography (CT) or magnetic resonance imaging (MRI), plays a vital role in this differentiation. Noncontrast CT is sensitive for detecting mass lesions and acute hemorrhage but less effective in detecting strokes within 3 hours of the event and has even lower sensitivity for small or posterior fossa strokes. In contrast, MRI, especially diffusion-weighted imaging, offers better resolution and greater sensitivity for detecting acute ischemic stroke and is as sensitive as noncontrast CT for intracerebral hemorrhagic stroke (Vymazal et al., 2012). Mechanisms A key aspect of ischemic stroke pathophysiology involves the immune system. In the acute phase, innate immune cells invade the brain and meninges, contributing to damage but also potentially offering protection. This phase is characterized by the damaged brain cells releasing danger signals, such as damage-associated molecular patterns (DAMPs), into the circulation, activating systemic immunity. In the chronic phase, antigen presentation triggers an adaptive immune response targeted at the brain, possibly underlying the neuropsychiatric sequelae that significantly contribute to morbidity (Chamorro et al., 2012; Nakamura and Shichita, 2019). A mechanism of ischemic stroke as a result of COVID-19 vaccination remains to be established. However, it can be hypothesized that temporary inflammation of the arterial wall could be a contributing factor in cerebral hemorrhage (de MÃ©lo Silva and Lopes, 2021). The proposed immune response could also trigger a systemic prothrombotic state, characterized by endothelial dysfunction and activation, complement and platelet activation, and infiltration of inflammatory cells into atherosclerotic plaques. These processes lead to amplified inflammatory responses and potential thrombosis within these plaques (Bonaventura et al., 2021). This is in line with the concept that inflammatory conditions, especially in atherosclerosis, are precursors to thrombotic events, including cerebrovascular ones (Assiri et al., 2022). Some argue that COVID-19 vaccination could induce an inflammatory cascade similar to that in COVID-19 infection, leading to disseminated intravascular coagulation, vascular endothelial dysfunction, and large-vessel cerebral infarctions. Following messenger ribonucleic acid (mRNA) vaccination, the introduction of mRNA sequences coding for the SARS-CoV-2 spike protein into host cells leads to its synthesis and release, stimulating an inflammatory immune response (Assiri et al., 2022; Famularo, 2022). Epidemiological Evidence BNT162b2 and Ischemic Stroke Table 6-5 presents six studies that contributed to the causality assessment. PREPUBLICATION COPYâUncorrected Proofs

172 VACCINE EVIDENCE REVIEW TABLE 6-5 Epidemiological Studies in the BNT162b2âIschemic Stroke Evidence Review Number Author N of Events Results (95% CI) Ab Rahman et Dose 1: 8.7 million vaccinees Dose 1: 535 IRR 1.05 (0.95â1.15) al. (2022) Dose 2: 6.7 million vaccinees Dose 2: 471 IRR 1.11 (1.00â1.23) Botton et al. Dose 1: 11,282 vaccinees Week 1: 329 RI 0.84 (0.74â0.94) (2022) Week 2: 366 RI 0.95 (0.85â1.06) Dose 2: 9,344 vaccinees Week 1: 279 RI 0.93 (0.81â1.06) Week 2: 307 RI 1.09 (0.96â1.23) Burn et al. Dose 1: 1.8 million vaccinees 146 SIR 1.10 (0.93â1.29) (2022a) Dose 2: 1.3 million vaccinees 68 SIR 0.68 (0.54â0.86) Burn et al. Dose 1: 2.0 million vaccinees 521 SIR 0.98 (0.90â1.07) (2022b) Dose 2: 1.3 million vaccinees 515 SIR 1.01 (0.92â1.10) Jabagi et al. Dose 1: 3.9 million vaccinees 9,162 RI 0.90 (0.84â0.98) (2022) Dose 2: 3.2 million vaccinees 6,531 RI 1.04 (0.93â1.16) Whiteley et al. Dose 1: 8.7 million vaccinees 4,143 <70 years: HR 0.90 (0.83â0.97) (2022) >70 years: HR 0.71 (0.68â0.75) NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name ComirnatyÂ®. Number of events refers to events in vaccinees only. CI: confidence interval; HR: hazard ratio; IRR: incidence rate ratio; RI: relative incidence; SIR: standardized incidence ratio. SOURCES: Ab Rahman et al., 2022; Botton et al., 2022; Burn et al., 2022a, 2022b; Jabagi et al., 2022; Whiteley et al., 2022. PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 173 The two papers from France report on one study, addressing adults younger than and over 75, respectively (Botton et al., 2022; Jabagi et al., 2022). This study, as noted, reported only two separate weeks of postimmunization outcomes. Botton et al. showed no increased risk of stroke after either week (Botton et al., 2022), and Jabagi et al. (2022) studied the oldest population (over 74) and found similar results. The UK study (Burn et al., 2022a) and the Catalonia, Spain study (Burn et al., 2022b) also found no increased stroke risk with this vaccine. The Malaysian study, with a different design, had the same findings (Ab Rahman et al., 2022). Whiteley et al. (2022) from England had one of the largest immunized populations, over 8 million, but presented findings separately for those over and under 70. Hazard ratios were reported for two separate age groups: younger than 70 and 70+. All studies showed no increased risk of ischemic stroke with the BNT162b2 vaccine in all major analytical groups. mRNA-1273 and Ischemic Stroke Table 6-6 summarizes one study that contributed to the causality assessment. TABLE 6-6 Epidemiological Study in the mRNA-1273âIschemic Stroke Evidence Review Number of Results Author N Events (95% CI) Botton et al. Dose 1: 1,491 vaccinees Week 1: 42 RI 0.76 (0.55â1.07) (2022) Week 2: 40 RI 0.76 (0.54â1.07) Dose 1: 1,200 vaccinees Week 1: 45 RI 1.15 (0.82â1.62) Week 2: 41 RI 1.12 (0.77â1.62) NOTES: mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name SpikevaxÂ®. Number of events refers to events in vaccinees only. CI: confidence interval; RI: relative incidence. SOURCE: Botton et al., 2022. Only one relevant scientific report attempted to link mRNA-1273 with ischemic stroke risk. As seen in other sections, Botton et al. (2022), covering adults 18â74 years, reported ischemic stroke risk in the 2 weeks after immunization. Some weaknesses included inability to fully assess the risk association on the day of immunization, the reporting of each outcome week risk separately, and that, as in many of the other reports, outpatient-only clinical events were not surveyed. The risk was not significantly increased in either postimmunization week. The companion paper (Jabagi et al., 2022) on persons 75+ in this study did not include this vaccine. Ad26.COV2.S and Ischemic Stroke Table 6-7 summarizes one study that contributed to the causality assessment. PREPUBLICATION COPYâUncorrected Proofs

174 VACCINE EVIDENCE REVIEW TABLE 6-7 Epidemiological Study in the Ad26.COV2.SâIschemic Stroke Evidence Review Number of Author N Events Results (95% CI) Botton et al. Dose 1: 196 vaccinees Week 1: 14 RI 0.78 (0.43â1.41) (2022) Week 2: 19 RI 1.09 (0.66â1.81) NOTES: Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen. The primary series of Ad26.COV2.S is one dose. CI: confidence interval; RI: relative incidence. SOURCE: Botton et al., 2022. Botton et al. (2022), as mentioned in the discussion on BNT162b2 and mRNA-1273, other vaccines, was the only available report on the association of Ad26.COV2.S with ischemic stroke. Its strengths and limitations are similar. One additional limitation for this vaccine is that the number of outcome events was modest, which should be considered in statistical evaluation of the findings. However, within these limitations, no significantly increased risk of ischemic stroke was found. From Evidence to Conclusions All six studies that assessed the association between BNT162b2 and ischemic stroke, comprising five robust studies from multiple countries and exploring younger and older adults, found no evidence of increased risk, despite modest difference in the study designs Ab Rahman et al., 2022; Botton et al., 2022; Burn et al., 2022a, 2022b; Jabagi et al., 2022; Whiteley et al., 2022). Conclusion 6-5: The evidence favors rejection of a causal relationship between the BNT162b2 vaccine and ischemic stroke. A single study assessed the relationship between mRNA-1273 and Ad26.COV2.S and ischemic stroke (Botton et al., 2022). Although it was generally well designed, it had limitations: a lack of representation of older persons (over 75), separate presentation of outcome rates for each postimmunization week, a group with high ischemic stroke risk, and a modest number of stroke outcomes. No studies evaluated the relationship between NVX-CoV2373 and ischemic stroke. Conclusion 6-6: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and ischemic stroke. Conclusion 6-7: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and ischemic stroke. Conclusion 6-8: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and ischemic stroke. PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 175 HEMORRHAGIC STROKE BOX 6-3 Conclusions for Hemorrhagic Stroke Conclusion 6-9: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and hemorrhagic stroke. Conclusion 6-10: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and hemorrhagic stroke. Conclusion 6-11: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and hemorrhagic stroke. Conclusion 6-12: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and hemorrhagic stroke. Background As with other strokes, hemorrhagic stroke (HS) is usually an acute event that occurs after bleeding within the cerebrum or more specifically within the brain, usually caused by a ruptured blood vessel. It has been estimated that about 750,000 persons in the United States die of stroke each year. About 20 percent of incident strokes are due to hemorrhage. Often, the bleeding that comes with HS can damage the brain and impair neurological function by many mechanisms, such as due to physical pressure or inflammation. HS has many causes, such as ruptured aneurysms, head trauma, vascular malformations, and anticoagulants (Caplan, 2023). Some of the risk factors are similar to those of other important vascular conditions, such as MI or ischemic stroke (e.g., smoking, hypertension, diabetes), so prevention is an important part of the management of this condition. HS may occur in several areas of the brain, such as epidural, intraparenchymal, subdural, and subarachnoid locations. The extent of diagnostic specificity depends, as with other vascular conditions, on regional and national diagnostic and therapeutic practices and health care resources, such as advanced imaging and other neuroradiological techniques. This is particularly important because in studies of vaccine use and clinical outcomes, the latter will depend on these resources and diagnostic nomenclature. For example, an HS may be primarily called a âruptured aneurysmâ or a âsubarachnoid hemorrhage,â which may have causal implications. As COVID-19 infection may be a cause of HS, this complicates assessing vaccine causation due to interacting comorbid conditions and treatments (Wang et al., 2020). Research has advanced the use of artificial intelligence to help identify anatomic locations of hemorrhage and its classification (Neves et al., 2023), but how this is being applied to causal studies, such as those related to vaccines, is uncertain. Yet, as noted, validation studies of ICD coding of HS have been positive and useful (Kirkman et al., 2009). PREPUBLICATION COPYâUncorrected Proofs

176 VACCINE EVIDENCE REVIEW Mechanisms HS occurs when a blood vessel within the brain ruptures, leading to bleeding in or around the brain, and can result from various etiologies, including hypertension, aneurysms, and arteriovenous malformations. Chronic hypertension may lead to Charcot-Bouchard microaneurysms in small penetrating arterioles, which are prone to rupture under sustained high pressure. Subarachnoid hemorrhage is often due to the rupture of a saccular aneurysm, and arteriovenous malformations, which are tangles of blood vessels with abnormal connections between arteries and veins, can also rupture (Montano et al., 2021; Smith and Eskey, 2011). The secondary injury mechanisms include the mass effect and increase intracranial pressure, where blood accumulation causes compression of brain tissue, leading to blocked blood flow and the toxic effects of blood breakdown products (Serrone et al., 2015). Hemoglobin degradation products can be toxic to brain tissue and contribute to vasospasm, particularly in subarachnoid hemorrhage (Gross et al., 2019). An immune response after hemorrhage is characterized by the activation of microglia and infiltration of macrophages and lymphocytes, which can exacerbate neuronal damage. Proinflammatory cytokines, such as TNF-Î±, IL-1Î², and IL-6, are elevated, contributing to secondary injury and brain edema (Li and Chen, 2023). Some vaccines, notably those associated with a risk of thrombocytopenia, could theoretically lead to HS, although this is exceedingly rare; an autoimmune response leading to platelet destruction and severe thrombocytopenia might predispose individuals to hemorrhage. The proposed mechanism of HS is similar to that of ischemic stroke, as mentioned. Epidemiological Evidence BNT162b2 and HS Table 6-8 presents six studies that contributed to the causality assessment. PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 177 TABLE 6-8 Epidemiological Studies in the BNT162b2âHemorrhagic Stroke Evidence Review Number Author N of Events Results (95% CI) Ab Rahman et al. Dose 1: 8.7 million vaccinees 119 IRR 1.29 (1.05â1.59) (2022) Dose 2: 6.7 million vaccinees 80 IRR 1.05 (0.82â1.34) Botton et al. (2022) Dose 1: 3,141 vaccinees Week 1: 112 RI 0.97 (0.80â1.19) Week 2: 119 RI 1.07 (0.88â1.30) Dose 2: 2,372 vaccinees Week 1: 86 RI 0.98 (0.77â1.25) Week 2: 71 RI 0.86 (0.67â1.11) Chui et al. (2022) Dose 1: 2.9 million vaccinees 31 IRR 1.67 (1.04â2.69) Dose 2: 2.7 million vaccinees 26 IRR 1.68 (0.99â2.84) Jabagi et al. (2022) Dose 1: 3.9 million vaccinees 2,050 RI 0.90 (0.78â1.04) Dose 2: 3.2 million vaccinees 1,366 RI 0.97 (0.81â1.15) Patone et al. (2021) Dose 1: 12.1 million vaccinees 151 RI 1.24 (1.07â1.43) Whiteley et al. Dose 1: 8.7 million vaccinees 440 <70 years: HR 0.77 0.62â0.96) (2022) >70 years: HR 0.65 (0.57â0.74) NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name ComirnatyÂ®. Number of events refers to events in vaccinees only. CI: confidence interval; HR: hazard ratio; IRR: incidence rate ratio; RI: relative incidence; RR: risk ratio. SOURCES: Ab Rahman et al., 2022; Botton et al., 2022; Chui et al., 2022; Jabagi et al., 2022; Patone et al., 2021; Whiteley et al., 2022. PREPUBLICATION COPYâUncorrected Proofs

178 VACCINE EVIDENCE REVIEW Six reports represent five studies addressing the association of HS with this vaccine, and several reports were used in other sections of this chapter. One was a cohort study; the remainder were self-controlled designs. The committee examined the data on the first dose of the primary series. All but Patone et al. (2021) and Chui et al. (2022) have been discussed. Patone et al. (2021) was conducted using the English National Immunization Database, using a self-controlled design. Only first-dose outcomes and hospitalized patients were evaluated. The study showed a modestly increased risk of (RI 1.24, 95% CI: 1.07â1.43). However, this group also conducted a validation study using similar methods on Scottish data and found no increased risk of HS, using a somewhat smaller sample size. An important issue with this report is that subarachnoid hemorrhage was considered as a separate outcome from HS; as discussed in the background of this section, these two diseases may have some amount of overlap and/or misclassification, although no further information was offered. Chui et al. (2022) was conducted in Hong Kong, China, and used geography-wide medical care and immunization databases, a âmodifiedâ self-control design with seasonal adjustment, and a 28-day postimmunization outcomes interval. They found an increased risk of HS associated with BNT162b2 (IRR 1.67, 95% CI: 1.04â2.69). In addition, Ab Rahman et al. (2022) from Malaysia showed a marginally increased risk of HS (IRR 1.29, 95% CI: 1.05â1.59). The remaining studies showed no increased risk, including two analyses that separated the findings into older and younger adults (Botton et al., 2022; Jabagi et al., 2022). mRNA-1273 and HS Table 6-9 summarizes the one study that contributed to the causality assessment. TABLE 6-9 Epidemiological Study in the mRNA-1273âHemorrhagic Stroke Evidence Review Number of Author N Events Results (95% CI) Botton et al. Dose 1: 414 vaccinees Week 1: 12 RI 0.73 (0.39â1.37) (2022) Week 2: 14 RI 0.91 (0.51â1.61) Dose 2: 299 vaccinees Week 1: 10 RI 1.06 (0.56â2.00) Week 2: 4 RI 0.45 (0.16â1.23) NOTES: mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name SpikevaxÂ®. Number of events refers to events in vaccinees only. CI: confidence interval; RI: relative incidence. SOURCE: Botton et al., 2022. Botton et al. (2022) used the French national health system to explore the association between mRNA-1273 and HS. This was a study of HS outcomes after the first dose of the primary series. As in the other applications of this study, only 2 weeks of the postimmunization interval were presented, and the risks for each week were presented separately. This study included adults up to 74, but the number of HS case outcomes in the first 2 weeks was only 26. The portion of the study describing outcomes in persons 75+ showed no findings on mRNA- 1273 and HS (Jabagi et al., 2022), likely because of an inadequate number of case outcomes. PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 179 Ad26.COV2.S and HS Table 6-10 summarizes one study that contributed to the causality assessment. TABLE 6-10 Epidemiological Study in the Ad26.COV2.SâHemorrhagic Stroke Evidence Review Number Author N of Events Results (95% CI) Botton et al. Dose 1: 38 vaccinees Week 1: 6 RI 1.28 (0.46â3.61) (2022) Week 2: 6 RI 1.59 (0.60â4.21) NOTES: Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen. The primary series for Ad26.COV2.S is one dose. Number of events refers to events in vaccinees only. CI: confidence interval; RI: relative incidence. SOURCE: Botton et al., 2022. As with mRNA-1273, only one study evaluated Ad26.COV2.S described for adults aged 18â74 (Botton et al., 2022). The same limitations apply here, and only 12 HS cases occurred in the 2-week postimmunization interval. The outcomes for the older patient set (75+ years) were not available (Jabagi et al., 2022). From Evidence to Conclusions The findings from the studies evaluating BNT162b2 and HS were mixed, with some finding an increased risk. Additionally, evidence of possible disease misclassification of HS with other sources of intracranial hemorrhage could not be resolved, as suggested by the general medical literature. Only two of the five studies showed an increased signal of HS risk, and an additional study showed a marginally increased risk (Ab Rahman et al., 2022; Chui et al., 2022; Patone et al., 2021). Conclusion 6-9: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and hemorrhagic stroke. Only one study evaluated the relationship between mRNA-1273 and HS; it had only 2 weeks of postimmunization follow-up (Botton et al., 2022). Only 26 HS cases occurred in those who received mRNA-1273. Conclusion 6-10: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and hemorrhagic stroke. Only one study evaluated the relationship between Ad26.COV2.S and HS, which showed no evidence of increased risk; it had only 2 weeks of postimmunization follow-up with only 12 cases (Botton et al., 2022). No studies evaluated the association between NVX-CoV2373 and HS. Conclusion 6-11: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and hemorrhagic stroke. PREPUBLICATION COPYâUncorrected Proofs

180 VACCINE EVIDENCE REVIEW Conclusion 6-12: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and hemorrhagic stroke. PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 181 DEEP VEIN THROMBOSIS, PULMONARY EMBOLISM, AND VENOUS THROMBOEMBOLISM BOX 6-4 Conclusions for Deep Vein Thrombosis, Pulmonary Embolism, and Venous Thromboembolism Conclusion 6-13: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and deep vein thrombosis, pulmonary embolism, and venous thromboembolism. Conclusion 6-14: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and deep vein thrombosis, pulmonary embolism, and venous thromboembolism. Conclusion 6-15: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and deep vein thrombosis, pulmonary embolism, and venous thromboembolism. Conclusion 6-16: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and deep vein thrombosis, pulmonary embolism, and venous thromboembolism. Background Deep vein thrombosis (DVT), pulmonary embolism (PE), and venous thromboembolism (VTE) are related conditions, often with common risk factors, clinical manifestations, pathogenetic mechanisms, treatments, and preventive interventions. â VTEâ mostly or entirely may represent a category including PE and DVT. Occurrence rates can depend on the chronicity, comorbidity, and prevalent risk factors. The mortality risk among adults â¥65 with VTE is 3.1 percent at 30 days and 19.6 percent at 1 year (Giorgio et al., 2023). Other vascular and related immunologic outcomes, such as immune thrombotic purpura (ITP) and immune thrombocytopenic purpura (ITP), are considered separately in Chapter 5. The evidence regarding association of each of the three conditions with COVID-19 vaccines will be discussed separately, but conclusions and the relevant justifications appear together at the end of this section. DVT, PE and VTE, in part because of these overlapping characteristics, present a dilemma in research and clinical outcome studies because regional and national variation in diagnostic practices and medical terminology may lead to misclassification, which can be substantial. For example, in an important report cited in this chapter (Shoaibi et al., 2023), a medical chart review of PE from the U.S. Medicare system found that the PPV for accuracy of 101 cases was only 45 percent. Other, similar validation studies show varying results. In a study of over 4,000 VTE cases, also from the United States, Fang et al. (2017) found a PPV of 64.6 percent in patients who were hospitalized or seen in an emergency department but only 30.9 percent for outpatients. In a systematic review of matching medical records to claim codes. On the other hand, Tamariz et al. (2012) found the highest PPV values among ICD-9 codes for combined PE and DVT to range from 65â95 percent accuracy, with the highest among those at PREPUBLICATION COPYâUncorrected Proofs

182 VACCINE EVIDENCE REVIEW greatest risk of VTE. These studies overall found important variation in accuracy according to patient risk, location seen in the health care system, whether the diagnosis was primary or secondary and anatomic site, highlighting factors related to variation accuracy. Pathophysiology The pathophysiology of DVT is often explained by Virchowâs triad: venous stasis, endothelial injury, and hypercoagulability. PE involves not only the mechanical obstruction of the pulmonary artery but also the release of vasoactive substances that cause pulmonary vasoconstriction, leading to an increase in pulmonary vascular resistance and right ventricular strain. Immune responses, particularly those involving inflammatory mediators, can exacerbate this by increasing vascular permeability and promoting further thrombosis. VTE occurs at higher frequency in the context of inflammation, such as during infections, in autoimmune conditions, and postoperatively. In an immune-mediated context, inflammation plays a critical role. Proinflammatory cytokines can alter the coagulation cascade, leading to a prothrombotic state. For instance, elevated levels of IL-6 have been implicated in increased thrombin generation (Tang et al., 2015). COVID-19 vaccines have been shown to increase IL-6 production both in situ (Zhu et al., 2023) and ex vivo (Langgartner et al., 2023). Other ways that the immune system can lead to a hypercoagulable state include monocytes and neutrophil release of tissue factor, a potent activator of the coagulation cascade, and the formation of neutrophil extracellular traps, which can provide a scaffold for thrombus formation. Deep Vein Thrombosis DVT occurs when blood clots develop and persist in a larger vein, such as in the thighs, pelvis, arms, splanchnic vasculature, and cerebrum. Most of these clots, however, form in the legs, with varying signs and symptoms, altered persistence, and uncertain clinical consequences (Mithoowani, 2022). Signs and symptoms may include edema, redness, pain, and disability. The diagnosis can be challenging, made by a combination of clinical signs and symptoms, biomarkers, imaging studies, and physiological measures. DVT may occur acutely or chronically, the latter supporting the importance of having a history of DVT. This is important because prior DVT and its underlying conditions may be central to understanding the pathogenetic underpinnings during acute exposures, such as vaccines. Various studies, some reviewed here, may or may not have included prior comorbidity occurrence in DVT risk models. DVT (and VTE in general) may have different rates across countries and global regions. Epidemiological Evidence BNT162b2 and DVT Table 6-11 lists five studies that contributed to the causality assessment. PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 183 TABLE 6-11 Epidemiological Studies in the BNT162b2âDeep Vein Thrombosis Evidence Review Number of Author N Events Results (95% CI) Barda et al. (2021) Dose 1: 884,828 vaccinees 39 RR 0.87 (0.55â1.40) Burn et al. (2022a) Dose 1: 1.8 million vaccinees 303 SIR 1.00 (0.89â1.12) Dose 2: 1.3 million vaccinees 182 SIR 0.85 (0.74 to 0.99) Burn et al. (2022b) Dose 1: 2.0 million vaccinees 182 SIR 1.03 (0.89â1.19) Dose 2: 1.3 million vaccinees 130 SIR 0.80 (0.67â0.95) Hviid et al. (2022) Dose 1: 101,212 vaccinees 13 RD 2.05 (-2.49â6.59) Whiteley et al. Dose 1: 8.7 million vaccinees 555 Age <70: HR 0.82 (0.71â0.95) (2022) Age <70: HR 0.61 (0.53â0.70) NOTES: Refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name ComirnatyÂ®. Number of events refers to events in vaccinees only. CI: confidence interval; IR: incidence rate; RD: risk difference; RR: rate ratio; SIR: standardized incidence rate. SOURCES: Barda et al., 2021; Burn et al., 2022a, 2022b; Hviid et al., 2022; Whiteley et al., 2022. PREPUBLICATION COPYâUncorrected Proofs

184 VACCINE EVIDENCE REVIEW Five scientific reports from Europe and Israel explored the association of relevant COVID-19 vaccines to DVT. Of the four vaccines that are the focus of the committeeâs review, only BNT162b2 was included in these analyses. The five studies included three cohort designs and one each with a self-controlled design and a matched case-control design. The sample sizes were generally robust, except for the Danish study (Hviid et al., 2022), where these were more modest. This study was also the only one that presented its outcome statistics as risk differences. Whiteley et al. (2022) presented its findings separately for persons under and over 70. Burn et al. (2022a) from the United Kingdom included VTE and DVT outcomes. Hviid et al. (2022) had many fewer cases, and the confidence interval (CI) was wide but not significant in this relative difference analysis. All the studies showed no significantly increased risk. Pulmonary Embolism PE is the obstruction of a pulmonary artery by a physical entity, the embolus, that travels to the heart, lodging in the lungs. This âobstructionâ may often be from blood clots forming elsewhere, usually due to some form of DVT, but in it could be a tumor, air, or fat globule. This could be quite traumatic and acute or chronic, and it may be fatal, depending on the extent and cause of the embolus. According to the American Lung Association, about 900,000 people have a PE each year (ALA, 2023). Because these may be symptomatic or asymptomatic and have varying degrees of clinical severity, difficulties may arise in making a definitive diagnosis. Due to the challenges and variations in PE diagnostic practices and technology and in coding and classification systems, apparent PE rates may vary across populations and countries, and this variation may lead to variations in community and regional study findings and in identifying risk factors and outcomes, as is the case for DVT (see above). As is with DVT, the nomenclature for diagnostic coding varies, leading to some of these thromboembolic events being designated under different rubrics, such as DVT, PE or VTE. This complicates the interpretation of vaccine-related population studies, and only a few of them address these issues in detail or with validation studies. Epidemiological Evidence BNT162b2 and PE Table 6-12 presents eight studies that contributed to the causality assessment. PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 185 TABLE 6-12 Epidemiological Studies in the BNT162b2âPulmonary Embolism Evidence Review Number of Author N Events Results (95% CI) Barda et al. (2021) Dose 1: 884,828 vaccinees 10 RR 0.56 (0.21â1.15) Botton et al. (2022) Dose 1: 7,242 vaccinees Week 1: 203 RI 0.81 (0.70â0.94) Week 2: 200 RI 0.83 (0.71â0.96) Dose 2: 5,665 vaccinees Week 1: 156 RI 0.83 (0.70â0.99) Week 2: 178 RI 1.00 (0.85â1.17) Burn et al. (2022a) Dose 1: 1.8 million vaccinees 324 SIR 1.25 (1.12â1.40) Dose 2: 1.3 million vaccinees 153 SIR 0.84 (0.71â0.98) Burn et al. (2022b) Dose 1: 2.0 million vaccinees 154 SIR 1.25 (1.07â1.46) Dose 2: 1.3 million vaccinees 116 SIR 1.00 (0.84â1.20) Hviid et al. (2022) Dose 1: 101,212 vaccinees 8 RD 1.32 (-2.55â5.19) Jabagi et al. (2022) Dose 1: 3.9 million vaccinees 3,993 RI 0.85 (0.75â0.96) Dose 2: 3.2 million vaccinees 2,889 RI 1.10 (0.95â1.26) Shoaibi et al. (2023) Doses 1 and 2: 1,684 IRR 1.19 (1.03â1.38) 3.4 million vaccinees Whiteley et al. (2022) Dose 1: 8.7 million vaccinees 928 Age <70: HR 0.78 (0.69â0.88) Age >70: HR 0.54 (0.49â0.69) NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name ComirnatyÂ®. Shoaibi et al. (2023) combined the number of BNT162b2 and mRNA-1273 vaccinees. The primary series for BNT162b2 is two doses. Number of events refers to events in vaccinees only. CI: confidence interval; HR: hazard ratio; IR: incidence rate; IRR: incidence rate ratio; RD: risk difference; RI: relative incidence; RR: risk ratio. SOURCES: Barda et al., 2021; Botton et al., 2022; Burn et al., 2022a, 2022b; Hviid et al., 2022; Jabagi et al., 2022; Shoaibi et al., 2023; Whiteley et al., 2022. PREPUBLICATION COPYâUncorrected Proofs

186 VACCINE EVIDENCE REVIEW PE outcomes were explored in nine scientific reports, including eight separate studies and three vaccines (BNT162b2, mRNA-1273, and Ad26.COV2.S). Eight represented findings from the first dose of the primary COVID-19 vaccination series; Shoaibi et al. (2023) reflected the combined effects of doses 1 and 2. The eight studies represented countries in Europe, and one was in the United States. Two studies in three reports presented older and younger vaccines separately (see Table 6-1 for more detail) (Botton et al., 2022; Jabagi et al., 2022; Whiteley et al., 2022). All the outcomes shown were listed only as derived from the outcome rubric âPE.â As described for certain reports, some of the statistical models were adjusted for demographic characteristics, length of postimmunization follow-up interval, prevalent comorbidity at baseline, and other features, such as season. Study designs included self-controls, cohort studies and matched case-control, all noted in Table 6-1. Hviid et al. (2022) from Denmark had the smallest number of follow-up patients. Six reports from five studies showed no evidence of increased risk of PE, but three studies showed increased risk (Burn et al., 2022a, 2022b; Shoaibi et al., 2023). Hviid et al. (2022), despite not showing an increased risk, had a very wide CI of the estimate, likely due to a smaller sample size in the base population and number of cases (RD 1.32, 95% CI: -2.55â5.19). mRNA-1273 and PE Table 6-13 presents two studies that contributed to the causality assessment. TABLE 6-13 Epidemiological Studies in the mRNA-1273âPulmonary Embolism Evidence Review Number Author N of Events Results (95% CI) Botton et al. (2022) Dose 1: 1,003 vaccinees Week 1: 18 RI 0.43 (0.26â0.71) Week 2: 26 RI 0.72 (0.48â1.09) Dose 2: 769 vaccinees Week 1: 36 RI 1.31 (0.90â1.91) Week 2: 23 RI 0.88 (0.56â1.40) Shoaibi et al. (2023) Doses 1 and 2: 786 IRR 1.15 (0.94â1.41) 3.4 million vaccinees NOTES: Shoaibi et al. (2023) combined the number of BNT162b2 and mRNA-1273 vaccinees. The primary series for mRNA-1273 is two doses. Number of events refers to events in vaccinees only. CI: confidence interval, IRR: incidence rate ratio; RI: relative incidence SOURCES: Botton et al., 2022; Shoaibi et al., 2023. The mRNA-1273 association with PE was explored in two reports (Botton et al., 2022; Shoaibi et al., 2023). These studies are summarized in this section and Tables 6-1 and 6-13. The findings from Botton et al. (2022), representing persons 18â74 years of age, showed no increased risk of PE, but only 44 cases were noted. Shoaibi et al. (2023) also showed no increased risk. However, uniquely among all the reports assessed in this chapter, Shoaibi et al. (2023) conducted a medical record review of PE validated against the ICD codes. For the 101 cases identified by code, over half of the diagnoses were inaccurate or could not be determined. This suggests that case misclassification could be an important problem. PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 187 Ad26.COV2.S and PE Table 6-14 summarizes one study that contributed to the causality assessment. TABLE 6-14 Epidemiological Study in the Ad26.COV2.SâPulmonary Embolism Evidence Review Number of Author N Events Results (95% CI) Botton et al. (2022) Dose 1: 77 vaccinees Week 1: 7 RI 0.94 (0.40â2.21) Week 2: 3 RI 0.42 (0.13â1.32) NOTES: Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen. The primary series for Ad26.COV2.S is one dose. Number of events refers to events in vaccinees only. CI: confidence interval; RI: relative incidence. SOURCE: Botton et al., 2022. Only one scientific report related Ad26.COV2.S to PE: Botton et al. (2022), an assessment from the French national health system, covering persons aged 18â74. The findings showed no increased association of this vaccine with PE, but only 10 cases of PE recorded in the 2 postimmunization weeks were available for analysis. Venous Thromboembolism Although VTE is used throughout the literature on vascular and coagulation-related diseases, it appears to be used differently in different literature reports, as noted. For example, it often appears to include both thrombotic conditions (deep and superficial) in various anatomic sites and for embolic phenomena. A few studies have been done on validation of the rubric as used in ICD coding. One study of VTE using ICD-9 coding concluded that it was not an effective code for determining underlying conditions (Fang et al., 2017). Another study of VTE coding in the emergency department setting concluded that the ICD-10 code was only moderately effective in identifying DVT and PE (Al-Ani et al., 2015). Shoaibi et al. (2023) found validation problems with these entities, and this calls into question the potential validity of VTE outcomes in certain population studies that apply institutional coding systems, where validation studies have not been performed. Epidemiological Evidence BNT162b2 and VTE Table 6-15 presents four studies that contributed to the causality assessment. PREPUBLICATION COPYâUncorrected Proofs

188 VACCINE EVIDENCE REVIEW TABLE 6-15 Epidemiological Studies in the BNT162b2âVenous Thromboembolism Evidence Review Number of Author N Events Results (95% CI) Ab Rahman et al. Dose 1: 103 IRR 1.34 (1.07â1.26) (2022) 8.7 million vaccinees Dose 2: 63 IRR 1.09 (0.83â1.44) 6.7 million vaccinees Burn et al. (2022a) Dose 1: 595 SIR 1.12 (1.03â1.21) 1.8 million vaccinees Dose 2: 324 SIR 0.86 (0.77â0.96) 1.3 million vaccinees Burn et al. (2022b) Dose 1: 313 SIR 1.18 (1.06â1.32) 2.0 million vaccinees Dose 2: 227 SIR 0.92 (0.81â1.05) 1.3 million vaccinees Hippisley-Cox et Dose 1: Total: 2,054 Days 8â14: al. (2021) 9.5 million vaccinees Days 8â14: 555 IRR 0.99 (0.90â1.08) NOTES: Refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name ComirnatyÂ®. Number of events refers to events in vaccinees only. CI: confidence interval; IRR: incidence rate ratio; SIR: standardized incidence ratio. SOURCES: Ab Rahman et al., 2022; Burn et al., 2022a, 2022b; Hippisley-Cox et al., 2021. Despite issues of outcome identification and the possibility of case misclassification, the committee assessed the three studies that used the VTE outcome rubric. The four reports presented VTE outcomes, available for BNT162b2 only. Hippisley-Cox et al. (2021) presented VTE outcomes for four separate 1-week postimmunization outcomes, without any further summarization; the week with the highest risk outcome (days 8â14) is included in Table 6-15. Burn et al. (2022a, 2022b) showed a very slight increased risk after dose 1. Given the limitations noted, three of the four studies showed an increased risk of VTE associated with this vaccine, albeit modest increases. From Evidence to Conclusions Five population studies from Europe and Israel evaluated the association between BNT162b2 and the risk of DVT. None showed any significant increased risk. However, Hviid et al. (2022) had a much smaller number of patient outcomes and a wide CI. The dilemma for these five studies is that some had other clinical rubrics or outcome categories denoting coagulation disorders or âVTE.â This and the general problem of uncertainty in disease classification raised the issue that some of these patients may not have had DVT, leading to some possible loss of sample size and disease misclassification. Eight reports from seven studies addressed the association between BNT162b2 and risk of PE (Barda et al., 2021; Botton et al., 2022; Burn et al., 2022a, 2022b; Hviid et al., 2022; Jabagi et al., 2022; Shoaibi et al., 2023; Whiteley et al., 2022). All studies were informative for the committeeâs analysis, but they varied to some extent in epidemiological design. All but one study had suitably robust sample sizes. Some concern arose based on a validation study whether PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 189 all diagnoses of PE could be confirmed on further review. Four studies showed no evidence of increased risk of PE, but three found a statistically significant increased risk. The number of studies addressing VTE was limited (four) and addressed only BNT126b2, three pointed in the direction of increased risk, albeit modest (Ab Rahman et al., 2022; Burn et al., 2022a, 2022b; Hippisley-Cox et al., 2021). A composite outcome, VTE could have been analyzed in the other studies that reported only PE and DVT as the outcomes, so the results might be at greater risk of reporting bias compared with other outcomes. The remaining issue is potential validation problems for VTE, and its constituent DVT and PE diagnoses, based on some of the quality assessment literature consulted. Conclusion 6-13: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and deep vein thrombosis, pulmonary embolism, and venous thromboembolism. No studies evaluated the relationship between mRNA-1273 and DVT or VTE. Only two studies provided evidence for PE outcomes (Botton et al., 2022; Shoaibi et al., 2023); both showed no evidence of increased risk. The sample sizes were generally more modest than with BNT162b2. The results are complicated by the problem noted with diagnostic validation. Conclusion 6-14: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and deep vein thrombosis, pulmonary embolism, and venous thromboembolism. Only one study was available to assess the evidence between Ad26.COV2.S and PE (Botton et al., 2022). The number of cases was very small in the 2-week postimmunization follow-up period, although no increased risk was found. The committee notes the case validation issue. No studies evaluated the relationship between NVX-CoV2373 and DVT, PE, or VTE. Conclusion 6-15: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and deep vein thrombosis, pulmonary embolism, and venous thromboembolism. Conclusion 6-16: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and deep vein thrombosis, pulmonary embolism, and venous thromboembolism. PREPUBLICATION COPYâUncorrected Proofs

190 VACCINE EVIDENCE REVIEW REFERENCES Ab Rahman, N., M. T. Lim, F. Y. Lee, S. C. Lee, A. Ramli, S. N. Saharudin, T. L. King, E. B. Anak Jam, N. A. Ayub, R. K. Sevalingam, R. Bahari, N. N. Ibrahim, F. Mahmud, S. Sivasampu, and K. M. Peariasamy. 2022. Risk of serious adverse events after the BNT162b2, CoronaVac, and ChAdOx1 vaccines in Malaysia: A self-controlled case series study. Vaccine 40(32):4394â4402. https://doi.org/10.1016/j.vaccine.2022.05.075. ALA (American Lung Association). 2023. Learn about pulmonary embolism. https://www.lung.org/lung- health-diseases/lung-disease-lookup/pulmonary-embolism/learn-about-pulmonary-embolism (accessed December 12, 2023). Al-Ani, F., S. Shariff, L. Siqueira, A. Seyam, and A. Lazo-Langner. 2015. Identifying venous thromboembolism and major bleeding in emergency room discharges using administrative data. Thrombosis Research 136(6):1195â1198. https://doi.org/10.1016/j.thromres.2015.10.035. Assiri, S. A., R. M. M. Althaqafi, K. Alswat, A. A. Alghamdi, N. E. Alomairi, D. M. Nemenqani, Z. S. Ibrahim, and A. Elkady. 2022. Post COVID-19 vaccination-associated neurological complications. Neuropsychiatric Disease and Treatment 18:137â154. https://doi.org/10.2147/ndt.S343438. Barda, N., N. Dagan, Y. Ben-Shlomo, E. Kepten, J. Waxman, R. Ohana, M. A. HernÃ¡n, M. Lipsitch, I. Kohane, D. Netzer, B. Y. Reis, and R. D. Balicer. 2021. Safety of the BNT162b2 mRNA COVID-19 vaccine in a nationwide setting. New England Journal of Medicine 385(12):1078â 1090. https://doi.org/10.1056/NEJMoa2110475. Bonaventura, A., A. VecchiÃ©, L. Dagna, K. Martinod, D. L. Dixon, B. W. Van Tassell, F. Dentali, F. Montecucco, S. Massberg, M. Levi, and A. Abbate. 2021. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nature Reviews: Immunology 21(5):319â329. https://doi.org/10.1038/s41577-021-00536-9. Botton, J., M. J. Jabagi, M. Bertrand, B. Baricault, J. Drouin, S. Le Vu, A. Weill, P. Farrington, M. Zureik, and R. Dray-Spira. 2022. Risk for myocardial infarction, stroke, and pulmonary embolism following COVID-19 vaccines in adults younger than 75 years in France. Annals of Internal Medicine 175(9):1250â1257. https://doi.org/10.7326/m22-0988. Burn, E., X. Li, A. Delmestri, N. Jones, T. Duarte-Salles, C. Reyes, E. Martinez-Hernandez, E. Marti, K. M. C. Verhamme, P. R. Rijnbeek, V. Y. Strauss, and D. Prieto-Alhambra. 2022a. Thrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2 in the United Kingdom. Nature Communications 13(1):7167. https://doi.org/10.1038/s41467-022-34668-w. Burn, E., E. Roel, A. Pistillo, S. FernÃ¡ndez-BertolÃn, M. AragÃ³n, B. RaventÃ³s, C. Reyes, K. Verhamme, P. Rijnbeek, X. Li, V. Y. Strauss, D. Prieto-Alhambra, and T. Duarte-Salles. 2022b. Thrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2 in Catalonia, Spain. Nature Communications 13(1):7169. https://doi.org/10.1038/s41467-022-34669-9. Caplan, L. R. 2023. Patient education: Hemorrhagic stroke treatment (beyond the basics). https://www.uptodate.com/contents/hemorrhagic-stroke-treatment-beyond-the-basics (accessed November 6, 2023). Chamorro, A., A. Meisel, A. M. Planas, X. Urra, D. van de Beek, and R. Veltkamp. 2012. The immunology of acute stroke. Nature Reviews: Neurology 8(7):401â410. https://doi.org/10.1038/nrneurol.2012.98. Chui, C. S. L., M. Fan, E. Y. F. Wan, M. T. Y. Leung, E. Cheung, V. K. C. Yan, L. Gao, Y. Ghebremichael-Weldeselassie, K. K. C. Man, K. K. Lau, I. C. H. Lam, F. T. T. Lai, X. Li, C. K. H. Wong, E. W. Chan, C. L. Cheung, C. W. Sing, C. K. Lee, I. F. N. Hung, C. S. Lau, J. Y. S. Chan, M. K. Lee, V. C. T. Mok, C. W. Siu, L. S. T. Chan, T. Cheung, F. L. F. Chan, A. Y. Leung, B. J. Cowling, G. M. Leung, and I. C. K. Wong. 2022. Thromboembolic events and hemorrhagic stroke after mRNA (BNT162b2) and inactivated (CoronaVac) COVID-19 vaccination: A self- PREPUBLICATION COPYâUncorrected Proofs

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192 VACCINE EVIDENCE REVIEW Risk of thrombocytopenia and thromboembolism after COVID-19 vaccination and SARS-CoV-2 positive testing: Self-controlled case series study. British Journal of Medicine 374:n1931. https://doi.org/10.1136/bmj.n1931. Hviid, A., J. V. Hansen, E. M. Thiesson, and J. Wohlfahrt. 2022. Association of AZD1222 and BNT162b2 COVID-19 vaccination with thromboembolic and thrombocytopenic events in frontline personnel: A retrospective cohort study. Annals of Internal Medicine 175(4):541â546. https://doi.org/10.7326/m21-2452. Jabagi, M. J., J. Botton, M. Bertrand, A. Weill, P. Farrington, M. Zureik, and R. Dray-Spira. 2022. Myocardial infarction, stroke, and pulmonary embolism after BNT162b2 mRNA COVID-19 vaccine in people aged 75 years or older. JAMA 327(1):80â82. https://doi.org/10.1001/jama.2021.21699. Kirkman, M. A., W. Mahattanakul, B. A. Gregson, and A. D. Mendelow. 2009. The accuracy of hospital discharge coding for hemorrhagic stroke. Acta Neurologica Belgica 109(2):114â119. Langgartner, D., R. Winkler, J. Brunner-Weisser, N. Rohleder, M. N. Jarczok, H. GÃ¼ndel, K. Weimer, and S. O. Reber. 2023. COVID-19 vaccination exacerbates ex vivo IL-6 release from isolated PBMCS. Scientific Reports 13(1):9496. https://doi.org/10.1038/s41598-023-35731-2. Li, X., and G. Chen. 2023. CNS-peripheral immune interactions in hemorrhagic stroke. Journal of Cerebral Blood Flow and Metabolism 43(2):185â197. https://doi.org/10.1177/0271678x221145089. McCormick, N., V. Bhole, D. Lacaille, and J. A. Avina-Zubieta. 2015. Validity of diagnostic codes for acute stroke in administrative databases: A systematic review. PLoS One 10(8):e0135834. https://doi.org/10.1371/journal.pone.0135834. Mithoowani, S. 2022. Deep vein thrombosis (DVT) (beyond the basics). www.uptodate.com/contents/deep-vein-thrombosis-dvt-beyond-the-basics (accessed November 16, 2023). Montano, A., D. F. Hanley, and J. C. Hemphill, III. 2021. Hemorrhagic stroke. Handbook of Clinical Neurology 176:229â248. https://doi.org/10.1016/B978-0-444-64034-5.00019-5. Nakamura, K., and T. Shichita. 2019. Cellular and molecular mechanisms of sterile inflammation in ischaemic stroke. Journal of Biochemistry 165(6):459â464. https://doi.org/10.1093/jb/mvz017. Neves, G., P. I. Warman, A. Warman, R. Warman, T. Bueso, J. D. Vadhan, and T. Windisch. 2023. External validation of an artificial intelligence device for intracranial hemorrhage detection. World Neurosurgery 173:e800âe807. https://doi.org/10.1016/j.wneu.2023.03.019. NHLBI (National Heart, Lung, and Blood Institute). 2023. What is a stroke? https://www.nhlbi.nih.gov/health/stroke (accessed November 16, 2023). Patone, M., L. Handunnetthi, D. Saatci, J. Pan, S. V. Katikireddi, S. Razvi, D. Hunt, X. W. Mei, S. Dixon, F. Zaccardi, K. Khunti, P. Watkinson, C. A. C. Coupland, J. Doidge, D. A. Harrison, R. Ravanan, A. Sheikh, C. Robertson, and J. Hippisley-Cox. 2021. Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection. Nature Medicine 27(12):2144â2153. https://doi.org/10.1038/s41591-021-01556-7. Prabhu, S. D., and N. G. Frangogiannis. 2016. The biological basis for cardiac repair after myocardial infarction: From inflammation to fibrosis. Circulation Research 119(1):91â112. https://doi.org/10.1161/CIRCRESAHA.116.303577. Robinson, K., J. M. Katzenellenbogen, T. J. Kleinig, J. Kim, C. A. Budgeon, A. G. Thrift, and L. Nedkoff. 2023. Large burden of stroke incidence in people with cardiac disease: A linked data cohort study. Clinical Epidemiology 15:203â211. https://doi.org/10.2147/CLEP.S390146. Salari, N., F. Morddarvanjoghi, A. Abdolmaleki, S. Rasoulpoor, A. A. Khaleghi, L. A. Hezarkhani, S. Shohaimi, and M. Mohammadi. 2023. The global prevalence of myocardial infarction: A systematic review and meta-analysis. BMC Cardiovascular Disorders 23(1):206. https://doi.org/10.1186/s12872-023-03231-w. PREPUBLICATION COPYâUncorrected Proofs

VASCULAR CONDITIONS 193 Serrone, J. C., H. Maekawa, M. Tjahjadi, and J. Hernesniemi. 2015. Aneurysmal subarachnoid hemorrhage: Pathobiology, current treatment and future directions. Expert Review of Neurotherapeutics 15(4):367â380. https://doi.org/10.1586/14737175.2015.1018892. Shoaibi, A., P. C. Lloyd, H. L. Wong, T. C. Clarke, Y. Chillarige, R. Do, M. Hu, Y. Jiao, A. Kwist, A. Lindaas, K. Matuska, R. McEvoy, M. Ondari, S. Parulekar, X. Shi, J. Wang, Y. Lu, J. Obidi, C. K. Zhou, J. A. Kelman, R. A. Forshee, and S. A. Anderson. 2023. Evaluation of potential adverse events following COVID-19 mRNA vaccination among adults aged 65 years and older: Two self- controlled studies in the U.S. Vaccine 41(32):4666â4678. https://doi.org/10.1016/j.vaccine.2023.06.014. Siddiqi, H. K., P. Libby, and P. M. Ridker. 2021. COVID-19 - a vascular disease. Trends in Cardiovascular Medicine 31(1):1â5. https://doi.org/10.1016/j.tcm.2020.10.005. Smith, S. D., and C. J. Eskey. 2011. Hemorrhagic stroke. Radiologic Clinics of North America 49(1):27â 45. https://doi.org/10.1016/j.rcl.2010.07.011. Tamariz, L., T. Harkins, and V. Nair. 2012. A systematic review of validated methods for identifying venous thromboembolism using administrative and claims data. Pharmacoepidemiology and Drug Safety 21(Suppl 1):154â162. https://doi.org/10.1002/pds.2341. Tang, Y. H., S. Vital, J. Russell, H. Seifert, and D. N. Granger. 2015. Interleukin-6 mediates enhanced thrombus development in cerebral arterioles following a brief period of focal brain ischemia. Experimental Neurology 271:351â357. https://doi.org/10.1016/j.expneurol.2015.06.004. Thygesen, K., J. S. Alpert, A. S. Jaffe, B. R. Chaitman, J. J. Bax, D. A. Morrow, and H. D. White. 2018. Fourth universal definition of myocardial infarction (2018). Journal of the American College of Cardiology 72(18):2231â2264. https://doi.org/doi:10.1016/j.jacc.2018.08.1038. Vymazal, J., A. M. Rulseh, J. Keller, and L. Janouskova. 2012. Comparison of CT and MR imaging in ischemic stroke. Insights Imaging 3(6):619â627. https://doi.org/10.1007/s13244-012-0185-9. Wang, H., X. Tang, H. Fan, Y. Luo, Y. Song, Y. Xu, and Y. Chen. 2020. Potential mechanisms of hemorrhagic stroke in elderly COVID-19 patients. Aging 12(11):10022â10034. https://doi.org/10.18632/aging.103335. Whiteley, W. N., S. Ip, J. A. Cooper, T. Bolton, S. Keene, V. Walker, R. Denholm, A. Akbari, E. Omigie, S. Hollings, E. Di Angelantonio, S. Denaxas, A. Wood, J. A. C. Sterne, and C. Sudlow. 2022. Association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, or thrombocytopenic events: A population-based cohort study of 46 million adults in England. PLoS Medicine 19(2):e1003926. https://doi.org/10.1371/journal.pmed.1003926. Zafar, U., H. Zafar, M. S. Ahmed, and M. Khattak. 2022. Link between COVID-19 vaccines and myocardial infarction. World Journal of Clinical Cases 10(28):10109â10119. https://doi.org/10.12998/wjcc.v10.i28.10109. Zhu, X., K. A. Gebo, A. G. Abraham, F. Habtehyimer, E. U. Patel, O. Laeyendecker, T. J. Gniadek, R. E. Fernandez, O. R. Baker, M. Ram, E. R. Cachay, J. S. Currier, Y. Fukuta, J. M. Gerber, S. L. Heath, B. Meisenberg, M. A. Huaman, A. C. Levine, A. Shenoy, S. Anjan, J. E. Blair, D. Cruser, D. N. Forthal, L. L. Hammitt, S. Kassaye, G. S. Mosnaim, B. Patel, J. H. Paxton, J. S. Raval, C. G. Sutcliffe, M. Abinante, P. Broderick, V. Cluzet, M. E. Cordisco, B. Greenblatt, J. Petrini, W. Rausch, D. Shade, K. Lane, A. L. Gawad, S. L. Klein, A. Pekosz, S. Shoham, A. Casadevall, E. M. Bloch, D. Hanley, D. J. Sullivan, and A. A. R. Tobian. 2023. Dynamics of inflammatory responses after SARS-CoV-2 infection by vaccination status in the USA: A prospective cohort study. The Lancet Microbe 4(9):e692âe703. https://doi.org/https://doi.org/10.1016/S2666- 5247(23)00171-4. PREPUBLICATION COPYâUncorrected Proofs

PREPUBLICATION COPYâUncorrected Proofs

Vaccines are a public health success story, as they have prevented or lessened the effects of many infectious diseases. To address concerns around potential vaccine injuries, the Health Resources and Services Administration (HRSA) administers the Vaccine Injury Compensation Program (VICP) and the Countermeasures Injury Compensation Program (CICP), which provide compensation to those who assert that they were injured by routine vaccines or medical countermeasures, respectively. The National Academies of Sciences, Engineering, and Medicine have contributed to the scientific basis for VICP compensation decisions for decades.

HRSA asked the National Academies to convene an expert committee to review the epidemiological, clinical, and biological evidence about the relationship between COVID-19 vaccines and specific adverse events, as well as intramuscular administration of vaccines and shoulder injuries. This report outlines the committee findings and conclusions.

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Pulmonary CT imaging findings in fat embolism syndrome: case series and literature review

Affiliations.

1 West China Hospital, Sichuan University, Chengdu, China.
2 West China Hospital, Sichuan University, Chengdu, China. Electronic address: [email protected].
PMID: 38614505
DOI: 10.7861/clinmed.2022-0428

Background: Fat embolism syndrome (FES) is a rare life-threatening complication, which commonly affects the lung. Currently, the most widely accepted criteria for the diagnosis of FES are the Gurd and Wilson Criteria established nearly 40 years ago, but without pulmonary images involved. Our study aims to analyse the pulmonary computed tomography (CT) findings seen in FES.

Case presentation: This report enrolled four cases of FES with lung involvement. The mainly symptoms and signs included dyspnea, disturbance of consciousness, anemia, thrombocytopenia and, most notably, ground-glass opacities, septal thickening, ill-defined centrilobular nodules, and patchy consolidation were demonstrated on bilateral lungs. Combining the clinical manifestations and laboratory tests, the diagnosis of FES was confirmed. With the treatment of steroids, anti-coagulation and supportive treatment, the four patients' symptoms were relieved, abnormalities in chest CT were absorbed significantly and the patients were finally discharged.

Conclusions: There are several common manifestations of FES in pulmonary CT images, and the lung parenchymal features give more information for the diagnosis of FES than the pulmonary vessel findings. Given the absence of a gold standard diagnostic test for FES, further investigation to explore new diagnostic criteria of FES involving pulmonary radiological features is needed in the future.

Keywords: Fat embolism syndrome; case report; chest computed tomography; pulmonary imaging.

Publication types

Case Reports
Consciousness
Dyspnea / etiology
Embolism, Fat* / diagnostic imaging
Embolism, Fat* / etiology
Patient Discharge
Tomography, X-Ray Computed*

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Pulmonary Embolism Case Study

Pulmonary Embolism

Liney Cintron
Jarrod Kissling
Megan Sheppard
Tanija Smoot

Our rationale for choosing this condition:

As acute-care nurses, we are accustomed to taking care of patients with a diagnosis of a pulmonary embolism. Pulmonary embolism affects thousands of people per year. Because of its vague symptoms, pulmonary embolisms can mask as other diseases such as pneumonia, myocardial infarction, pneumothorax, and acute CHF exacerbations. We chose to study this condition because we feel that pulmonary embolisms are an important topic to discuss as symptoms can be sudden and the formation of many DVTs can be prevented.

4 thoughts on “ Pulmonary Embolism Case Study ”

Very good explanation. It is precise & easy to understand. Thank You.

i need your case

i like your case report

DR.OMAR KHATTB: IT IS INFORMATIVE AND COMPREHENSIVE THANK YOU.

Residual Pulmonary Vascular Obstruction Index Computed With Ventilation/Perfusion SPECT/CT Imaging to Predict the Risk of Venous Thromboembolism Recurrence in Patients With Pulmonary Embolism (PRONOSPECT) (PRONOSPECT)

Study Details
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No Results Posted

Major risk after pulmonary embolism (PE) is recurrence, fatal in 10% of patients. Patients with PE can be stratified in 3 groups according to the risk of recurrence : very low risk, high risk or Intermediate risk. Little is known about this last group.

Anticoagulation is efficient to prevent recurrence but is currently not recommended for patient with an intermediate risk of recurrence.

Identifying risk factors of recurrent PE remains a major issue to identify sub-groups of patients who would require lifelong anticoagulation.

In 30-40% of cases, PE patients develop residual pulmonary vascular obstruction (RPVO), which has been found to be associated with an increased recurrence risk. This last observation was mostly reported in patients with unprovoked PE (patients with high risk of recurrence) and RPVO was measured using conventional planar lung scan.

In patients with an intermediate risk of recurrence, the impact of RPVO has been much less studied. In addition, the definition of RPVO was variable according to studies and correlation between RPVO burden and recurrence risk has not been clearly demonstrated. This might be explained by the inherent limitation of RPVO quantification using conventional planar imaging, which is only based on a visual estimation on 2-dimensional images.

Ventilation/Perfusion Single Photon Emission Computed Tomography (V/Q SPECT/CT) is a new method of scintigraphic image acquisition that offers the advantage of 3-dimensional imaging, enabling more accurate and reproducible quantification of RPVO.

The main hypothesis of this study is that in patients with PE at intermediate risk of recurrence, RPVO computed with V/Q SPECT/CT imaging may be an important predictor of recurrence.

In case of a suspected VTE or death during follow-up, the study personnel will collect related clinical data on the electronic case report form, and prepare an adjudication file, including symptoms, clinical notes, hospital discharge summary, and results of all diagnostic tests. All suspicion of VTE recurrence will be adjudicated blindly by an independent central Clinical Events Committee.

To assess the primary objective, RPVO will be defined by a perfusion mismatched defect of at least 5% of the whole lung, corresponding to a segmental defect. SPECT imaging should not be used at inclusion and should not result in proposing prolonged anticoagulation. SPECT images will be numerically stored and interpretation will be later performed independently by two nuclear medicine physicians who will be blinded to clinical history and the patient's outcome. Any difference in interpretation will be resolved by consensus.

PADIS-PE (score derived from the PADIS study : Prolonged Anticoagulation During eighteen months versus placebo after Initial Six-month treatment for a first episode of idiopathic Pulmonary Embolism randomized trial).

A higher score indicates a higher risk of recidive.

Inclusion Criteria:

Patients ≥ 18 years,
who experienced an objectively proven PE,
who have been treated initially with anticoagulant therapy for 3 to 6 uninterrupted months (180 - 210 days) and for whom anticoagulation will not be prolonged.

Exclusion Criteria:

Unwilling or unable to give written informed consent (protected adults, under tutorship or curatorship)
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Published: 18 April 2024

Potential application of mesenchymal stromal cells as a new therapeutic approach in acute respiratory distress syndrome and pulmonary fibrosis

Giulia Gazzaniga 1 , 2 , 3 ,
Marta Voltini 1 , 2 ,
Alessandro Carletti 4 ,
Elisa Lenta 5 ,
Federica Meloni 6 , 7 ,
Domenica Federica Briganti 6 , 7 ,
Maria Antonietta Avanzini 5 , 8 ,
Patrizia Comoli 5 , 8 na1 &
Mirko Belliato 1 na1

Respiratory Research volume 25 , Article number: 170 ( 2024 ) Cite this article

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While the COVID-19 outbreak and its complications are still under investigation, post-inflammatory pulmonary fibrosis (PF) has already been described as a long-term sequela of acute respiratory distress syndrome (ARDS) secondary to SARS-CoV2 infection. However, therapeutical strategies for patients with ARDS and PF are still limited and do not significantly extend lifespan. So far, lung transplantation remains the only definitive treatment for end-stage PF. Over the last years, numerous preclinical and clinical studies have shown that allogeneic mesenchymal stromal cells (MSCs) might represent a promising therapeutical approach in several lung disorders, and their potential for ARDS treatment and PF prevention has been investigated during the COVID-19 pandemic. From April 2020 to April 2022, we treated six adult patients with moderate COVID-19-related ARDS in a late proliferative stage with up to two same-dose infusions of third-party allogeneic bone marrow-derived MSCs (BM-MSCs), administered intravenously 15 days apart. No major adverse events were registered. Four patients completed the treatment and reached ICU discharge, while two received only one dose of MSCs due to multiorgan dysfunction syndrome (MODS) and subsequent death. All four survivors showed improved gas exchanges (PaO2/FiO2 ratio > 200), contrary to the others. Furthermore, LDH trends after MSCs significantly differed between survivors and the deceased. Although further investigations and shared protocols are still needed, the safety of MSC therapy has been recurrently shown, and its potential in treating ARDS and preventing PF might represent a new therapeutic strategy.

To the Editor

Pulmonary fibrosis (PF) is a relatively rare but severe condition characterized by reduced lung compliance and function. Despite having a multifactorial etiology, post-inflammatory PF can be the consequence of severe pulmonary infection and acute respiratory distress syndrome (ARDS). While the COVID-19 outbreak and its complications are still under investigation, ARDS-related PF has already been described as a long-term sequela. However, pharmacologic therapy has been largely ineffective for patients with ARDS, and management mainly focuses on supportive care measures. Likewise, PF has limited treatment options, as currently approved therapies do not significantly extend lifespan. So far, lung transplantation remains the only definitive treatment for end-stage PF, though this option is not always available and is associated with peri-operative high morbidity and mortality and poor long-term survival.

Over the last few years, numerous preclinical and clinical studies have shown that advanced therapy medicinal products (ATMP) based on allogeneic mesenchymal stromal cells (MSCs) might represent a promising therapeutical approach in several lung disorders [ 1 , 2 , 3 ]. Several data have described the potential of MSCs and their ability to migrate to a site of injury and guide tissue regeneration. Moreover, when intravenously administered, 50–80% of MSCs tend to localize in the lungs with a first-pass effect [ 4 ]. Furthermore, since MSCs do not express the two primary human receptors for host-pathogen interaction in SARS-CoV-2 infection [ 5 ], their potential for ARDS treatment and PF prevention has been exploited during the COVID-19 pandemic.

From April 2020 to April 2022, we treated six adult patients in mechanical ventilation for moderate COVID-19-related ARDS (median PaO 2 /FiO 2 ratio 130, median Crs 26.5 cmH 2 O) in a late proliferative stage with third-party allogeneic bone marrow-derived MSCs (BM-MSCs) on a compassionate use basis [ 6 ]. The work was approved by the local Ethics Committee, and conducted in accordance with the Declaration of Helsinki.

The patients (1 female and 5 males) had a median age of 65 years (44–76 year) and a median body mass index (BMI) of 27.8 [(25.8–33.9) IQR 3.03] and received up to two same-dose infusions (1 × 10 6 /kg body weight) of BM-MSCs, administered intravenously 15 days apart. They were then monitored and considered for subsequent monthly BM-MSC infusions if signs of PF were observed. All subjects had already been treated with pronation cycles, myorelaxants, dexamethasone, and antibiotics according to international and national guidelines. Moreover, four patients had also received hyperimmune plasma for COVID-19 before BM-MSC’s first infusion (median 15 days). The cohort’s demographic and clinical characteristics are described in Table 1 .

Four patients completed the treatment, while the remaining two received only one dose of MSCs due to a rapid deterioration in their clinical conditions and exitus after the onset of septic shock and multiorgan dysfunction syndrome (MODS). However, the other four patients were successfully discharged from the Intensive Care Unit (ICU) and are still alive at 1-year follow-up. In this regard, several studies have widely discussed mortality as a primary outcome after MSC therapy, but consistent results still need to be provided. However, a decreased length of hospital stay might be a better indicator of efficacy since it entails improved clinical conditions and reduced mortality [ 7 , 8 ].

Regarding clinical outcomes, all patients showed improved gas exchange after the first dose of MSCs (Fig. 1 ), but that was insufficient to hinder the disease progression in those with severe ARDS (P3 and P6). Nevertheless, the other individuals showed an increase in PaO 2 /FiO 2 ratio > 200 either after the first (P1 and P4) or the second (P2 and P5) MSC infusion, thus evolving in mild ARDS. However, clear radiological signs of improvement were not detected after the last administration, though survivors showed moderate resolution of bilateral parenchymal damage or lack of deterioration, as reported in the literature [ 9 ]. Still, notable lung structure changes may take some time after MSC treatment. Finally, no patients required further monthly BM-MSC infusions.

Trends of PaO 2 /FiO 2 ratio of each patient at the time of enrollment (T0), within 24 h after the infusion of the first (T1) and second (T2) dose of BM-MSCs, administrated 15 days apart PaO 2 partial pressure (arterial) of oxygen; FiO 2 fraction of inspired oxygen

From the laboratory’s perspective, we observed an improvement in lymphocyte numbers in survivors, while patients who died still displayed lower levels after the last dose [ 10 ] (Fig. 2 ). Furthermore, lactate dehydrogenase (LDH) trends after MSCs differed between survivors and the deceased (Fig. 3 ). High LDH blood levels are a biomarker commonly associated with higher mortality and poor prognosis in several conditions, including ARDS [ 11 ]. Recent studies on COVID-19 patients documented a correlation between high levels of LDH and the severity of the disease and intra-hospital mortality [ 12 ]. Regarding inflammation markers, C-reactive protein (CRP) trends declined in all cases except one (P3) but did not show any substantial correlation with outcomes (Fig. 4 ). However, in the literature, the association of this parameter with MSC treatment is controversial since some studies reported no differences in CRP trends between cases and controls, while others documented inferior blood values in MSC recipients [ 13 ]. Moreover, some authors have suggested that steroids and hyperimmune plasma may mitigate the anti-inflammatory effect of MCSs [ 14 ]. Furthermore, despite initially not being considered subject to rejection, recent studies have indicated that MSCs may be influenced by the host’s immune response, particularly in the inflammatory milieu and hypoxia [ 15 ].

Trends of lymphocytes’ levels of each patient at the time of enrollment (T0), within 24 h after the infusion of the first (T1) and second (T2) dose of BM-MSCs, administrated 15 days apart

Trends of lactate dehydrogenase (LDH) levels of each patient at the time of enrollment (T0), within 24 h after the infusion of the first (T1) and second (T2) dose of BM-MSCs, administrated 15 days apart

Trends of C-reactive protein (CRP) levels of each patient at the time of enrollment (T0), within 24 h after the infusion of the first (T1) and second (T2) dose of BM-MSCs, administrated 15 days apart

The literature has extensively documented the pleiotropic anti-inflammatory and regenerative effects of MSCs, and this ATMP likely plays a significant role in ameliorating COVID-19 through immunomodulation. However, it is essential to mention that MSCs may have modest constitutive immune-modulating properties. Some studies have described the potential discrepancies in MSC phenotype induction when exposed to the host’s pro-inflammatory mediator [ 16 ]. In patients with severe or critical COVID-19, high levels of pro-inflammatory cytokines during MSC treatment may induce a stronger phenotype, even without prior ex vivo priming, while in patients with mild or moderate COVID-19, the immune modulatory phenotype may be less effective. Moreover, age-related quantitative and qualitative changes in the immune system may affect the host’s immune response to MSC treatment [ 17 ]. Furthermore, the interaction between allogenic and resident MSCs is still under investigation [ 18 ].

Finally, no major adverse events were registered after BM-MSC administration, including venous thromboembolism (VTE) or pulmonary embolism (PE). The safety of MSC therapy in COVID-19 patients has already been documented in the literature. A recent randomized study of BM-MSCs versus placebo in early-onset COVID-19-related ARDS reported the absence of infusion-related toxicities and similar serious adverse events over 30 days between the enrolled groups [ 19 ]. Data from systematic reviews also described the lack of significant adverse effects after MSC therapy [ 13 ] or reported mild adverse events that resolved spontaneously or with minimal supportive treatment in all patients [ 14 ].

Although the results of MSC treatment in ARDS and PF are encouraging, additional information from controlled studies should be obtained regarding MSCs source, administration schedule, and dose to design a shared clinical protocol for BM-MSC therapy in early chronic lung injury and prevention of PF secondary to post-infective ARDS. Moreover, a deeper understanding of the interactions between infused third-party allogeneic MSCs and lung-resident cellular populations, including resident MSCs, macrophages, and lymphocytes, might offer valuable insight into the pathogenesis of PF and provide novel therapeutic tools [ 18 , 20 , 21 ]. In conclusion, the dual nature of MSCs in developing and treating post-inflammatory fibrotic diseases represents an inviting challenge for research and might have pivotal applications in clinical settings.

Data availability

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

acute respiratory distress syndrome

advanced therapy medicinal products

body mass index

bone marrow-derived MSCs

coronavirus disease 19

C-reactive protein

intensive care unit

lactate dehydrogenase

mesenchymal stromal cells

multiorgan dysfunction syndrome

pulmonary fibrosis

pulmonary embolism

severe acute respiratory syndrome coronavirus 2

venous thromboembolism

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Acknowledgements

Not applicable.

The study was funded by the Italian Ministry of Health (RC 8073221).

Author information

Patrizia Comoli and Mirko Belliato share senior authorship.

Authors and Affiliations

SC Anestesia e Rianimazione 2, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi 19, Pavia, PV, 27100, Italy

Giulia Gazzaniga, Marta Voltini & Mirko Belliato

Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy

Giulia Gazzaniga & Marta Voltini

Cardio-Thoracic Surgery Department, Heart & Vascular Centre, Maastricht University Medical Centre (MUMC+), P. Debyelaan 25, Maastricht, 6229 HX, The Netherlands

Giulia Gazzaniga

SC Anestesia e Rianimazione 3 – TIPO, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

Alessandro Carletti

SSD Cell Factory and Center for Advanced Therapies, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

Elisa Lenta, Maria Antonietta Avanzini & Patrizia Comoli

UOS Transplant Center, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

Federica Meloni & Domenica Federica Briganti

Department of Internal Medicine, University of Pavia, Pavia, Italy

Pediatric Hematology/Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

Maria Antonietta Avanzini & Patrizia Comoli

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Contributions

Gazzaniga G contributed to this work through analysis and interpretation of data and manuscript writing and editing.Voltini M, Carletti A, Lenta E, Meloni F, Briganti DF, Avanzini MA, Comoli P, and Belliato M contributed to data collection, revision, conceptualization, and supervision.

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Correspondence to Giulia Gazzaniga .

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The work was approved by the local Ethics Committee, and conducted in accordance with the Declaration of Helsinki. Informed consent and consent for publication were acquired retrospectively from each patient or, in case of unconsciousness or death, a substitute (next of kin, when appropriate), according to local laws.

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Gazzaniga, G., Voltini, M., Carletti, A. et al. Potential application of mesenchymal stromal cells as a new therapeutic approach in acute respiratory distress syndrome and pulmonary fibrosis. Respir Res 25 , 170 (2024). https://doi.org/10.1186/s12931-024-02795-1

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The Clinical Impact of the Pulmonary Embolism Severity Index on the Length of Hospital Stay of Patients with Pulmonary Embolism: A Randomized Controlled Trial

Marco paolo donadini.

1 Thrombosis and Haemostasis Center, Ospedale di Circolo, ASST Sette Laghi, 21100 Varese, Italy; [email protected] (M.P.D.); [email protected] (F.D.); [email protected] (W.A.)

2 Research Center on Thromboembolic Diseases and Antithrombotic Therapies, University of Insubria, 21100 Varese and 22100 Como, Italy; [email protected] (L.B.); [email protected] (A.S.)

Nicola Mumoli

3 Department of Internal Medicine, Magenta Hospital, 20013 Magenta, Italy; [email protected]

4 Presidio Ospedaliero di Livorno, Azienda USL Toscana Nord Ovest, 57124 Livorno, Italy; moc.liamg@airelavizzam

Patrizia Fenu

5 Presidio Ospedaliero di Cecina, Azienda USL Toscana Nord Ovest, 57023 Cecina, Italy; [email protected]

Fulvio Pomero

6 Internal Medicine Unit, Michele e Pietro Ferrero Hospital, 12060 Verduno, Italy; ti.oohay@oremopoivluf (F.P.); [email protected] (L.S.)

7 Medicina Interna, Ospedale S. Andrea, ASL Vercelli, 13100 Vercelli, Italy; [email protected]

Gerardo Palmiero

8 Ospedale Versilia, Azienda USL Toscana Nord Ovest, 55049 Viareggio, Italy; ti.orebil@2002odrareg

Laura Spadafora

Valeria mazzi, alessandra grittini, lorenza bertù, drahomir aujesky.

9 Department of General Internal Medicine, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; [email protected]

Francesco Dentali

Walter ageno, alessandro squizzato.

10 Internal Medicine Unit, ‘Sant’Anna’ Hospital, ASST Lariana, 22042 San Fermo della Battagli, Italy

Associated Data

The data are available upon request. The trial protocol is registered on ClinicalTrials.gov, identification number {"type":"clinical-trial","attrs":{"text":"NCT03002467","term_id":"NCT03002467"}} NCT03002467 , and is fully accessible upon request to the corresponding author.

Background: The Pulmonary Embolism Severity Index (PESI) is an extensively validated prognostic score, but impact analyses of the PESI on management strategies, outcomes and health care costs are lacking. Our aim was to assess whether the adoption of the PESI for patients admitted to an internal medicine ward has the potential to safely reduce the length of hospital stay (LOS). Methods: We carried out a multicenter randomized controlled trial, enrolling consecutive adult outpatients diagnosed with acute PE and admitted to an internal medicine ward. Within 48 h after diagnosis, the treating physicians were randomized, for every patient, to calculate and report the PESI in the clinical record form on top of the standard of care (experimental arm) or to continue routine clinical practice (standard of care). The ClinicalTrials.gov identifier is {"type":"clinical-trial","attrs":{"text":"NCT03002467","term_id":"NCT03002467"}} NCT03002467 . Results: This study was prematurely stopped due to slow recruitment. A total of 118 patients were enrolled at six internal medicine units from 2016 to 2019. The treating physicians were randomized to the use of the PESI for 59 patients or to the standard of care for 59 patients. No difference in the median LOS was found between the experimental arm (8, IQR 6–12) and the standard-of-care arm (8, IQR 6–12) ( p = 0.63). A pre-specified secondary analysis showed that the LOS was significantly shorter among the patients who were treated with DOACs (median of 8 days, IQR 5–11) compared to VKAs or heparin (median of 9 days, IQR 7–12) ( p = 0.04). Conclusions: The formal calculation of the PESI in the patients already admitted to internal medicine units did not impact the length of hospital stay.

1. Introduction

Pulmonary embolism (PE) is a common cardiovascular disease with an estimated incidence of ~1 out of 1000 persons per year [ 1 , 2 ]. PE is associated with a wide prognostic spectrum, ranging from the prompt and complete resolution of symptoms after few hours of treatment to sudden death [ 3 , 4 ]. Patients with PE are commonly admitted to the hospital for their initial treatment, though some of them may be suitable for a short hospital stay or a complete home treatment [ 5 , 6 , 7 , 8 ]. Indeed, in recent years, research has focused on stratifying the risk of adverse outcomes associated with PE to tailor treatment and management strategies. Although some prognostic scores have been adequately derived and validated, especially the PESI score (Pulmonary Embolism Severity Index) [ 7 , 9 , 10 , 11 ], there is no evidence that the use of these scores changes physicians’ behaviors and improves patient outcomes and/or reduces health care costs [ 12 , 13 ]. The PESI calculation is currently recommended by clinical practice guidelines as a tool to identify patients with PE who are at low risk of short-term adverse outcomes and may be discharged early [ 7 ]. Of note, many additional factors may have an impact on the possibility to safely allow for the early discharge of patients with low-risk acute PE, including the choice of anticoagulant drugs, adequate family and/or home care support, co-morbidities, the need for oxygen supply, and pain control. Indeed, the duration of hospitalization for PE still remains long in many clinical contexts [ 8 , 14 , 15 , 16 , 17 ].

Parenteral anticoagulants and direct oral anticoagulants (DOACs) are the current options for the acute treatment of non-high-risk PE [ 18 , 19 , 20 , 21 ]. Parenteral drugs (i.e., unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) and fondaparinux) are efficacious but not optimal for home treatment [ 6 , 7 ]. DOACs have simplified the management of PE thanks to their pharmacologic properties (rapid onset of action, short half-life, and predictable anticoagulant effect) compared to vitamin K antagonists (VKAs).

Our hypothesis was that the use of a validated clinical prediction model to stratify acute PE prognosis would have an impact on the attitudes of clinicians and on the management of patients with PE who were already admitted to the hospital. We postulated that physicians would be able to optimize the duration of hospital stay for PE by shortening it, thus potentially also reducing hospital-related complications and costs without increasing the risk of PE-related adverse outcomes. Furthermore, we postulated that DOACs, as opposed to VKA treatment, may simplify, and thus promote, home treatment for the acute phase of PE.

The Impact Analysis of Prognostic Stratification for Pulmonary Embolism (iAPP) study is a randomized, parallel-group, open-label trial that was conducted from 2016 to 2019 at internal medicine units of six Italian hospitals from different provinces (Livorno, Viareggio, Cecina, Novara, Cuneo, and Magenta) that were already part of a collaborative study group evaluating the length of hospital stay for patients with PE [ 14 ].

The study protocol was approved by the Ethics Committee of Insubria, Varese, Italy and by all of the participating centers. This study was conducted following the Good Clinical Practice rules and in agreement with the Declaration of Helsinki.

2.1. Participants

Consecutive adult outpatients with an objectively confirmed diagnosis of suspected or unsuspected acute PE at the emergency department (ED) and subsequently admitted to one of the participating internal medicine units were eligible and enrolled after providing written informed consent. No exclusion criteria were applied.

Suspected PE was defined as a diagnosis of PE confirmed by an imaging test (i.e., computed tomographic pulmonary angiography [CTPA], pulmonary angiography, or V/Q lung scan) prescribed by a physician who had a clinical suspicion of PE. Unsuspected PE was defined as a diagnosis of PE that was made incidentally by an imaging test performed for other clinical indications (e.g., cancer staging or follow-up; investigation for chest diseases other than PE).

An objective diagnosis of acute PE was defined as the presence of at least one intra-luminal filling defect of pulmonary arteries at CTPA or pulmonary angiography, a high-probability ventilation/perfusion (V/Q) lung scan (or perfusion lung scan with negative chest X-ray), or an intermediate-probability V/Q or perfusion lung scan with proximal deep-vein thrombosis (DVT) documented by ultrasonography.

2.2. Interventions

Within 48 h of an acute PE diagnosis, a local investigator (treating physician) was centrally randomized for every included patient to the experimental approach, i.e., formal PESI calculation and documentation of the PESI in the clinical record form on top of routine clinical practice, or to the standard of care, i.e., no routine calculation of the PESI. A pre-printed form for annotating the PESI score, including the corresponding short-term mortality according to the PESI class, was filled out and added to the clinical record form of patients randomized to the experimental arm (available upon request).

2.3. Outcomes

The primary efficacy outcome was the median length of hospital stay (LOS).

Secondary efficacy outcomes included the proportions of patients undergoing a short hospital stay (i.e., <48 h in hospital), the proportion of post-discharge outpatients visiting the emergency department, the hospital re-admission rate within 90 days, and quality of life (5-point Likert scale questionnaire)

Other outcomes were represented by in-hospital and 90-day overall mortality, recurrent PE and/or DVT, major bleeding (according to the International Society on Thrombosis and Haemostasis (ISTH) criteria [ 22 ]), and other anticoagulation-related complications (hematoma/infection at heparin or fondaparinux injection sites or heparin-induced thrombocytopenia).

Additional hospitalization-related outcomes were recorded, including hospital-acquired infections (pneumonia; urinary tract infection; or other), iatrogenic complications, immobilization syndrome, and pressure sores.

2.4. Sample Size

In a previously published observational study conducted by the same study group [ 14 ], the median hospital stay for PE in internal medicine units was 12 days (interquartile range [IQR] of 9-17), which was concordant with the administrative data from the Lombardia Region of the mean LOS of 11.5 days [ 15 ]. Based on those data, we hypothesized that the mean LOS would be reduced by at least 15% in all patients with PE managed with the formal calculation of the PESI score and by 5% in the standard-of-care arm (because of increased knowledge of PE prognostic stratification in recent years). Therefore, with an α error of 0.05 and a statistical power (1-β error) of 80%, 200 patients in each group (a total of 400 patients) were estimated to be necessary to find a statistically significant difference ( p < 0.05) between the mean LOS of the two experimental arms. As the variable LOS has an expected non-normal distribution and needs to be expressed and reported as a median, 10% extra patients were needed to reach a statistically significant difference with the previous statistical assumptions. The final total sample size was therefore estimated to be 440 patients (220 patients for each group).

2.5. Randomization

Randomization was performed centrally with a 1:1 ratio following a computer-generated list of randomizations and was stratified by the previously declared anticoagulant treatment choice of the local investigator (i.e., LMWH +/− VKA (VKA group) vs. DOACs as single drug or with lead-in heparin (DOACs group) in order to prevent the treatment choice from having any influence on the final results.

The allocation was concealed to the local investigators. The list of randomizations was maintained only by the study coordinator (AS), who assigned the treating physician to the management arm according to the randomization sequence, after being notified by any local investigator of a new patient’s enrolment and anticoagulant treatment choice.

2.6. Statistical Analysis

The categorical variables measured are expressed as numbers and percentages. Continuous variables are reported as means (standard deviation) or medians (interquartile range [IQR]) depending on the normal distribution of the data.

The primary outcome was analyzed across the study groups by means of the Mann–Whitney U test.

Additional analyses were performed using the chi-square test or unpaired t -test, as appropriate. As a prespecified secondary analysis, the LOS was also compared between the DOACs group versus the VKA group.

A statistical analysis was performed by using the IBM SPSS Statistics software, version 27 (SPSS, Inc., IBM corporation, U.S., Armonk, NY, USA).

This study was prematurely stopped after reaching 27% of the planned sample size due to a slow recruitment rate, which made it unfeasible to reach the originally planned number of patients.

From July 2016 to October 2019, 125 patients who were consecutively admitted to the six participating internal medicine units within 48 h of a PE diagnosis were enrolled in the trial. For 7 patients, the local investigators did not perform study procedures after randomization, thus leaving 118 allocated patients. The local investigators were randomized to formally calculate and report the PESI score on top of the standard of care for 59 patients or to use the standard of care alone for 59 patients. No patient was excluded after allocation, and all data were available for the primary outcome ( Figure 1 ).

An external file that holds a picture, illustration, etc.
Object name is diagnostics-14-00776-g001.jpg

iAPP flow diagram.

Overall, the study population included 62 males (52.5%) and 56 females (47.5%), with a mean age of 75.6 years (SD 12.8). PE was incidentally diagnosed in 20 patients (16.9%) and was provoked by at least one major risk factor in 40 patients (33.9%). Concomitant DVT was diagnosed in 65 patients (55.1%). The clinical presentation of PE was characterized by sustained hypotension (i.e., high-risk PE) in three patients (2.5%). The baseline characteristics of the study population according to the assigned management arm are presented in Table 1 .

Baseline characteristics: DVT, deep vein thrombosis; PE, pulmonary embolism; DOAC, direct oral anticoagulant; RVD, right ventricular dysfunction; SBP, systolic blood pressure; TTE, transthoracic echocardiography; n, number.

* Data available for 95 patients; § PESI was calculated for all patients a posteriori.

The median LOS was 8 days (IQR 6–12). No difference was found between the experimental arm (median of 8 days, IQR 6–12) and the standard-of-care arm (median of 8 days, IQR 6–12) ( p = 0.63). No patient was discharged within 48 h of PE diagnosis.

The mortality rate at 90 days was 6.8% (8 patients) and did not differ between the two arms ( p = 0.48). Recurrent VTE occurred in two patients within the standard-of-care arm (3.4%).

Two patients experienced major bleeding, both in the standard-of-care arm (3.4%).

All secondary efficacy outcomes and safety outcomes are presented in Table 2 according to the randomization arm.

Outcomes: percentage calculated on available data: * 25 patients; § 97 patients; ¶ 107 patients.

LOS, length of hospital stay; h, hours; n, number; VTE, venous thromboembolism.

Data on the discharge destinations and on the clinical and family/social determinants of the LOS according to the randomization arm are presented in Table 3 and Table 4 .

Discharge destination: * chi-square p value relative to home discharge vs. other destinations.

Clinical and family/social determinants of LOS: LOS, length of hospital stay; PE, pulmonary embolism; n, number; ys, years; RVD, right ventricular dysfunction.

There were no significant differences between the randomization groups on the quality of life items ( Table 5 ).

Quality of life questionnaire: LOS, length of hospital stay; SD, standard deviation; PE pulmonary embolism.

Secondary Analysis

DOACs were used in 71 patients (with or without lead-in heparin, according to indication), whereas parenteral anticoagulants alone or followed by VKA were used in 47 patients. Patients treated with DOACs, compared to those treated with parenteral anticoagulation alone or followed by VKA, were significantly younger (72.4 vs. 80.5 years; p 0.0006) and had a lower prevalence of active cancer (11.3% vs. 31.9%; p 0.001). Moreover, a significantly higher proportion of patients were classified as low-risk PESI classes among those treated with DOACs (28 patients, 39.4%) compared to those treated with parenteral anticoagulation alone or followed by VKA (7 patients, 14.9%).

The LOS was significantly shorter among patients treated with DOACs (median of 8 days, IQR 5–11) compared to those treated with parenteral anticoagulation (median of 9 days, IQR 7–12). Patients that were treated with DOACs also had a significantly lower incidence of pressure sores and in-hospital and 90-day mortality rates ( Table 6 ).

Outcomes according to anticoagulant treatment regimen: DOAC, direct oral anticoagulant; LMWH, low-molecular-weight heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism; h, hours.

4. Discussion

Our study suggests that the mere calculation and documentation of the PESI in patients with PE who were already admitted to internal medicine units may not have a clinically relevant impact on the duration of hospital stay. However, since this study was prematurely interrupted and did not reach the planned sample size, the results do not allow for any firm conclusion to be drawn.

Since 2008, the European Society of Cardiology (ESC) [ 23 ] has proposed a stepwise risk stratification approach to optimize the management of patients with PE, using a combination of clinical findings, imaging, and biochemical markers to distinguish between patients with high, intermediate, and low risks of an early adverse outcome. One of the most challenging tasks is to identify, within the large group of normotensive and apparently stable patients, those whose risk is ‘sufficiently low’ to permit early discharge and outpatient treatment [ 3 , 7 , 24 ]. Such an approach may minimize early complications related to hospitalization and may have an impact on health care costs as well as on patient satisfaction and quality of life. Clinical decision rules (CDRs) are the best available tools to combine clinical findings, and among them, the PESI and simplified PESI are recommended by current guidelines [ 7 , 25 , 26 ].

However, the PESI is used in clinical practice and recommended by current guidelines without any solid/definitive evidence that any CDR may assist clinicians in determining the best treatment and the appropriate setting for the initial therapy, except for an RCT in which e-health care record-based risk stratification of the PESI (plus teaching) has been shown to reduce hospital admissions [ 12 , 27 ]. Three steps are involved in the development and testing of a new CDR [ 12 , 13 ]. The first stage is derivation, where the independent and combined effects of explanatory variables such as symptoms, signs, and/or investigations are established. The second stage is validation, where the final derived CDR is evaluated first in different clinical settings. The final stage of evaluation is to test the impact of using the CDR in clinical practice, ideally in a randomized controlled trial (RCT), for relevant clinical outcomes. To the best of our knowledge, this is the first RCT that explored the clinical impact of PESI itself on inpatients with PE [ 3 , 6 ]. A recently published study used a combined strategy involving risk stratification by using the PESI followed by predefined criteria for mobilization and discharge, which was effective in reducing the LOS [ 28 ]. Indeed, even if our study was stopped prematurely, the results do not suggest that the PESI has any clinically relevant impact on the LOS. The PESI was primarily developed to avoid hospital admission for outpatients with PE, and not to decrease the LOS of patients with PE in a medical ward [ 9 ]. However, the lack of effect may be differently explained. Prognosis is only a medical description of a patient’s condition; indeed, discharge is not only based on the predictive risk of complications, but it is also a multiparametric choice based on social, family, and psychological factors. The lack of a caregiver at home, difficulties in performing imaging and lab tests outside the hospital, and a fear of being treated without nursing and/or medical assistance may be major determinants of the length of hospital stay. Another important factor is patients’ preferences; outpatient care or early discharge for a serious condition such as PE may be socially inacceptable to many patients or physicians. Finally, the question remains whether mere calculation and documentation, without any further educational support, is enough to change practice.

The difference in the LOS between VKA and DOAC in our study and in the literature seems to support this hypothesis [ 29 ]. Indeed, for many patients, the use of LMWH and fondaparinux requires daily nurse assistance for subcutaneous injections, and VKA treatment management may need more time for patients to be settled out of hospital compared to DOACs, in addition to the potential for the treating physician to wait for at least one therapeutic INR before discharging patients with acute PE.

Worldwide, several papers have reported a median length of hospital stay of 5 days or less for PE. In our population, the median length of hospital stay was approximately 8 days. It may be hypothesized that a major determinant of the length of hospital stay could be the organization of the health care system, as in Italy, the length of hospital stay has been similar in the past 10 years [ 15 , 16 ], as confirmed by similar LOSs in other European countries, such as France (11.6 days) or Spain (6.8 days) [ 29 ].

Our study has several limitations. First, this study was prematurely interrupted due to a slow recruitment rate; therefore, by definition, this study is underpowered to detect any difference among groups. Second, the main inclusion criterion was the admission to an internal medicine unit. In all recruiting centers, patients with PE are also admitted in other units, such as cardiology, pneumology, or intensive care units. Therefore, the results of our study may only be applied to these subgroups of admitted patients with PE, and whether this is also the case in patients hospitalized in cardiology or pneumology units, where patients may be more selected, younger, and less multimorbid, is still unknown. In addition, the PESI was primarily developed to avoid hospital admission for outpatients with PE and not to decrease the LOS of patients admitted to the medical ward. Third, the treating physicians were centrally randomized for every patient; some authors suggest that cluster randomization is the most appropriate study design to test the impact of a CPR to avoid the risk of contamination. Indeed, taking part in an interventional study improves the knowledge of the participating investigators on the topic irrespective of the study design and may potentially bias the results by reducing the difference between the intervention and control groups, i.e., physicians randomized to usual care might also calculate/use the PESI to determine the LOS. Moreover, contamination might also play a role, as physicians working at the same ward/hospital might also become contaminated in terms of their practices if they know what the study is about. Therefore, we included this consideration into the sample size calculation, as we anticipated that the LOS would have been reduced by 5% in the standard-of-care arm (compared to 15% in the interventional group); however, this estimate may not be accurate. Fourth, DOACs may facilitate outpatient care. However, the patients were not randomized based on the treatment received, and it is possible that the patients who were perceived to be at a low risk were more likely to be discharged early and to receive DOACS. So, whether the shorter LOS in the patients treated with DOACs is a consequence of the DOACs or confounded by less severe PE still needs to be determined. Indeed, there seemed to be fewer severe PE cases (66% vs. 75%) and more patients with incidental PE (24% vs. 10%) in the PESI group compared to the standard of care group, respectively (see Table 1 )

In conclusion, the knowledge of the PESI in patients with PE who were hospitalized in internal medicine units did not appear to reduce the duration of hospital stay in our study. Future studies should assess the role of the PESI in other inpatient settings or explore its use in combination with other major potential determinants of hospital stay.

Acknowledgments

iAPP study investigators: Hospital of Livorno: Lorenzo Luschi; Hospital of Magenta: Isabella Evangelista, Cesare Porta, Alessandra Colombo, and Giulia Conte.

Funding Statement

The trial was conducted without funding.

Author Contributions

Conceptualization, M.P.D., N.M. and A.S.; methodology, M.P.D. and A.S.; software, M.P.D. and A.S.; validation, M.P.D. and A.S.; formal analysis, M.P.D. and A.S.; investigation, M.P.D., N.M., P.F., F.P., R.R., G.P., L.S., V.M., A.G., L.B., D.A., F.D., W.A. and A.S.; resources, M.P.D., N.M., P.F., F.P., R.R., G.P., L.S., V.M., A.G., L.B., D.A., F.D., W.A. and A.S.; data curation, M.P.D., N.M. and A.S.; writing—original draft preparation, M.P.D. and A.S.; writing—review and editing, M.P.D. and A.S.; visualization, M.P.D., N.M., W.A. and A.S.; supervision, M.P.D., N.M., W.A. and A.S.; project administration, M.P.D., N.M., W.A. and A.S.; All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Insubria University (0055254, 3 November 2015), Varese, Italy.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study. Written informed consent was obtained from the patients to publish this paper.

Data Availability Statement

Conflicts of interest.

M.P.D. has been a part of the Data Safety Monitoring Board for PlasFree and has received a research grant from the Italian Ministry of Health, outside the submitted work and paid to his institution. G.P. received honoraria from Chiesi, Novartis, Abiogen, Mundipharma, Boehringer-Ingelheim. D.A. received a research grant from the Swiss National Science Foundation and free drug supply for a study from Bayer. W.A. received a research grant from Bayer; honoraria for lectures from Bayer, BMS Pfizer, Daiichi Sankyo, Viatris, Werfen, and Leo Pharma; support for attending meetings from Bayer, BMS-Pfizer, and Norgine; and has been a part of the Data Safety Monitoring Board or advisory boards for Bayer, Sanofi, Norgine, Viatris, and Leo Pharma. A.S. received consulting fees from Bayer and honoraria from Pfizer, Bristol-Myers Squibb/Pfizer, Bayer, Novartis, Roche, Daiichi Sankyo, Sanofi, and Werfen and Alexion and has been a part of the Data Safety Monitoring Board or advisory boards for Bayer, Viatris, and Daiichi Sankyo. N.M., P.F., F.P., R.R., L.S., V.M., A.G., L.B., and F.D. declare no conflicts of interest in relation to this study.

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Acute Pulmonary Embolism Presenting as Hypotension and Hypoxic Respiratory Failure

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Acute pulmonary embolism with loss of consciousness as the first manifestation: a case report

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Introduction

Case presentation

The pathophysiological mechanism of pulmonary embolism causing syncope

Differential diagnosis of syncope or loss of consciousness in clinic

Screening of patients at risk for pulmonary embolism

Formulation of the subsequent treatment plan after definite diagnosis

Etiology screening of pulmonary embolism

Conclusions

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Diagnosis of acute pulmonary embolism: when photon-counting-detector CT replaces energy-integrating-detector CT in daily routine

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