new research on sickle cell anemia

FDA approves cure for sickle cell disease, the first treatment to use gene-editing tool CRISPR

The Food and Drug Administration on Friday approved a powerful treatment for sickle cell disease , a devastating illness that affects more than 100,000 Americans, the majority of whom are Black.

The therapy, called Casgevy, from Vertex Pharmaceuticals and CRISPR Therapeutics, is the first medicine to be approved in the United States that uses the gene-editing tool CRISPR , which won its inventors the Nobel Prize in chemistry in 2020.

“I think this is a pivotal moment in the field,” said Dr. Alexis Thompson, chief of the division of hematology at Children’s Hospital of Philadelphia, who has previously consulted for Vertex. “It’s been really remarkable how quickly we went from the actual discovery of CRISPR, the awarding of a Nobel Prize, and now actually seeing it being an approved product.”

The approval marks the first of two potential breakthroughs for the inherited blood disorder. The FDA on Friday also approved a second treatment for sickle cell disease, called Lyfgenia, a gene therapy from drugmaker Bluebird Bio. Both treatments work by genetically modifying a patient’s own stem cells.

Until now, the only known cure for sickle cell disease was a bone marrow transplant from a donor, which carries the risk of rejection by the immune system, in addition to the difficult process of finding a matching donor.

Casgevy, which was approved for people ages 12 and older, removes the need for a donor. Using CRISPR, it edits the DNA found in a patient’s stem cells to remove the gene that causes the disease.

“The patient is their own donor,” Thompson said.

“It’s a game-changer,” said Dr. Asmaa Ferdjallah, a pediatric hematologist and bone marrow transplant physician at the Mayo Clinic in Rochester, Minnesota. “To really reimagine and re-discuss sickle cell disease as a curable disease and not as this painful and debilitating chronic disease is hope enough with this news.”

Still, the new therapy is extremely expensive — $2.2 million per patient, Vertex said. The pricing strategy, experts argue, may place it out of reach for many families. What’s more, that price doesn’t include the cost of care associated with the treatment, like a stay in the hospital or chemotherapy.

“We really have to make sure that it is accessible,” said Dr. Rabi Hanna, a pediatric hematologist-oncologist at the Cleveland Clinic who has previously served on the advisory board for Vertex. “This could be an equalizer for people with sickle cell because many patients cannot pursue career options” because of the illness.

“It’s something families have been aware of in the early research stage, and they’ve been very patiently waiting for years,” Ferdjallah said. “It’s been eagerly awaited by patients and families, but also by providers and physicians.”

How Casgevy works

In patients with sickle cell disease, red blood cells, which are usually disk-shaped, take on a crescent or sickle shape. This change can cause cells to clump together, leading to clots and blockages in the blood vessels, starving tissues of oxygen. Patients can experience excruciating pain, breathing problems and stroke .

Casgevy works by editing the DNA in a patient’s stem cells — which are responsible for making the body’s blood cells — so that they no longer produce sickle-shaped cells.

While technically a one-time treatment, a number of steps that span months are required before the patient actually gets the modified stem cells. It begins with a series of blood transfusions over three to four months, after which the stem cells are extracted from the patient’s bone marrow and sent off to a lab where they are edited, Hanna said.

Before they can be reinfused into the patient, however, doctors need to make sure no flawed stem cells remain in the body. To do so, chemotherapy is used to destroy the patient’s bone marrow. 

Only then can the edited stem cells be reinfused into the patient, followed by another month or two in the hospital to allow the cells to grow and the patient to recover.

Hanna said he’s always “cautious” when telling families and patients about the one-time treatment because they may have unrealistic expectations.

“There are multiple phases of this journey,” he said.

The clinical trial included 46 people in the U.S. and abroad, 30 of whom had at least 18 months of follow-up care after the treatment. Of those, the treatment has been successful in 29.

LaRae Morning, 29, of Phoenix, was among the trial patients whose treatment was successful.

Her doctors did not expect her to live past the age of 11. Her mother lost several jobs when Morning was a child and a teenager because of her frequent hospital visits.

In April 2021, Morning joined the clinical trial at Sarah Cannon Research Institute and HCA Healthcare’s The Children’s Hospital at TriStar Centennial in Nashville, Tennessee, a decision she initially regretted. Living in Phoenix, she had to fly to Nashville once a month for treatment. It included several blood transfusions, which lasted eight hours each, and taking a medication, called plerixafor, which she recalled causing her intense stomachaches. When she started chemotherapy, her hair began to fall out and her skin changed color, resembling the appearance of a chemical burn. She also experienced nausea.

It took about six to seven months for her to feel back to normal following the CRISPR treatment. Now, she said, she’s feeling the benefits, going out to coffee shops, spending time with her friends and finishing her first semester of law school in Washington, D.C.

“Now that I’m here, I’m so happy that I did it,” she said of the trial. “I’m just like a regular person. I wake up and do a 5K. I lift weights. If I wanted to swim, I can swim. I’m still trying to know how far I can stretch it, like what are all the things I can do.”

That’s been the experience for several other patients in the trial as well, according to Dr. Monica Bhatia, chief of pediatric stem cell transplantation at NewYork-Presbyterian/Columbia University Irving Medical Center. Bhatia is a principal investigator at one of the clinical trial sites in New York City.

Following the treatment, most patients were going back to school, going to the gym or resuming other activities — “things that a lot of people take for granted,” she said — after about three to four months.

“They’re really able to live life without restrictions,” Bhatia said.

Dr. Haydar Frangoul, medical director of pediatric hematology-oncology for the Sarah Cannon Research Institute, said he is hopeful the therapy will provide relief to more patients.

“I think this is a huge moment for patients with sickle cell disease,” said Frangoul, who was the lead investigator on the clinical trial and treated Morning.

Long-term questions 

Although Casgevy has been shown to be effective, experts still don’t know about potential long-term effects, since the trial is only set to run for two years.

During a meeting in October, an FDA advisory committee discussed the risk of “off-target” effects , which refers to when the gene-editing tool makes cuts to other stretches of DNA other than the intended target and how the FDA should consider those risks moving forward.

It’s unclear what effects an off-target edit would have on a patient, but the fear is that it could result in unintended health consequences down the road, Thompson said. “To date, there do not appear to be measurable consequences.”

The FDA did, however, add a boxed warning — the strongest safety warning label— to Bluebird Bio’s Lyfgenia, noting that in rare cases the treatment can cause certain blood cancers.

Dr. Nicole Verdun, director of the Office of Therapeutic Products in the FDA's Center for Biologics Evaluation and Research, said Lyfgenia was given the warning after two patients who got the therapy in a clinical trial died from a form of leukemia.

It's unclear whether the gene therapy itself or another part of the treatment process, such as the chemotherapy, caused the cancer, but Verdun said the agency thought the deaths "rose to the level of a black-box warning." No cases were seen in the Vertex clinical trial, she said.

Bhatia is following the patients for 15 years as part of a post-approval study for Casgevy and will be monitoring for signs of long-term effects.

“Long-term follow-up is still going to be so crucial,” she said.

Christopher Vega, 31, from Allentown, Pennsylvania, said the possibility of long-term effects aren’t a concern for him; he is happy to be living a life free of chronic pain.

He joined the clinical trial at the Children’s Hospital of Philadelphia in late 2020. He had suffered from chronic fatigue since he was a young child and would end up in the hospital every year with a pain crisis.

“When I was younger, my mom used to always tell me things happen for a reason. And I had so much trouble believing that, because I always thought, ‘Why me?’” he said.

While the treatment process was not always easy — Vega temporarily lost his hair, felt weak and nauseous and developed skin rashes — he said it was worth it.

“I am a whole different person,” said Vega, who is now attending the Los Angeles Film School online for visual effects while taking care of his 5-year-old daughter.

“Sometimes I would get small moments of anxiety that I would have a crisis,” he said. “And after going years now, I’m slowly coming to terms with, I’m OK, and I know I’m going to be here, present.”

Berkeley Lovelace Jr. is a health and medical reporter for NBC News. He covers the Food and Drug Administration, with a special focus on Covid vaccines, prescription drug pricing and health care. He previously covered the biotech and pharmaceutical industry with CNBC.

Marina Kopf is an associate producer with the NBC News Health and Medical Unit.

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FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease

FDA News Release

Today, the U.S. Food and Drug Administration approved two milestone treatments, Casgevy and Lyfgenia, representing the first cell-based gene therapies for the treatment of sickle cell disease (SCD) in patients 12 years and older. Additionally, one of these therapies, Casgevy, is the first FDA-approved treatment to utilize a type of novel genome editing technology, signaling an innovative advancement in the field of gene therapy. 

Sickle cell disease is a group of inherited blood disorders affecting approximately 100,000 people in the U.S. It is most common in African Americans and, while less prevalent, also affects Hispanic Americans. The primary problem in sickle cell disease is a mutation in hemoglobin, a protein found in red blood cells that delivers oxygen to the body’s tissues. This mutation causes red blood cells to develop a crescent or “sickle” shape. These sickled red blood cells restrict the flow in blood vessels and limit oxygen delivery to the body’s tissues, leading to severe pain and organ damage called vaso-occlusive events (VOEs) or vaso-occlusive crises (VOCs). The recurrence of these events or crises can lead to life-threatening disabilities and/or early death. 

“Sickle cell disease is a rare, debilitating and life-threatening blood disorder with significant unmet need, and we are excited to advance the field especially for individuals whose lives have been severely disrupted by the disease by approving two cell-based gene therapies today,” said Nicole Verdun, M.D., director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research. “Gene therapy holds the promise of delivering more targeted and effective treatments, especially for individuals with rare diseases where the current treatment options are limited.” 

Casgevy, a cell-based gene therapy, is approved for the treatment of sickle cell disease in patients 12 years of age and older with recurrent vaso-occlusive crises. Casgevy is the first FDA-approved therapy utilizing CRISPR/Cas9, a type of genome editing technology. Patients’ hematopoietic (blood) stem cells are modified by genome editing using CRISPR/Cas9 technology. 

CRISPR/Cas9 can be directed to cut DNA in targeted areas, enabling the ability to accurately edit (remove, add, or replace) DNA where it was cut. The modified blood stem cells are transplanted back into the patient where they engraft (attach and multiply) within the bone marrow and increase the production of fetal hemoglobin (HbF), a type of hemoglobin that facilitates oxygen delivery. In patients with sickle cell disease, increased levels of HbF prevent the sickling of red blood cells.

Lyfgenia is a cell-based gene therapy. Lyfgenia uses a lentiviral vector (gene delivery vehicle) for genetic modification and is approved for the treatment of patients 12 years of age and older with sickle cell disease and a history of vaso-occlusive events. With Lyfgenia, the patient’s blood stem cells are genetically modified to produce HbA T87Q , a gene-therapy derived hemoglobin that functions similarly to hemoglobin A, which is the normal adult hemoglobin produced in persons not affected by sickle cell disease. Red blood cells containing HbA T87Q have a lower risk of sickling and occluding blood flow. These modified stem cells are then delivered to the patient. 

Both products are made from the patients’ own blood stem cells, which are modified, and are given back as a one-time, single-dose infusion as part of a hematopoietic (blood) stem cell transplant. Prior to treatment, a patients’ own stem cells are collected, and then the patient must undergo myeloablative conditioning (high-dose chemotherapy), a process that removes cells from the bone marrow so they can be replaced with the modified cells in Casgevy and Lyfgenia. Patients who received Casgevy or Lyfgenia will be followed in a long-term study to evaluate each product’s safety and effectiveness. 

“These approvals represent an important medical advance with the use of innovative cell-based gene therapies to target potentially devastating diseases and improve public health,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. “Today’s actions follow rigorous evaluations of the scientific and clinical data needed to support approval, reflecting the FDA’s commitment to facilitating development of safe and effective treatments for conditions with severe impacts on human health.”

Data Supporting Casgevy

The safety and effectiveness of Casgevy were evaluated in an ongoing single-arm, multi-center trial in adult and adolescent patients with SCD. Patients had a history of at least two protocol-defined severe VOCs during each of the two years prior to screening. The primary efficacy outcome was freedom from severe VOC episodes for at least 12 consecutive months during the 24-month follow-up period. A total of 44 patients were treated with Casgevy. Of the 31 patients with sufficient follow-up time to be evaluable, 29 (93.5%) achieved this outcome. All treated patients achieved successful engraftment with no patients experiencing graft failure or graft rejection. 

The most common side effects were low levels of platelets and white blood cells, mouth sores, nausea, musculoskeletal pain, abdominal pain, vomiting, febrile neutropenia (fever and low white blood cell count), headache and itching. 

Data Supporting Lyfgenia

The safety and effectiveness of Lyfgenia is based on the analysis of data from a single-arm, 24-month multicenter study in patients with sickle cell disease and history of VOEs between the ages of 12- and 50- years old. Effectiveness was evaluated based on complete resolution of VOEs (VOE-CR) between 6 and 18 months after infusion with Lyfgenia. Twenty-eight (88%) of 32 patients achieved VOE-CR during this time period. 

The most common side effects included stomatitis (mouth sores of the lips, mouth, and throat), low levels of platelets, white blood cells, and red blood cells, and febrile neutropenia (fever and low white blood cell count), consistent with chemotherapy and underlying disease. 

Hematologic malignancy (blood cancer) has occurred in patients treated with Lyfgenia. A black box warning is included in the label for Lyfgenia with information regarding this risk. Patients receiving this product should have lifelong monitoring for these malignancies. 

Both the Casgevy and Lyfgenia applications received Priority Review , Orphan Drug , Fast Track and Regenerative Medicine Advanced Therapy designations. 

The FDA granted approval of Casgevy to Vertex Pharmaceuticals Inc. and approval of Lyfgenia to Bluebird Bio Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, radiation-emitting electronic products, and for regulating tobacco products.

December 8, 2023

FDA Approves First CRISPR Gene Editing Treatment for Sickle Cell Disease

Most people with sickle cell disease who received a new gene editing treatment saw their pain resolve for at least one year, but longer follow up is needed

By Sara Reardon

Sickle cell disease causes red blood cells to take on a sickle-like shape, making them fragile and less able to transport oxygen.

BSIP SA/Alamy Stock Photo

CRISPR, the gene-editing technology that has revolutionized biological research, is finally available as a medical treatment with regulatory approval. On December 8 the U.S. Food and Drug Administration approved the first CRISPR treatment for sickle cell disease.

The treatment, called exa-cel and made by the companies Vertex and CRISPR Therapeutics, edits a gene involved in red blood cell shape and function. It appears to functionally cure the disease for at least one year. The FDA’s decision makes the U.S. the second country to approve a CRISPR therapy, following exa-cel’s approval for sickle cell disease in the U.K. in November.

Scientifically speaking, exa-cel is “an incredible asset to have,” says Michael DeBaun, a hematologist at Vanderbilt University. But it is still early to say whether the treatment will be permanent and without side effects, he adds.

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The FDA also approved another type of gene therapy for sickle cell disease today called lovo-cel, which is made by the company bluebird bio.

What is sickle cell disease, and how does the new CRISPR therapy work?

The CRISPR system used in exa-cel targets genes that produce hemoglobin, the protein that carries oxygen in blood cells. In a form of sickle cell disease called sickle cell anemia, mutations in a gene called HBB affect the protein’s structure, causing it to twist normally round red blood cells into a curved sickle shape. These sickled cells clog blood vessels, leading to severe pain and fatigue. In a related condition called beta-thalassemia, which sometimes occurs with sickle cell anemia, the body does not produce enough hemoglobin or red blood cells, resulting in symptoms caused by low blood oxygen levels. These symptoms include fatigue and growth problems in children.

Exa-cel directs an enzyme called Cas9 to a gene, called BCL11A, that typically prevents the body from making a form of hemoglobin found only in fetuses. Cas9 deactivates BCL11A in bone marrow stem cells, where red blood cells are made, by cutting its DNA, and the cells begin producing the fetal hemoglobin and creating red blood cells with a normal round shape. In the new therapy, physicians remove a person’s own bone marrow stem cells, edit them with exa-cel, destroy the rest of the person’s untreated bone marrow and then reinfuse the edited cells.

Because these edited cells eventually repopulate the body, exa-cel is considered a “curative” therapy that will theoretically last the rest of the recipient’s life, although Vertex and CRISPR Therapeutics have followed most of their trial participants for less than two years.

How effective is the treatment?

So far exa-cel has only been tested in around 100 people with either sickle cell anemia or beta-thalassemia. Nevertheless, in 2019 the FDA gave the companies a “fast-track” approval that allows it to test the therapy in smaller groups of people than would normally be required.

In these trials, which are still ongoing, 29 of the 30 study participants with sickle cell anemia had no pain for one year in the 18 months following their exa-cel transfusions. And 39 out of 42 beta-thalassemia patients no longer needed blood or bone marrow transplants—the standard treatment for this disease—for one year after the exa-cel intervention. Vertex and CRISPR Therapeutics are continuing to track the remaining participants who have not yet reached this time point and will follow all participants for up to 15 years.

What are the risks?

The results submitted to the FDA suggest that exa-cel has no major adverse health impacts, although it can cause side effects such as nausea and fever. But DeBaun points out that the participants have only been tracked for a short time and that problems could arise later.

Another concern raised by the FDA is that the Cas9 enzyme could remain active and cut the genome in places other than BCL11A, creating so-called off-target mutations. The companies modeled the most likely places in the genome where the enzyme could cut and found no evidence that this had happened in trial participants. “In light of any new therapy, we remain cautiously optimistic,” DeBaun says.

Besides exa-cel, what are some other promising therapies for sickle cell disease?

Bluebird bio's lovo-cel, the other gene therapy that was approved today by the FDA, uses a viral vector to deliver a functional version of an adult hemoglobin-producing gene and insert it permanently into a person’s genome. The data bluebird bio submitted to the FDA showed lovo-cel was effective in 36 people who were followed for a median of 32 months. Dozens of studies are investigating other types of gene therapies for sickle cell anemia and beta-thalassemia that deliver normal versions of HBB or other genes to the body.

Researchers have found that a technique called haploidentical transplant could also cure sickle cell anemia. In this treatment, which is already widely used to treat certain cancers, a person’s bone marrow cells are replaced with those from a parent or sibling who is 50 percent genetically identical to the recipient but does not have the disease. Results that will be presented next week at the American Society for Hematology’s annual conference found that 88 percent of adults who received these transplants continued to make normal red blood cells after two years. DeBaun says this technique could be particularly useful in low- and middle-income countries because it is likely to cost much less than gene editing or gene therapy.

Will exa-cel or lovo-cell be available to everyone with sickle cell disease?

Like most gene editing therapies, exa-cel and lovo-cell are likely to be very expensive. Neither Vertex, CRISPR Therapeutics nor bluebird bio have said how much their respective therapies will cost, but estimates suggest that the price for each could be as much as $2 million per patient. It is still unclear whether insurers, especially government services such as Medicaid, will cover the therapies or in which cases they will do so. Sickle cell disease disproportionately affects people of African descent, including African Americans, who are more likely to have public insurance through Medicaid than most other groups in the U.S.

DeBaun says that deciding whether to pursue CRISPR gene editing or another approach such as haploidentical transplant will need to be a shared decision by patients, their families and their physicians. Even if gene editing proves to be more effective at permanently curing the disease, it is likely to be less widely available and may take longer than a transplant from a donor.

Nevertheless, DeBaun says that exa-cel is a good first step, and he expects that the technology will improve as more is learned about CRISPR therapies over the next decade. “This is the first mile of a marathon,” he says.

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• 25 August 2021

Gene therapies close in on a cure for sickle-cell disease

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Michael Eisenstein is a science writer based in Philadelphia, Pennsylvania.

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Seventy years ago, sickle-cell disease was at the cutting edge of biomedical research as the first medical condition to be linked to a molecular cause. But the ensuing decades saw little progress in terms of clinical care, leaving patients afflicted with severe pain and dramatically shortened life expectancy. “There was a long period of time without any types of treatment,” says Vence Bonham, leader of the Health Disparities Unit at the US National Human Genome Research Institute in Bethesda, Maryland. Indeed, the first sickle-cell drug was approved only in 1998.

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doi: https://doi.org/10.1038/d41586-021-02138-w

This article is part of Nature Outlook: Sickle-cell disease , an editorially independent supplement produced with the financial support of third parties. About this content .

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First Patient Begins Newly Approved Sickle Cell Gene Therapy

A 12-year-old boy in the Washington, D.C., area faces months of procedures to remedy his disease. “I want to be cured,” he said.

By Gina Kolata

Photographs by Kenny Holston

Gina Kolata visited Kendric and his parents at the hospital in Washington, D.C., when he was having his stem cells extracted

On Wednesday, Kendric Cromer, a 12-year-old boy from a suburb of Washington, became the first person in the world with sickle cell disease to begin a commercially approved gene therapy that may cure the condition.

For the estimated 20,000 people with sickle cell in the United States who qualify for the treatment, the start of Kendric’s monthslong medical journey may offer hope. But it also signals the difficulties patients face as they seek a pair of new sickle cell treatments.

For a lucky few, like Kendric, the treatment could make possible lives they have longed for. A solemn and shy adolescent, he had learned that ordinary activities — riding a bike, going outside on a cold day, playing soccer — could bring on episodes of searing pain.

“Sickle cell always steals my dreams and interrupts all the things I want to do,” he said. Now he feels as if he has a chance for a normal life.

Near the end of last year, the Food and Drug Administration gave two companies authorization to sell gene therapy to people with sickle cell disease — a genetic disorder of red blood cells that causes debilitating pain and other medical problems. An estimated 100,000 people in the United States have sickle cell, most of them Black. People are born with the disease when they inherit the mutated gene for the condition from each parent.

The treatment helped patients in clinical trials , but Kendric is the first commercial patient for Bluebird Bio, a Somerville, Mass., company. Another company, Vertex Pharmaceuticals of Boston, declined to say if it had started treatment for any patients with its approved CRISPR gene-editing-based remedy .

Kendric — whose family’s health insurance agreed to cover the procedure — began his treatment at Children’s National Hospital in Washington. Wednesday’s treatment was only the first step. Doctors removed his bone marrow stem cells, which Bluebird will then genetically modify in a specialized lab for his treatment.

That will take months. But before it begins, Bluebird needs hundreds of millions of stem cells from Kendric, and if the first collection — taking six to eight hours — is not sufficient, the company will try once or twice more.

If it still doesn’t have enough, Kendric will have to spend another month in preparation for another stem cell extraction.

The whole process is so involved and time-consuming that Bluebird estimates it can treat the cells of only 85 to 105 patients each year — and that includes not just sickle cell patients, but also patients with a much rarer disease — beta thalassemia — who can receive a similar gene therapy.

Medical centers also have the capacity to handle only a limited number of gene therapy patients. Each person needs expert and intensive care. After a patient’s stem cells have been treated, the patient has to stay in the hospital for a month. For most of that time, patients are severely ill from powerful chemotherapy.

Children’s National can accept only about 10 gene therapy patients a year.

“This is a big effort,” said Dr. David Jacobsohn, chief of the medical center’s division of blood and marrow transplantation.

Top of the Waiting List

Last week, Kendric came prepared for the stem cell collection — he has spent many weeks in this hospital being treated for pain so severe that on his last visit, even morphine and oxycodone could not control it. He brought his special pillow with a Snoopy pillowcase that his grandmother gave him and his special Spider-Man blanket. And he had a goal.

“I want to be cured,” he said.

Bone marrow stem cells, the source of all the body’s red and white blood cells, are normally nestled in a person’s bone marrow. But Kendric’s doctors infused him with a drug, plerixafor, which pried them loose and let them float in his circulatory system.

To isolate the stem cells, staff members at the hospital inserted a catheter into a vein in Kendric’s chest and attached it to an apheresis machine, a boxlike device next to his hospital bed. It spins blood, separating it into layers — a plasma layer, a red cell layer and a stem cell layer.

Once enough stem cells have been gathered, they will be sent to Bluebird’s lab in Allendale, N.J., where technicians will add a healthy hemoglobin gene to correct the mutated ones that are causing his sickle cell disease.

They will send the modified cells back three months later. The goal is to give Kendric red blood cells that will not turn into fragile crescent shapes and get caught in his blood vessels and organs.

Although it takes just a couple of days to add a new gene to stem cells, it takes weeks to complete tests for purity, potency and safety. Technicians have to grow the cells in the lab before doing these tests.

Bluebird lists a price of $3.1 million for its gene therapy, called Lyfgenia. It’s one of the highest prices ever for a treatment.

Despite the astronomical price and the grueling process , medical centers have waiting lists of patients hoping for relief from a disease that can cause strokes, organ damage, bone damage, episodes of agonizing pain and shortened lives.

At Children’s National, Dr. Jacobsohn said at least 20 patients were eligible and interested. The choice of who would go first came down to who was sickest, and whose insurance came through.

Kendric qualified on both counts. But even though his insurance was quick to approve the treatment, the insurance payments are only part of what it will cost his family.

Chances and Hopes

Deborah Cromer, a realtor, and her husband, Keith, who works in law enforcement for the federal government, had no idea they might have a child with sickle cell.

They found out only when Deborah was pregnant with Kendric. Tests showed that their baby would have a one-in-four chance of inheriting the mutated gene from each parent and having sickle cell disease. They could terminate the pregnancy or take a chance.

They decided to take a chance.

The news that Kendric had sickle cell was devastating.

He had his first crisis when he was 3. Sickled blood cells had become trapped in his legs and feet. Their baby was inconsolable, in such pain that Deborah couldn’t even touch him.

She and Keith took him to Children’s National.

“Little did we know that that was our introduction to many many E.R. visits,” Deborah said.

The pain crises became more and more severe. It seemed as though anything could set them off — 10 minutes of playing volleyball, a dip in a swimming pool. And when they occurred, Kendric sometimes needed five days to a week of treatment in the hospital to control his pain.

His parents always stayed with him. Deborah slept on a narrow bench in the hospital room. Keith slept in a chair.

“We’d never dream of leaving him,” Deborah said.

Eventually the disease began wreaking severe damage. Kendric developed avascular necrosis in his hips — bone death that occurs when bone is deprived of blood. The condition spread to his back and shoulders. He began taking a large daily dose of gabapentin, a medicine for nerve pain.

His pain never let up. One day he said to Deborah, “Mommy, I’m in pain every single day.”

Kendric wants to be like other kids, but fear of pain crises has held him back. He became increasingly sedentary, spending his days on his iPad, watching anime or building elaborate Lego structures.

Despite his many absences, Kendric kept up in school, maintaining an A average.

Deborah and Keith began to hope for gene therapy. But when they found out what it would cost, they lost some of their hope.

But their insurer approved the treatment in a few weeks, they said.

Now it has begun.

“We always prayed this day would come,” Deborah said. But, she added, “We’re nervous reading through the consents and what he will have to go through.”

Kendric, though, is looking forward to the future. He wants to be a geneticist.

And, he said, “I want to play basketball.”

An earlier version of this article misstated the location of a lab. It is in Allendale, N.J., not Allentown.

How we handle corrections

Gina Kolata reports on diseases and treatments, how treatments are discovered and tested, and how they affect people. More about Gina Kolata

Kenny Holston is a Times photographer based in Washington, primarily covering Congress, the military and the White House. More about Kenny Holston

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Sickle cell patient's success with gene editing raises hopes and questions

In London to address a gene-editing summit last week, Victoria Gray took a break to visit Sir John Soane's Museum. In 2019, Gray became the first patient to be treated for sickle cell disease using CRISPR, an experimental gene-editing technique. She was invited to talk about her experiences at the Third International Summit on Human Genome Editing. Orlando Gili for NPR hide caption

In London to address a gene-editing summit last week, Victoria Gray took a break to visit Sir John Soane's Museum. In 2019, Gray became the first patient to be treated for sickle cell disease using CRISPR, an experimental gene-editing technique. She was invited to talk about her experiences at the Third International Summit on Human Genome Editing.

Victoria Gray was wandering through the British Museum in London last week when she spotted a small wooden cross hanging on the wall.

"It's nice seeing all the old artifacts, especially the cross," Gray said. "Religion is something that I hold close to my heart, and my faith is what brought me this far."

Almost four years ago, Gray became one of the first patients with a genetic disorder — and the first patient with sickle cell disease — to get an experimental treatment that uses the revolutionary gene-editing technique known as CRISPR .

Today, all of Gray's symptoms are gone, and she was in London last week to describe her landmark experience at the Third International Summit on Human Genome Editing . The summit brought together more than 400 scientists, doctors, patients, bioethicists and others from around the world to air the promise of gene editing as well as a host of thorny questions that the technology is raising.

"God did his part for what I prayed about for years," Gray said. "And together, hand in hand, God and science worked for me."

In 2019, Gray was recovering after billions of her bone marrow cells had been modified, using the gene-editing technique CRISPR, and reinfused into her body. Her father, Timothy Wright (right), traveled from Mississippi to Nashville, Tenn., to keep her company. Meredith Rizzo/NPR hide caption

In 2019, Gray was recovering after billions of her bone marrow cells had been modified, using the gene-editing technique CRISPR, and reinfused into her body. Her father, Timothy Wright (right), traveled from Mississippi to Nashville, Tenn., to keep her company.

Shots - Health News

A year in, 1st patient to get gene editing for sickle cell disease is thriving.

An NPR reporting team, which has had exclusive access to chronicle Gray's experience , spent the day with Gray before her appearance at the three-day summit.

"I'm excited," said Gray, who lives in Forest, Mississippi. "Nervous, but excited."

Throughout Gray's life before she got the treatment, the deformed, sickle-shaped red blood cells caused by the genetic disorder would regularly incapacitate her with intense, unpredictable attacks of pain. Those crises would send Gray rushing to the hospital for pain medication and blood transfusions. She could barely get out of bed many days; when she became a mom, she struggled to care for her four children and couldn't finish school or keep a job.

But then she received the treatment on July 2, 2019. Doctors removed some of her bone marrow cells, genetically modified them with CRISPR and infused billions of the modified cells back into her body. The genetic modification was designed to make the cells produce fetal hemoglobin , in the hopes the cells would compensate for the defective hemoglobin that causes the disease .

In 2019, as part of a clinical trial to treat sickle cell disease, Gray had vials of blood drawn by nurses Bonnie Carroll (left) and Kayla Jordan at TriStar Centennial Medical Center in Nashville. Meredith Rizzo/NPR hide caption

In 2019, as part of a clinical trial to treat sickle cell disease, Gray had vials of blood drawn by nurses Bonnie Carroll (left) and Kayla Jordan at TriStar Centennial Medical Center in Nashville.

Gray landed in London before the summit and checked out local tourist sites, including the British Museum. It was her first trip outside the United States. Orlando Gili for NPR hide caption

Gray landed in London before the summit and checked out local tourist sites, including the British Museum. It was her first trip outside the United States.

Gray, who's 37, now works full time as a Walmart cashier, is able to keep up with her teenagers and was eager to explore London on her first trip outside the United States. Though she hadn't slept much on the overnight flight, Gray couldn't wait to see the sights with her husband, Earl.

"I would never have been able to walk this long before," she said while sightseeing through Trafalgar Square. "It's a huge difference — night and day. I feel like I got a second chance."

After the museum, Gray and her husband headed to the London Eye, a huge Ferris wheel that towers over the city. Gray was keen for a ride, even though she's afraid of heights.

"It's a beautiful view," she said as they circled to the top and she saw Big Ben and other landmarks in the distance. "Part of my dreams coming true."

Gray sees the view of the city from the London Eye. Orlando Gili for NPR hide caption

Gray sees the view of the city from the London Eye.

Since undergoing treatment for sickle cell disease using CRISPR, Gray feels stronger and is enjoying travel — she had no issues walking all over London. She says the difference between her life before the treatment and after CRISPR is like "night and day." Orlando Gili for NPR hide caption

Since undergoing treatment for sickle cell disease using CRISPR, Gray feels stronger and is enjoying travel — she had no issues walking all over London. She says the difference between her life before the treatment and after CRISPR is like "night and day."

The next morning, Gray and her husband made their way through the crowd at the conference, held at the Francis Crick Institute, and found seats in the auditorium.

"Hello, everyone. I'm very pleased to see so many people here," said Robin Lovell-Badge , who led the summit.

Speaker after speaker described the latest scientific advances in gene editing.

"There are more than 200 patients to date, including Victoria, Patrick and Carlene pictured here, that have been treated in clinical trials with CRISPR nucleases targeting DNA sequences that, when disrupted, offer clinical benefit," David Liu told the crowd via a remote link.

Liu has developed new gene-editing techniques at the Broad Institute in Cambridge, Massachusetts. "You'll hear more from Victoria about her experience directly later today."

Finally, it was Gray's turn at the podium.

"Good evening. I'm Victoria Gray. And I'm a 37-year-old mother of four and a sickle cell survivor," she began. "Take a moment to go on a journey with me."

For 10 minutes, Gray repeatedly choked back tears as she described her life with sickle cell, including her children's fears that she would die. She detailed one especially tortuous pain crisis.

"During this hospital stay, with a ketamine infusion in one arm and a Dilaudid infusion in the next — but still no pain relief — I called all the doctors into the room and told them I could no longer live like this," Gray said. "I went home and continued to pray, and looked to God for answers."

Gray explained how she finally received the CRISPR gene-edited cells — "supercells," she calls them — as part of a study.

Alexis Thompson (left) of Children's Hospital of Philadelphia and the University of Pennsylvania, Gray (center) and Gautam Dongre of the Indian-based National Alliance of Sickle Cell Organisations were panelists at the gene-editing summit in London. The Royal Society hide caption

Alexis Thompson (left) of Children's Hospital of Philadelphia and the University of Pennsylvania, Gray (center) and Gautam Dongre of the Indian-based National Alliance of Sickle Cell Organisations were panelists at the gene-editing summit in London.

"The life that I once felt like I was only existing in, I am now thriving in," she told the assembled scientists, doctors, bioethicists and others. "I stand here before you today as proof that miracles still happen — and that God and science can coexist."

As Gray walked off the stage, the crowd gave her a standing ovation.

Vertex Pharmaceuticals and CRISPR Therapeutics , the companies that sponsored the study that Gray volunteered for, say they have now treated 75 patients who have sickle cell or the related condition beta thalassemia .

After the gene-editing treatment, 42 of 44 beta thalassemia patients were able to discontinue the transfusions that had been keeping them alive. And all 31 sickle cell patients were free of symptoms, even though all had been previously diagnosed with severe cases.

Based on those results, the companies are asking the Food and Drug Administration to approve the treatment for severe sickle cell and beta thalassemia. That approval could come as soon as this summer and would make it the first therapy created through this sort of gene editing to become widely available.

But for the rest of summit, speakers warned that there are still important questions about this treatment and other gene-editing therapies in the pipeline, including how long the benefits will last. Also, the sickle cell treatment is expected to be very expensive — possibly costing millions of dollars. That raises questions about whether it will be available to the patients who need it the most, especially less affluent people in the U.S. and in countries where sickle cell is most common, such as those in sub-Saharan Africa.

Ethical concerns temper optimism about gene-editing for human diseases

For patients with sickle cell disease, fertility care is about reproductive justice

"I worry that when gene editing comes to market for sickle cell, that the very states in the United States that won't expand Medicaid or access to insurance, which are some of the very states where prevalence is the highest, will inhibit the affordability and availability of the therapy," said Melissa Creary of the University of Michigan, who studies policy issues raised by sickle cell.

An estimated 1,000 babies are born every day worldwide with sickle cell. The disease affects an estimated 100,000 people in the U.S., many of whom are African American, along with an estimated 20 million people worldwide.

"The absolute central factor in the uptake of a new therapy is cost and accessibility. A new therapy can be extremely effective, and even a cure for sickle cell, but if it's not made accessible to the average patient, it won't be used," said Arafa Salim Said of the Sickle Cell Disease Patients Community of Tanzania.

The sickle cell treatment that helped Gray is expected to be expensive once it gets approved by the Food and Drug Administration, potentially putting it out of reach for people who need it most. "It's horrible knowing that something is out there that can cure your disease but you can't access it," Gray told NPR. Orlando Gili for NPR hide caption

The sickle cell treatment that helped Gray is expected to be expensive once it gets approved by the Food and Drug Administration, potentially putting it out of reach for people who need it most. "It's horrible knowing that something is out there that can cure your disease but you can't access it," Gray told NPR.

In addition, the treatment is complicated, requiring a bone marrow transplant. Very few countries in sub-Saharan Africa currently have the resources to perform that procedure.

"I hope this will be available to everyone who needs it," Gray said after speaking and listening to the summit's other presentations. She has relatives who are still struggling with sickle cell. "It's horrible knowing that something is out there that can cure your disease but you can't access it."

• gene-editing
• sickle cell disease

• Cells collected from 1st SCD patient receiving gene therapy Lyfgenia

After collection, stem cells are treated then infused via stem cell transplant

by Andrea Lobo, PhD | May 9, 2024

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Bluebird Bio has announced it’s completed collecting cells from the first sickle cell disease (SCD) patient receiving the gene therapy Lyfgenia (lovotibeglogene autotemcel), following its recent approval in the U.S.

The cells were collected at Children’s National Hospital in Washington D.C., which is part of the company’s national network of qualified treatment centers . The. centers are selected based on their expertise in cell and gene therapy, transplant, and SCD, and they receive specialized training on how to administer Lyfgenia.

“We are thrilled to be the first center in the country to commercially collect cells from a person living with sickle cell disease and are proud to be the trailblazers in using this new approach,” David Jacobsohn, MD, chief of the division of Blood and Marrow Transplantation at Children’s, said in a company press release . “The recent approval of gene therapies to treat patients with sickle cell is an enormous breakthrough in patient care and a silver lining to families witnessing their children’s struggles with this condition.”

Meanwhile, Minaris Regenerative Medicine , a global cell and gene therapy manufacturer, has announced the first commercial run of Lyfgenia at its facility in Allendale, New Jersey.

“The commencement of commercial manufacturing for Lyfgenia represents an important step for the cell and gene therapy industry as it will allow many patients fighting sickle cell disease to benefit from this new, potentially curative medicine,” Hiroto Bando, PhD, Minaris’ CEO, said in a separate press release .

SCD is caused  by mutations in the  HBB gene that lead to an abnormal form of hemoglobin, the protein in red blood cells that carries oxygen through the body, being produced. Defective hemoglobin tends to form clumps and causes red blood cells to acquire a sickle-like shape, which are prone to getting stuck inside blood vessels, restricting blood flow and reducing oxygen delivery to tissues. This can lead to episodes of acute pain known as vaso-occlusive crises (VOCs).

Casgevy gene therapy conditionally approved in EU for SCD and TDT

How does lygenia gene therapy work.

Lyfgenia is a one-time gene therapy approved last year by the U.S. Food and Drug Administration for SCD patients, ages 12 and older, with a history of vaso-occlusive events (VOEs), including VOCs and other sickle cell-related complications. It’s designed to provide patients with a modified HBB  gene that produces a form of hemoglobin, called HbA T87Q , which is resistant to clumping.

The treatment involves collecting patients’ hematopoietic stem cells, or blood cell precursors, and treating them with Lyfgenia before infusing them back into the patient via a stem cell transplant . Before the transplant, patients must undergo a round of chemotherapy to eliminate faulty blood stem cells.

After the transplant, red blood cells generated from the engineered stem cells should produce the anti-sickling hemoglobin, limiting red blood cell sickling and potentially reducing the frequency and severity of VOEs.

Lyfgenia’s approval was based on efficacy data from 36 patients, ages 12-50, who entered the completed Phase 1/2 HGB-206 trial (NCT02140554) , where all received the gene therapy.

Of 32 patients evaluated for the trial’s main efficacy goals, 30 (94%) had no severe VOEs and 28 (88.2%) had no VOEs after the treatment.

Safety data obtained for 54 patients who initiated the process of cell collection showed the most common side effects were inflammation of the lips, mouth, and throat, and low levels of blood cells.

The company is also conducting the Phase 3 HGB-210 trial (NCT04293185) , which is evaluating the efficacy of the gene therapy in about 35 SCD patients, ages 2-50. The trial is ongoing.

A long-term safety and efficacy follow-up study, LTF-307 (NCT04628585) is also underway. It’s open to SCD patients treated with Lyfgenia in previous clinical studies sponsored by the company. The study will follow the participants for 13 additional years.

“Seeing people living with sickle cell disease receive gene therapy in the real world is a vision that has fueled Bluebird for more than 10 years,” said Andrew Obenshain, Bluebird’s president and CEO. “This historic moment comes nearly a century after sickle cell disease was the first genetic disorder to be characterized at the molecular level and almost a decade after Bluebird initiated clinical development for Lyfgenia. We are grateful to the patients, caregivers, researchers, and clinicians whose work made this milestone possible, and look forward to continued partnership with the sickle cell disease community.”

About the Author

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Advances in the diagnosis and treatment of sickle cell disease

• A. M. Brandow 1 &
• R. I. Liem   ORCID: orcid.org/0000-0003-2057-3749 2  

Journal of Hematology & Oncology volume  15 , Article number:  20 ( 2022 ) Cite this article

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Sickle cell disease (SCD), which affects approximately 100,000 individuals in the USA and more than 3 million worldwide, is caused by mutations in the βb globin gene that result in sickle hemoglobin production. Sickle hemoglobin polymerization leads to red blood cell sickling, chronic hemolysis and vaso-occlusion. Acute and chronic pain as well as end-organ damage occur throughout the lifespan of individuals living with SCD resulting in significant disease morbidity and a median life expectancy of 43 years in the USA. In this review, we discuss advances in the diagnosis and management of four major complications: acute and chronic pain, cardiopulmonary disease, central nervous system disease and kidney disease. We also discuss advances in disease-modifying and curative therapeutic options for SCD. The recent availability of l -glutamine, crizanlizumab and voxelotor provides an alternative or supplement to hydroxyurea, which remains the mainstay for disease-modifying therapy. Five-year event-free and overall survival rates remain high for individuals with SCD undergoing allogeneic hematopoietic stem cell transplant using matched sibling donors. However, newer approaches to graft-versus-host (GVHD) prophylaxis and the incorporation of post-transplant cyclophosphamide have improved engraftment rates, reduced GVHD and have allowed for alternative donors for individuals without an HLA-matched sibling. Despite progress in the field, additional longitudinal studies, clinical trials as well as dissemination and implementation studies are needed to optimize outcomes in SCD.

Introduction

Sickle cell disease (SCD), a group of inherited hemoglobinopathies characterized by mutations that affect the β-globin chain of hemoglobin, affects approximately 100,000 people in the USA and more than 3 million people worldwide [ 1 , 2 ]. SCD is characterized by chronic hemolytic anemia, severe acute and chronic pain as well as end-organ damage that occurs across the lifespan. SCD is associated with premature mortality with a median age of death of 43 years (IQR 31.5–55 years) [ 3 ]. Treatment requires early diagnosis, prevention of complications and management of end-organ damage. In this review, we discuss recent advances in the diagnosis and management of four major complications in SCD: acute and chronic pain, cardiopulmonary disease, central nervous system disease and kidney disease. Updates in disease-modifying and curative therapies for SCD are also discussed.

Molecular basis and pathophysiology

Hemoglobin S (HbS) results from the replacement of glutamic acid by valine in the sixth position of the β-globin chain of hemoglobin (Fig.  1 ). Severe forms of SCD include hemoglobin SS due to homozygous inheritance of HbS and S/β 0 thalassemia due to co-inheritance of HbS with the β 0 thalassemia mutation. Other forms include co-inheritance of HbS with other β-globin gene mutations such as hemoglobin C, hemoglobin D-Los Angeles/Punjab or β + thalassemia. Hb S has reduced solubility and increased polymerization, which cause red blood cell sickling, hemolysis and vaso-occlusion (Table 1 ) that subsequently lead to pain episodes and end-organ damage such as cardiopulmonary, cerebrovascular and kidney disease (Table 2 ).

Genetic and molecular basis of sickle cell disease. SCD is caused by mutations in the β globin gene, located on the β globin locus found on the short arm of chromosome 11. The homozygous inheritance of Hb S or co-inheritance of Hb S with the β 0 thalassemia mutation results in the most common forms of severe SCD. Co-inheritance of Hb S with other variants such as Hb C, Hb D-Los Angeles/Punjab, Hb O-Arab or β + thalassemia also leads to clinically significant sickling syndromes (LCR, locus control region; HS, hypersensitivity site)

Acute and chronic pain

Severe intermittent acute pain is the most common SCD complication and accounts for over 70% of acute care visits for individuals with SCD [ 4 ]. Chronic daily pain increases with older age, occurring in 30–40% of adolescents and adults with SCD [ 5 , 6 ]. Acute pain is largely related to vaso-occlusion of sickled red blood cells with ischemia–reperfusion injury and tissue infarction and presents in one isolated anatomic location (e.g., arm, leg, back) or multiple locations. Chronic pain can be caused by sensitization of the central and/or peripheral nervous system and is often diffuse with neuropathic pain features [ 7 , 8 ]. A consensus definition for chronic pain includes “Reports of ongoing pain on most days over the past 6 months either in a single location or multiple locations” [ 9 ]. Disease complications such as avascular necrosis (hip, shoulder) and leg ulcers also cause chronic pain [ 9 ].

Diagnosis of acute and chronic pain

The gold standard for pain assessment and diagnosis is patient self-report. There are no reliable diagnostic tests to confirm the presence of acute or chronic pain in individuals with SCD except when there are identifiable causes like avascular necrosis on imaging or leg ulcers on exam. The effects of pain on individuals’ function are assessed using patient-reported outcome measures (PROs) that determine to what extent pain interferes with individuals’ daily function. Tools shown to be valid, reliable and responsive can be used in clinical practice to track patients’ pain-related function over time to determine additional treatment needs and to compare to population norms [ 10 ]. There are currently no plasma pain biomarkers that improve assessment and management of SCD acute or chronic pain.

Depression and anxiety as co-morbid conditions in SCD can contribute to increased pain, more pain-related distress/interference and poor coping [ 11 ]. The prevalence of depression and anxiety range from 26–33% and 6.5–36%, respectively, in adults with SCD [ 11 , 12 , 13 ]. Adults with SCD have an 11% higher prevalence of depression compared to Black American adults without SCD [ 14 ]. Depression and anxiety can be assessed using self-reported validated screening tools (e.g., Depression: Patient Health Questionnaire (PHQ-9) [ 15 ] for adults, Center for Epidemiologic Studies Depression Scale for Children (CES-DC) [ 16 ], PROMIS assessments for adults and children; Anxiety: Generalized Anxiety Disorder 7-item (GAD-7) scale for adults, State-Trait Anxiety Inventory for Children (STAIC) [ 17 ], PROMIS assessments for adults and children). Individuals who screen positive using these tools should be referred for evaluation by a psychologist/psychiatrist.

Management of acute and chronic pain

The goal of acute pain management is to provide sufficient analgesia to return patients to their usual function, which may mean complete resolution of pain for some or return to baseline chronic pain for others. The goal of chronic pain management is to optimize individuals’ function, which may not mean being pain free. When there is an identifiable cause of chronic pain, treatment of the underlying issue (e.g., joint replacement for avascular necrosis, leg ulcer treatment) is important. Opioids, oral for outpatient management and intravenous for inpatient management, are first line therapy for acute SCD pain. In the acute care setting, analgesics should be initiated within 30–60 min of triage [ 18 ]. Ketamine, a non-opioid analgesic, can be prescribed at sub-anesthetic (analgesic) intravenous doses (0.1–0.3 mg/kg per h, maximum 1 mg/kg per h) as adjuvant treatment for acute SCD pain refractory to opioids [ 18 , 19 ]. In an uncontrolled observational study of 85 patients with SCD receiving ketamine infusions for acute pain, ketamine was associated with a decrease in mean opioid consumption by oral morphine equivalents (3.1 vs. 2.2 mg/kg/day, p  < 0.001) and reductions in mean pain scores (0–10 scale) from baseline until discontinuation of the infusion (7.81 vs. 5.44, p  < 0.001) [ 20 ]. Nonsteroidal anti-inflammatory drugs (NSAIDs) are routinely used as adjuvant therapy for acute pain treatment [ 18 ]. In a RCT ( n  = 20) of hospitalized patients with acute pain, ketorolac was associated with lower total dose of meperidine required (1866.7 ± 12.4 vs. 2804.5 ± 795.1 mg, p  < 0.05) and shorter hospitalization (median 3.3 vs. 7.2 days, p  = 0.027) [ 21 ]. In a case series of children treated for 70 acute pain events in the ED, 53% of events resolved with ketorolac and hydration alone with reduction in 100 mm visual analog scale (VAS) pain score from 60 to 13 ( p  < 0.001) [ 22 ]. Patients at risk for NSAID toxicity (e.g., renal impairment, on anticoagulation) should be identified.

Despite paucity of data, chronic opioid therapy (COT) can be considered after assessing benefits versus harms [ 23 ] and the functional status of patients with SCD who have chronic pain. Harms of COT seen in patient populations other than SCD are dose dependent and include myocardial infarction, bone fracture, increased risk of motor vehicle collisions, sexual dysfunction and mortality [ 23 ]. There are few published studies investigating non-opioid analgesics for chronic SCD pain [ 24 , 25 , 26 ]. In a randomized trial of 39 participants, those who received Vitamin D experienced a range of 6–10 pain days over 24 weeks while those who received placebo experienced 10–16 pain days, which was not significantly different [ 26 ]. In a phase 1, uncontrolled trial of 18 participants taking trifluoperazine, an antipsychotic drug, 8 participants showed a 50% reduction in the VAS (10 cm horizontal line) pain score from baseline on at least 3 assessments over 24 h without severe sedation or supplemental opioid analgesics, 7 participants showed pain reduction on 1 assessment, and the remaining 3 participants showed no reduction [ 24 ]. Although published data are not available for serotonin and norepinephrine reuptake inhibitors (SNRIs), gabapentinoids and tricyclic antidepressants (TCAs) in individuals with SCD, evidence supports their use in fibromyalgia, a chronic pain condition similar to SCD chronic pain in mechanism. A Cochrane Review that included 10 RCTs ( n  = 6038) showed that the SNRIs milnacipran and duloxetine, compared to placebo, were associated with a reduction in pain [ 27 ]. A systematic review and meta-analysis of 9 studies ( n  = 520) showed the TCA amitriptyline improved pain intensity and function [ 28 ]. Finally, a meta-analysis of 5 RCTs ( n  = 1874) of the gabapentinoid pregabalin showed a reduction in pain intensity [ 29 ]. Collectively, the indirect evidence from fibromyalgia supports the conditional recommendation in current SCD practice guidelines to consider these 3 drug classes for chronic SCD pain treatment [ 18 ]. Standard formulary dosing recommendations should be followed and reported adverse effects considered.

Non-pharmacologic therapies (e.g., integrative, psychological-based therapies) are important components of SCD pain treatment. In a case–control study of 101 children with SCD and chronic pain referred for cognitive behavioral therapy (CBT) (57 CBT, 44 no CBT) [ 30 ], CBT was associated with more rapid decrease in pain hospitalizations (estimate − 0.63, p  < 0.05) and faster reduction in hospital days over time (estimate − 5.50, p  < 0.05). Among 18 children who received CBT and completed PROs pre- and 12 months posttreatment, improvements were seen in mean pain intensity (5.47 vs. 3.76, p  = 0.009; 0–10 numeric rating pain scale), functional disability (26.24 vs. 15.18, p  < 0.001; 0–60 score range) and pain coping (8.00 vs. 9.65, p  = 0.03; 3–15 score range) post treatment [ 30 ]. In 2 uncontrolled clinical trials, acupuncture was associated with a significant reduction in pain scores by 2.1 points (0–10 numeric pain scale) in 24 participants immediately after treatment [ 31 ] or a significant mean difference in pre-post pain scores of 0.9333 (0–10 numeric pain scale) ( p  < 0.000) after 33 acupuncture sessions [ 32 ].

Cardiopulmonary disease

Cardiopulmonary disease is associated with increased morbidity and mortality in individuals with SCD. Pulmonary hypertension (PH), most commonly pulmonary arterial hypertension (PAH), is present based on right-heart catheterization in up to 10% of adults with SCD [ 33 ]. Chronic intravascular hemolysis represents the biggest risk factor for development of PAH in SCD and leads to pulmonary arteriole vasoconstriction and smooth muscle proliferation. Based on pulmonary function testing (PFT), obstructive lung disease may be observed in 16% of children and 8% of adults with SCD, while restrictive lung disease may be seen in up to 28% of adults and only 7% of children with SCD [ 34 , 35 ]. Sleep-disordered breathing, which can manifest as obstructive sleep apnea or nocturnal hypoxemia, occurs in up to 42% of children and 46% of adults with SCD [ 36 , 37 ]. Cardiopulmonary disease, including PH or restrictive lung disease, presents with dyspnea with or without exertion, chest pain, hypoxemia or exercise intolerance that is unexplained or increased from baseline. Obstructive lung disease can also present with wheezing.

Diagnosis of cardiopulmonary disease

The confirmation of PH in patients with SCD requires right-heart catheterization. Recently, the mean pulmonary artery pressure threshold used to define PH in the general population was lowered from ≥ 25 to ≥ 20 mm Hg [ 38 ]. Elevated peak tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/s on Doppler echocardiogram (ECHO) is associated with early mortality in adults with SCD and may suggest elevated pulmonary artery pressures, especially when other signs of PH (e.g., right-heart strain, septal flattening) or left ventricular diastolic dysfunction, which may contribute to PH, are present [ 39 ]. However, the positive predictive value (PPV) of peak TRJV alone for identifying PH in adults with SCD is only 25% [ 40 ]. Increasing the peak TRJV threshold to at least 2.9 m/s has been shown to increase the PPV to 64%. For a peak TRJV of 2.5–2.8 m/s, an increased N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥ 164.5 pg/mL or a reduced 6-min walk distance (6MWD) < 333 m can also improve the PPV to 62% with a false negative rate of 7% [ 33 , 40 , 41 ].

PFT, which includes spirometry and measurement of lung volumes and diffusion capacity, is standard for diagnosing obstructive and restrictive lung disease in patients with SCD. Emerging modalities include impulse oscillometry, a non-invasive method using forced sound waves to detect changes in lower airway mechanics in individuals unable to perform spirometry [ 42 ], and airway provocation studies using cold air or methacholine to reveal latent airway hyperreactivity [ 43 ]. Formal in-lab, sleep study/polysomnography remains the gold standard to evaluate for sleep-disordered breathing, which may include nocturnal hypoxemia, apnea/hypopnea events and other causes of sleep disruption. Nocturnal hypoxemia may increase red blood cell sickling, cellular adhesion and endothelial dysfunction. In 47 children with SCD, mean overnight oxygen saturation was higher in those with grade 0 compared to grade 2 or 3 cerebral arteriopathy (97 ± 1.6 vs. 93.9 ± 3.7 vs. 93.5 ± 3.0%, p  < 0.01) on magnetic resonance angiography and lower overnight oxygen saturation was independently associated with mild, moderate or severe cerebral arteriopathy after adjusting for reticulocytosis (OR 0.50, 95% CI 0.26–0.96, p  < 0.05) [ 44 ].

Management of cardiopulmonary disease

Patients with SCD who have symptoms suggestive of cardiopulmonary disease, such as worsening dyspnea, hypoxemia or reduced exercise tolerance, should be evaluated with a diagnostic ECHO and PFT. The presence of snoring, witnessed apnea, respiratory pauses or hypoxemia during sleep, daytime somnolence or nocturnal enuresis in older children and adults is sufficient for a diagnostic sleep study.

Without treatment, the mortality rate in SCD patients with PH is high compared to those without (5-year, all-cause mortality rate of 32 vs. 16%, p  < 0.001) [ 33 ]. PAH-targeted therapies should be considered for SCD patients with PAH confirmed by right-heart catheterization. However, the only RCT ( n  = 6) in individuals with SCD and PAH confirmed by right-heart catheterization (bosentan versus placebo) was stopped early for poor accrual with no efficacy endpoints analyzed [ 45 ]. In SCD patients with elevated peak TRJV, a randomized controlled trial ( n  = 74) of sildenafil, a phosphodiesterase-5 inhibitor, was discontinued early due to increased pain events in the sildenafil versus placebo arm (35 vs. 14%, p  = 0.029) with no treatment benefit [ 46 ]. Despite absence of clinical trial data, patients with SCD and confirmed PH should be considered for hydroxyurea or monthly red blood cell transfusions given their disease-modifying benefits. In a retrospective analysis of 13 adults with SCD and PAH, 77% of patients starting at a New York Heart Association (NYHA) functional capacity class III or IV achieved class I/II after a median of 4 exchange transfusions with improvement in median pulmonary vascular resistance (3.7 vs. 2.8 Wood units, p  = 0.01) [ 47 ].

Approximately 28% of children with SCD have asthma, which is associated with increased pain episodes that may result from impaired oxygenation leading to sickling and vaso-occlusion as well as with acute chest syndrome and higher mortality [ 48 , 49 , 50 ]. First line therapies include standard beta-adrenergic bronchodilators and supplemental oxygen as needed. When corticosteroids are indicated, courses should be tapered over several days given the risk of rebound SCD pain from abrupt discontinuation. Inhaled corticosteroids such as fluticasone proprionate or beclomethasone diproprionate are reserved for patients with recurrent asthma exacerbations, but their anti-inflammatory effects and impact on preventing pain episodes in patients with SCD who do not have asthma is under investigation [ 51 ]. Finally, management of sleep-disordered breathing is tailored to findings on formal sleep study in consultation with a sleep/pulmonary specialist.

Central nervous system (CNS) complications

CNS complications, such as overt and silent cerebral infarcts, cause significant morbidity in individuals with SCD. Eleven percent of patients with HbSS disease by age 20 years and 24% by age 45 years will have had an overt stroke [ 52 ]. Silent cerebral infarcts occur in 39% by 18 years and in > 50% by 30 years [ 53 , 54 ]. Patients with either type of stroke are at increased risk of recurrent stroke [ 55 ]. Overt stroke involves large-arteries, including middle cerebral arteries and intracranial internal carotid arteries, while silent cerebral infarcts involve penetrating arteries. The pathophysiology of overt stroke includes vasculopathy, increased sickled red blood cell adherence, and hemolysis-induced endothelial activation and altered vasomotor tone [ 56 ]. Overt strokes present as weakness or paresis, dysarthria or aphasia, seizures, sensory deficits, headache or altered level of consciousness, while silent cerebral infarcts are associated with cognitive deficits, including lower IQ and impaired academic performance.

Diagnosis of CNS complications in SCD

Overt stroke is diagnosed by evidence of acute infarct on brain MRI diffusion-weighted imaging and focal deficit on neurologic exam. A silent cerebral infarct is defined by a brain “MRI signal abnormality at least 3 mm in one dimension and visible in 2 planes on fluid-attenuated inversion recovery (FLAIR) T2-weighted images” and no deficit on neurologic exam [ 57 ]. Since silent cerebral infarcts cannot be detected clinically, a screening baseline brain MRI is recommended in school-aged children with SCD [ 58 ]. Recent SCD clinical practice guidelines also suggest a screening brain MRI in adults with SCD to facilitate rehabilitation services, patient and family understanding of cognitive deficits and further needs assessment [ 58 ]. An MRA should be added to screening/diagnostic MRIs to evaluate for cerebral vasculopathy (e.g., moyamoya), which may increase risk for recurrent stroke or hemorrhage [ 59 ].

Annual screening for increased stroke risk by transcranial doppler (TCD) ultrasound is recommended by the American Society of Hematology for children 2–16 years old with HbSS or HbS/β° thalassemia [ 58 ]. Increased stroke risk on non-imaging TCD is indicated by abnormally elevated cerebral blood flow velocity, defined as ≥ 200 cm/s (time-averaged mean of the maximum velocity) on 2 occasions or a single velocity of > 220 cm/s in the distal internal carotid or proximal middle cerebral artery [ 60 ]. Many centers rely on imaging TCD, which results in velocities 10–15% lower than values obtained by non-imaging protocols and therefore, require adjustments to cut-offs for abnormal velocities. Data supporting stroke risk assessment using TCD are lacking for adults with SCD and standard recommendations do not exist.

Neurocognitive deficits occur in over 30% of children and adults with severe SCD [ 61 , 62 ]. These occur as a result of overt and/or silent cerebral infarcts but in some patients, the etiology is unknown. The Bright Futures Guidelines for Health Supervision of Infants, Children and Adolescents or the Cognitive Assessment Toolkit for adults are commonly used tools to screen for developmental delays or neurocognitive impairment [ 58 ]. Abnormal results should prompt referral for formal neuropsychological evaluation, which directs the need for brain imaging to evaluate for silent cerebral infarcts and facilitate educational/vocational accommodations.

Management of CNS complications

Monthly chronic red blood cell transfusions to suppress HbS < 30% are standard of care for primary stroke prevention in children with an abnormal TCD. In an RCT of 130 children, chronic transfusions, compared to no transfusions, were associated with a difference in stroke risk of 92% (1 vs. 10 strokes, p  < 0.001) [ 60 ]. However, children with abnormal TCD and no MRI/MRA evidence of cerebral vasculopathy can safely transition to hydroxyurea after 1 year of transfusions [ 63 ]. Lifelong transfusions to maintain HbS < 30% remain standard of care for secondary stroke prevention in individuals with overt stroke [ 64 ]. Chronic monthly red blood cell transfusions should also be considered for children with silent cerebral infarct [ 58 ]. In a randomized controlled trial ( n  = 196), monthly transfusions, compared to observation without hydroxyurea, reduced risk of overt stroke, new silent cerebral infarct or enlarging silent cerebral infarct in children with HbSS or HbS/β 0 thalassemia and an existing silent cerebral infarct (2 vs. 4.8 events, incidence rate ratio of 0.41, 95% CI 0.12–0.99, p  = 0.04) [ 57 ].

Acute stroke treatment requires transfusion therapy to increase cerebral oxygen delivery. Red blood cell exchange transfusion, defined as replacement of patients’ red blood cells with donor red blood cells, to rapidly reduce HbS to < 30% is the recommended treatment as simple transfusion alone is shown to have a fivefold greater relative risk (57 vs. 21% with recurrent stroke, RR = 5.0; 95% CI 1.3–18.6) of subsequent stroke compared to exchange transfusion [ 65 ]. However, a simple transfusion is often given urgently while preparing for exchange transfusion [ 58 ]. Tissue plasminogen activator (tPA) is not recommended for children with SCD who have an acute stroke since the pathophysiology of SCD stroke is less likely to be thromboembolic in origin and there is risk for harm. Since the benefits and risks of tPA in adults with SCD and overt stroke are not clear, its use depends on co-morbidities, risk factors and stroke protocols but should not delay or replace prompt transfusion therapy.

Data guiding treatment of SCD cerebral vasculopathy (e.g., moyamoya) are limited, and only nonrandomized, low-quality evidence exists for neurosurgical interventions (e.g., encephaloduroarteriosynangiosis) [ 66 ]. Consultation with a neurosurgeon to discuss surgical options in patients with moyamoya and history of stroke or transient ischemic attack should be considered [ 58 ].

Kidney disease

Glomerulopathy, characterized by hyperfiltration leading to albuminuria, is an early asymptomatic manifestation of SCD nephropathy and worsens with age. Hyperfiltration, defined by an absolute increase in glomerular filtration rate, may be seen in 43% of children with SCD [ 67 ]. Albuminuria, defined by the presence of urine albumin ≥ 30 mg/g over 24 h, has been observed in 32% of adults with SCD [ 68 ]. Glomerulopathy results from intravascular hemolysis and endothelial dysfunction in the renal cortex. Medullary hypoperfusion and ischemia also contribute to kidney disease in SCD, causing hematuria, urine concentrating defects and distal tubular dysfunction [ 69 ]. Approximately 20–40% of adults with SCD develop chronic kidney disease (CKD) and are at risk of developing end-stage renal disease (ESRD), with rapid declines in estimated glomerular filtration rate (eGFR) > 3 mL/min/1.73 m 2 associated with increased mortality (HR 2.4, 95% CI 1.31–4.42, p  = 0.005) [ 68 ].

Diagnosis of kidney disease in SCD

The diagnosis of sickle cell nephropathy is made by detecting abnormalities such as albuminuria, hematuria or CKD rather than by distinct diagnostic criteria in SCD, which have not been developed. Traditional markers of kidney function such as serum creatinine and eGFR should be interpreted with caution in individuals with SCD because renal hyperfiltration affects their accuracy by increasing both. Practical considerations preclude directly measuring GFR by urine or plasma clearance techniques, which achieves the most accurate results. The accuracy of eGFR, however, may be improved by equations that incorporate serum cystatin C [ 70 ].

Since microalbuminuria/proteinuria precedes CKD in SCD, annual screening for urine microalbumin/protein is recommended beginning at age 10 years [ 71 ]. When evaluating urine for microalbumin concentration, samples from first morning rather than random voids are preferable to exclude orthostatic proteinuria. Recent studies suggest HMOX1 and APOL1 gene variants may be associated with CKD in individuals with SCD [ 72 ]. Potential novel predictors of acute kidney injury in individuals with SCD include urine biomarkers kidney injury molecule 1 (KIM-1) [ 73 ], monocyte chemotactic protein 1 (MCP-1) [ 74 ] and neutrophil gelatinase-associated lipocalin (NGAL) [ 75 ]. Their contribution to chronic kidney disease and interaction with other causes of kidney injury in SCD (e.g., inflammation, hemolysis) are not clear.

Management of kidney disease

Managing kidney complications in SCD should focus on mitigating risk factors for acute and chronic kidney injury such as medication toxicity, reduced kidney perfusion from hypotension and dehydration, and general disease progression, as well as early screening and treatment of microalbuminuria/proteinuria. Acute kidney injury, either an increase in serum creatinine ≥ 0.3 mg/dL or a 50% increase in serum creatinine from baseline, is associated with ketorolac use in children with SCD hospitalized for pain [ 76 ]. Increasing intravenous fluids to maintain urine output > 0.5 to 1 mL/kg/h and limiting NSAIDs and antibiotics associated with nephrotoxicity in this setting are important. Despite absence of controlled clinical trials, hydroxyurea may be associated with improvements in glomerular hyperfiltration and urine concentrating ability in children with SCD [ 77 , 78 ]. Hydroxyurea is also associated with a lower prevalence (34.7 vs. 55.4%, p  = 0.01) and likelihood of albuminuria (OR 0.28, 95% CI 0.11–0.75, p  = 0.01) in adults with SCD after adjusting for age, angiotensin-converting enzyme inhibitor (ACE-I)/angiotensin receptor blockade (ARB) use and major disease risk factors [ 79 ].

ACE-I or ARB therapy reduces microalbuminuria in patients with SCD. In a phase 2 trial of 36 children and adults, a ≥ 25% reduction in urine albumin-to-creatinine ratio was observed in 83% ( p  < 0.0001) and 58% ( p  < 0.0001) of patients with macroalbuminuria (> 300 mg/g creatinine) and microalbuminuria (30–300 mg/g creatinine), respectively, after 6 months of treatment with losartan at a dose of 0.7 mg/kg/day (max of 50 mg) in children and 50 mg daily in adults [ 80 ]. However, ACE-I or ARB therapy has not been shown to improve kidney function or prevent CKD. Hemodialysis is associated with a 1-year mortality rate of 26.3% after starting hemodialysis and an increase risk of death in SCD patients with ESRD compared to non-SCD patients with ESRD (44.6 vs. 34.5% deaths, mortality hazard ratio of 2.8, 95% CI 2.31–3.38) [ 81 ]. Renal transplant should be considered for individuals with SCD and ESRD because of recent improvements in renal graft survival and post-transplant mortality [ 82 ].

Disease-modifying therapies in SCD

Since publication of its landmark trial in 1995, hydroxyurea continues to represent a mainstay of disease-modifying therapy for SCD. Hydroxyurea induces fetal hemoglobin production through stress erythropoiesis, reduces inflammation, increases nitric oxide and decreases cell adhesion. The FDA approved hydroxyurea in 1998 for adults with SCD. Subsequently, hydroxyurea was FDA approved for children in 2017 to reduce the frequency pain events and need for blood transfusions in children ≥ 2 years of age [ 63 ]. The landscape of disease-modifying therapies, however, has improved with the recent FDA approval of 3 other treatments— l -glutamine and crizanlizumab for reducing acute complications (e.g., pain), and voxelotor for improving anemia (Table 3 ) [ 83 , 84 , 85 ]. Other therapies in current development focus on inducing fetal hemoglobin, reducing anti-sickling or cellular adhesion, or activating pyruvate kinase-R.

l -glutamine

Glutamine is required for the synthesis of glutathione, nicotinamide adenine dinucleotide and arginine. The essential amino acid protects red blood cells against oxidative damage, which forms the basis for its proposed utility in SCD. The exact mechanism of benefit in SCD, however, remains unclear. In a phase 3 RCT of 230 participants (hemoglobin SS or S/β 0 thalassemia), l -glutamine compared to placebo was associated with fewer pain events (median 3 vs. 4, p  = 0.005) and hospitalizations for pain (median 2 vs. 3, p  = 0.005) over the 48-week treatment period [ 84 ]. The percentage of patients who had at least 1 episode of acute chest syndrome, defined as presence of chest wall pain with fever and a new pulmonary infiltrate, was lower in the l -glutamine group (8.6 vs. 23.1%, p  = 0.003). There were no significant between-group differences in hemoglobin, hematocrit or reticulocyte count. Common side effects of l -glutamine include GI upset (constipation, nausea, vomiting and abdominal pain) and headaches.

Crizanlizumab

P-selectin expression, triggered by inflammation, promotes adhesion of neutrophils, activated platelets and sickle red blood cells to the endothelial surface and to each other, which promotes vaso-occlusion in SCD. Crizanlizumab, given as a monthly intravenous infusion, is a humanized monoclonal antibody that binds P-selectin and blocks the adhesion molecule’s interaction with its ligand, P-selectin glycoprotein ligand 1. FDA approval for crizanlizumab was based on a phase 2 RCT ( n  = 198, all genotypes), in which the median rate of pain events (primary endpoint) was lower (1.63 vs. 2.68, p  = 0.01) and time to first pain event (secondary endpoint) was longer (4.07 vs. 1.38 months, p  = 0.001) for patients on high-dose crizanlizumab (5 mg/kg/dose) compared to placebo treated for 52 weeks (14 doses total) [ 83 ]. In this trial, patients with SCD on chronic transfusion therapy were excluded, but those on stable hydroxyurea dosing were not. Adverse events were uncommon but included headache, back pain, nausea, arthralgia and pain in the extremity.

Polymerization of Hb S in the deoxygenated state represents the initial step in red blood cell sickling, which leads to reduced red blood cell deformability and increased hemolysis. Voxelotor is a first-in-class allosteric modifier of Hb S that increases oxygen affinity. The primary endpoint for the phase 3 RCT of voxelotor ( n  = 274, all genotypes) that led to FDA approval was an increase in hemoglobin of at least 1 g/dL after 24 weeks of treatment [ 85 ]. More participants receiving 1500 mg daily of oral voxelotor versus placebo had a hemoglobin response of at least 1 g/dL (51%, 95% CI 41–61 vs. 7%, 95% CI 1–12, p < 0.001). Approximately 2/3 of the participants in these trials were on hydroxyurea, with treatment benefits observed regardless of hydroxyurea status. Despite improvements associated with voxelotor in biomarkers of hemolysis (reticulocyte count, indirect bilirubin and lactate dehydrogenase), annualized incidence rate of vaso-occlusive crisis was not significantly different among treatment groups. Adverse events included headaches, GI symptoms, arthralgia, fatigue and rash.

Curative therapies in SCD

For individuals with SCD undergoing hematopoietic stem cell transplantation (HSCT) using HLA-matched sibling donors and either myeloablative or reduced-intensity conditioning regimens, the five-year event-free and overall survival is high at 91% and 93%, respectively [ 86 ]. Limited availability of HLA-matched sibling donors in this population requires alternative donors or the promise of autologous strategies such as gene-based therapies (i.e. gene addition, transfer or editing) (Table 4 ). Matched unrelated donors have not been used routinely due to increased risk of graft-versus-host disease (GVHD) as high as 19% (95% CI 12–28) in the first 100 days for acute GVHD and 29% (95% CI 21–38) over 3 years for chronic GVHD [ 87 ]. Haplo-identical HSCT, using biological parents or siblings as donors, that incorporate post-transplant cyclophosphamide demonstrates acceptable engraftment rates, transplant-related morbidity and overall mortality [ 88 ]. Regardless of allogeneic HSCT type, older age is associated with lower event-free (102/418 vs. 72/491 events, HR 1.74, 95% CI 1.24–2.45) and overall survival (54/418 vs. 22/491 events, HR 3.15, 95% CI 1.86–5.34) in patients ≥ 13 years old compared to < 12 years old undergoing HSCT [ 87 ].

Advancing research in SCD

Despite progress to date, additional high-quality, longitudinal data are needed to better understand the natural history of the disease and to inform optimal screening for SCD-related complications. In the era of multiple FDA-approved therapies with disease-modifying potential, clinical trials to evaluate additional indications and test them in combination with or compared to each other are needed. Dissemination and implementation studies are also needed to identify barriers and facilitators related to treatment in everyday life, which can be incorporated into decision aids and treatment algorithms for patients and their providers [ 89 ]. Lastly, continued efforts should acknowledge social determinants of health and other factors that affect access and disease-related outcomes such as the role of third-party payers, provider and patient education, health literacy and patient trust. Establishing evidence-derived quality of care metrics can also drive public policy changes required to ensure care optimization for this population.

Conclusions

SCD is associated with complications that include acute and chronic pain as well as end-organ damage such as cardiopulmonary, cerebrovascular and kidney disease that result in increased morbidity and mortality. Several well-designed clinical trials have resulted in key advances in management of SCD in the past decade. Data from these trials have led to FDA approval of 3 new drugs, l -glutamine, crizanlizumab and voxelotor, which prevent acute pain and improve chronic anemia. Moderate to high-quality data support recommendations for managing SCD cerebrovascular disease and early kidney disease. However, further research is needed to determine the best treatment for chronic pain and cardiopulmonary disease in SCD. Comparative effectiveness research, dissemination and implementation studies and a continued focus on social determinants of health are also essential.

Availability of data and materials

Not applicable.

Abbreviations

Six-minute walk distance

Angiotensin-converting enzyme inhibitor

Angiotensin receptor blockade

Cognitive behavioral therapy

Chronic kidney disease

Chronic opioid therapy

Echocardiogram

End stage renal disease

Fluid-attenuated inversion recovery

Glomerular filtration rate

Graft-versus-host disease

Hemoglobin S

Hematopoietic stem cell transplant

Nonsteroidal anti-inflammatory drugs

N-terminal pro-brain natriuretic peptide

New York Heart Association

Pulmonary arterial hypertension

Pulmonary function test

Pulmonary hypertension

Positive predictive value

Patient-reported outcomes

Randomized controlled trial

• Sickle cell disease

Serotonin and norepinephrine reuptake inhibitors

Tricyclic antidepressants

Transcranial Doppler

Tissue plasminogen activator

Tricuspid regurgitant jet velocity

Visual Analog Scale

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Brandow, A.M., Liem, R.I. Advances in the diagnosis and treatment of sickle cell disease. J Hematol Oncol 15 , 20 (2022). https://doi.org/10.1186/s13045-022-01237-z

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Sickle cell anemia.

Ankit Mangla ; Moavia Ehsan ; Nikki Agarwal ; Smita Maruvada .

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• Continuing Education Activity

Sickle cell anemia is an inherited disorder of the globin chains that causes hemolysis and chronic organ damage. Sickle cell anemia is the most common form of sickle cell disease (SCD), with a lifelong affliction of hemolytic anemia requiring blood transfusions, pain crises, and organ damage. Since the first description of the irregular sickle-shaped red blood cells (RBC) more than 100 years ago, our understanding of the disease has evolved tremendously. Recent advances in the field, more so within the last three decades, have alleviated symptoms for countless patients, especially in high-income countries. This activity reviews the pathophysiology, presentation, complications, diagnosis, and treatment of sickle cell anemia and also highlights the role of the interprofessional team in the management of these patients.

• Describe the pathophysiology of sickle cell anemia.
• Summarize the epidemiology of sickle-cell anemia.
• List the management options for sickle cell anemia.
• Outline the importance of cooperation among healthcare professionals to educate the patients on getting vaccinated, remaining hydrated, and timely follow-up to prevent the development of complications in those with sickle cell disease.
• Introduction

Sickle cell disease (SCD) refers to a group of hemoglobinopathies that include mutations in the gene encoding the beta subunit of hemoglobin. The first description of SCA 'like' disorder was provided by Dr. Africanus Horton in his book The Disease of Tropical Climates and their treatment (1872). However, it was not until 1910 when Dr. James B Herrick and Dr. Ernest Irons reported noticing 'sickle-shaped' red cells in a dental student (Walter Clement Noel from Grenada). [1] In 1949, independent reports from Dr. James V Neel and Col. E. A. Beet described the patterns of inheritance in patients with SCD. In the same year, Dr. Linus Pauling described the molecular nature of sickle hemoglobin (HbS) in his paper 'Sickle Cell Anemia Hemoglobin.' Ingram Vernon, in 1956, used a fingerprinting technique to describe the replacement of negatively charged glutamine with neutral valine and validated the findings of Linus Pauling. [2]   

Within the umbrella of SCD, many subgroups exist, namely sickle cell anemia (SCA), hemoglobin SC disease (HbSC), and hemoglobin sickle-beta-thalassemia (beta-thalassemia positive or beta-thalassemia negative). Several other minor variants within the group of SCDs also, albeit not as common as the varieties mentioned above. Lastly, it is essential to mention the sickle cell trait (HbAS), which carries a heterozygous mutation and seldom presents clinical signs or symptoms. Sickle cell anemia is the most common form of SCD, with a lifelong affliction of hemolytic anemia requiring blood transfusions, pain crises, and organ damage. [3]  

Since the first description of the irregular sickle-shaped red blood cells (RBC) more than 100 years ago, our understanding of the disease has evolved tremendously. Recent advances in the field, more so within the last three decades, have alleviated symptoms for countless patients, especially in high-income countries. In 1984, Platt et al. first reported the use of hydroxyurea in increasing the levels of HbF. [4]  Since then, the treatment of sickle cell has taken to new heights by introducing several new agents (voxelotor, crinzalizumab, L-glutamine) and, most recently, gene therapy.

Hemoglobin (Hb) is a significant protein within the red blood cell (RBC). It comprises four globin chains, two derived from alpha-globin (locus on chromosome 16) and two from beta-globin (locus on chromosome 11). There are many subtypes of Hb. The most common ones that are found in adults without hemoglobinopathies are listed here:

• HbA1- comprises two chains of the alpha-globin and two chains of the beta-globin (a2b2) - This constitutes 95% of the adult hemoglobin.
• HbA2- comprises two chains of the alpha-globin and two chains of the delta-globin (a2d2) - This constitutes less than 4% of the adult hemoglobin.
• HbF- comprises two chains of the alpha-globin and two chains of the gamma-globin (a2g2) - This Hb is more prevalent in the fetus (due to the high oxygen binding affinity that helps extract oxygen from maternal circulation).

The sickle cell mutation occurs when negatively charged glutamine is replaced by a neutral valine at the sixth position of the beta-globin chain. The mutation is transmitted via Mendelian genetics and is inherited in an autosomal codominant fashion. [5]  A homozygous mutation leads to the severest form of SCD, i.e., SCA- also called HBSS disease. The coinheritance of beta-naught thalassemia and sickle cell mutation leads to HBS-Beta-0 disease, which phenotypically behaves like HBSS disease.

A heterozygous inheritance leads to HbAS. Patients with HbAS are not considered within the spectrum of SCD as most of them never present with typical symptoms of SCA. They might only be detected during childbirth, blood donation, or screening procedures. 

Several other compound heterozygotes exist where a single copy of the mutated beta-globin gene is coinherited with a single copy of another mutated gene. The second most common variant of SCD is the HbSC disease, where the sickle cell gene is coinherited with a single copy of the mutated hemoglobin C gene. HbC is formed when lysine replaces glutamine at the sixth position on the beta-globin chain. HbSC disease accounts for 30% of patients in the United States. 

• Epidemiology

The epidemiological data on SCD is scarce. It is well known that SCD and HbAS are more prevalent in sub-Saharan Africa, where the carrier of HbAS is afforded natural protection against severe Plasmodium falciparum malaria. It is estimated that ~230,000 children were born with SCA, and more than 3.5 million neonates were born with HbAS in sub-Saharan Africa in 2010. an estimated 75% of SCD-related births take place in sub-Saharan Africa. West Africa is home to the largest population of individuals with HbSC disease. [3]

The United States (US) Center for Disease Control (CDC) estimates that approximately 100,000 Americans have SCD. The CDC also estimates that 1 in 13 babies born to African-American parents have sickle cell trait, and 1 in 365 African-Americans have SCD. The estimated ratio of Hispanic Americans with SCD is 1 in 16,300. Children and adolescents make up to 40% of all SCD patients in the US. The incidence varies by state and geographical concentration of ethnicities. Besides, migration within the country and immigration from foreign countries alter the prevalence of SCD and HbAS. This is true for several countries where patients with SCD and SCA are living. Genetic studies in Brazil have also tied the origin of such patients to the slave trade originating from West Africa (Mina Coast and Angola). [6]  With the improvement in technology and ease of international migration, the incidence of SCA is predicted to rise. It is estimated that the annual number of newborns with SCA will exceed 400,000 by 2050.

There is also a stark difference in mortality and morbidity in high-income and low-income countries. Adopting vaccination guidelines for children with SCD and intensive screening procedures has sharply reduced the mortality of kids with SCD between 0 to 4 years (68% drop noted from 1999 to 2002 compared to 1983 to 1986). On the other hand, in sub-Saharan Africa, 50 to 90% of children born with SCD will die before their fifth birthday. Improving the care afforded in high-income countries and targeted training of healthcare providers have improved life expectancy. However, it still lags by decades compared to matched non-SCD cohorts (54 versus 76 years - projected life expectancy, and 33 years versus 67 years- quality-adjusted life expectancy). [7]

HbSC disease accounts for 30% of all patients with SCD in the US. As with HbAS, patients with the Hb C trait (heterozygous mutation) also remain asymptomatic for most of their lives. Although considered a milder variant of SCD, HbSC disease may present with severe morbidities. [8]

• Pathophysiology

Sickle cell anemia is characterized by two major components: Hemolysis and vaso-occlusive crises (VOC). The defect in the beta-globin gene makes the sickle hemoglobin (HbS) molecule susceptible to converting into rigid, elongated polymers in a deoxygenated state. The sickling process is cyclical initially, where sickle erythrocytes oscillate between the normal biconcave shape and the abnormal crescent shape (acquired under low oxygen pressure). However, there comes a time when the change becomes irreversible, and the sickle erythrocytes develop a permanent sickle shape increasing the risk for hemolysis and VOC. All variants of SCD share the same pathophysiology leading to polymerization of the HbS component. [3]  

Multiple factors inherent to sickle erythrocytes, like low affinity of HbS to oxygen, physiologically high 2,3-diphosphoglycerate, and increased sphingokinase-1 activity, lead to deoxygenation, which promotes polymerization of HbS. In addition to this, high concentration of HbS, abnormal activity of Gados channel leading to dehydration, and repeated damage to red blood cell (RBC) membrane also increase the risk of polymerization of HbS.

Oxidative stress contributes to hemolysis by auto-oxidation of HbS, leading to erythrocyte cell membrane damage. The increased expression of xanthine dehydrogenase, xanthine oxidase, and decreased expression of NADPH oxidase increase the oxidative stress within sickle RBC. A hemolyzed cell releases free hemoglobin (scavenges nitrous oxide) and arginase 1 (competes for L-arginine) that prevent the action and formation of nitrous oxide and contribute to oxidative stress and vascular remodeling (arginase-1 converts arginine to ornithine). [3]   

Besides the polymerization of the HbS and intravascular hemolysis, several other factors also contribute to vaso-occlusion. For example, the sickle RBC (expresses several adhesion molecules on the surface), free heme and Hb, reactive oxygen species, and endothelium interact with each other and with neutrophils and platelets to promote vaso-occlusion and thrombosis.  

• Histopathology

In patients with SCA, peripheral blood smear shows elongated RBC with tapering ends that look like a sickle (also called drepanocytes). Additional findings are present in a few patients. 

• Howell-Jolly bodies- Remnants of DNA are seen in the RBC and commonly seen in patients in whom the spleen has been removed. Therefore, patients with SCA have auto-splenectomy.
• Target cells (Leptocytes)- Most commonly seen in patients with Thalassemia. They are seen frequently in sickle-thalassemia syndromes and are sometimes noted in patients with SCA.
• Polychromatic cells - these are reticulocytes that signify marrow response to hemolysis. 
• Nucleated red blood cells can sometimes be visible on the peripheral smear. 

None of these findings are confirmatory. Confirmation is obtained only through hemoglobin electrophoresis, high-performance liquid chromatography, or isoelectric focusing. DNA-based techniques are not used routinely. Instead, they are used in patients with uncertain diagnoses. Pre-natal fetal testing involves using fetal DNA obtained through amniocentesis. Techniques to capture the fetal DNA in maternal blood remain investigational.

• History and Physical

Most patients with HbSS phenotype do not present with classical 'sickle cell crises' soon after birth. HbF is still present in the blood, helping maintain adequate tissue oxygenation, and it takes around 6-9 months to wean off completely. Not all SCA have the same phenotype, and multiple phenotypes exist that can either co-exist or present as a spectrum of the disease. [3]  

• Vaso-occlusive subphenotype - Distinguished by higher hematocrit (Hct) compared to other SCA. A higher Hct leads to higher viscosity that promotes frequent vaso-occlusive crises and acute chest syndrome. 
• Higher risk of gallstones, pulmonary hypertension, ischemic stroke, priapism, and nephropathy
• Severe anemia increases cardiac workload and blood flow through organs, making them susceptible to damage
• Higher free heme and Hb in blood vessels cause oxidative damage
• High Hb F subtype- A 10 to 15% level of HbF alleviates the symptoms of SCA. However, the distribution of HbF is not consistent throughout the body.
• Pain-sensitive subphenotype- Altered neurophysiology amongst various individuals make them susceptible to pain. Some individuals are more susceptible to pain compared to others with SCA.

The patients with SCA present wither with acute or chronic complications associated with the disease. The most common acute complication of SCA is Vaso-occlusive crisis (VOC). The treatment section below discusses the management of acute and chronic issues. 

Important points to be noted in the history of patients with SCA

• All patients with SCA will experience VOC during their lives. The earliest presentation is dactylitis in kids as young as six months of age.
• Any body organ can develop VOC (head, eyes, etc.), although extremities and the chest are most commonly involved. If a VOC pain sounds atypical, obtain a history to rule out other causes.
• When was the last pain crisis, and how many times in the previous year have they been admitted to the hospital with pain crises?
• If they take analgesics daily, it is prudent to know the type and quantity of the analgesic (opioid or non-opioid), the last use of analgesics, and whether they take the analgesics before coming to the ER/office
• History of taking disease-modifying drugs (hydroxyurea, voxelotor, crinzalizumab, etc.) 
• A history of substance abuse, psychiatric disorders, and use of psychotropic medications must be obtained. 
• History of receiving blood transfusions and exchange transfusions- helps assess the risk of iron overload, presence of alloantibodies (multiple transfusions in the past can lead to the development of alloantibodies, which will help assess the risk of transfusion reactions), and previous transfusion reactions. 
• History of any other diseases that may or may not be associated with SCA - previous history of stroke, thrombosis, priapism, etc.
• It is also advised to get in touch with the primary hematologist taking care of the patient- it is valuable to have their input in understanding the patient's normal physiology. 
• History of previous surgeries.
• History of life-threatening crises in the past- if present, should alert the clinician to ensure that a similar event is not occurring again. For example, fat embolism may occur more frequently in patients with SCA. 

The physical exam should focus on the general system exam to determine the need for oxygen requirements, pain management, and blood/exchange transfusion. However, a focused exam is also necessary to rule out any organ-specific problem. For example, a rapidly enlarging liver or spleen should alert the physician about sequestration crises. 

Patients with SCA are usually diagnosed in childhood. Intensive newborn screening programs in developed countries can identify patients in the neonatal stage. In the US, universal screening for SCA was implemented in all states by 2007. High-performance liquid chromatography and isoelectric focusing are the methods used in the US. In Europe, most countries deploy targeted screening in high-risk areas (where SCA is more common) and not a universal screen. In sub-Saharan Africa, no country has adopted a screening program. In India, the solubility test is used as the first step- if positive, then high-performance liquid chromatography is used to confirm at the reference center. [3]

Acute Complications in Patients with SCA

Acute Chest Syndrome (ACS):  ACS is the most common complication of SCA. It is also the most common cause of death and the second most common cause of hospital admission. A patient can either present with ACS or may develop it during hospitalization for any other reason. Hence, it is prudent to monitor all patients with SCA admitted to the hospital for ACS. It is important to recognize ACS early and act upon it to prevent respiratory failure.

• The risk factors for ACS include a previous history of ACS, asthma, or recent events like recent surgical procedures, pulmonary embolism, fluid overload, infection, etc.
• The clinical features include sudden onset of cough and shortness of breath. Fever may or may not be a part of the spectrum of presentation. If present, then it usually points towards infection.
• Laboratory evaluation includes a complete blood count with differential chemistries, including liver and kidney evaluation, blood cultures, and sputum cultures.
• Chest X-ray shows a new pulmonary infiltrate- this is a quintessential feature of defining ACS. CT and perfusion mismatch scans are only used if there is a strong clinical suspicion of pulmonary embolism or fat embolism. Therefore, they are not usually helpful in acute settings.

Sequestration Crises: This can either be hepatic or splenic sequestration.

• Patients experience rapid spleen enlargement associated with pain in the left upper quadrant. In children with SCA, it is common in children between 1 to 4 years of age, as the spleen is still intact.
• Patients with non-SCA variants (HbSC, HbS-beta+ thalassemia) are not prone to 'auto-splenectomy' commonly seen in patients with SCA. Hence they can develop splenic sequestration later in life. Such patients may have baseline splenomegaly, causing hypersplenism. Parents and patients must receive counseling regarding the signs and symptoms of an enlarging spleen.
• Younger patients present with acute anemia and hypovolemic shock due to smaller circulating volumes, whereas adults may present with a more insidious onset.
• Pain occurs due to stretching of the splenic capsule and new infarcts.
• Blood count shows a drop in Hb by more than 2gm/dL, increased reticulocyte count, and nucleated red blood cells. 
• Hepatic sequestration: Hepatic sequestration can occur across all phenotypes of SCA. Like the spleen, patients may have a baseline enlargement of the liver. Hepatic sequestration is also defined as rapid enlargement of the liver with stretching of the capsule. The hemoglobin shows a drop of more than 2gm/dL. Liver enzymes may not get elevated.

Acute Stroke:  Stroke is the most devastating complication of SCA. Since the advent of transcranial doppler (TCD) and the institution of primary prevention programs, the incidence of stroke has gone down in patients with SCA. In the absence of primary prevention, ~10% of children suffer from overt stroke, and approximately 20 to 35% have silent cerebral infarcts. TCD is not useful for adults. 

• Severe headache, altered mental status, slurred speech, seizures, and paralysis- are signs of stroke. 
• Urgent neurological consultation and CT scan followed by MRI/MRA must be done. 

Aplastic crises:  It is usually precipitated by parvovirus B-19 and is defined as a rapid drop in Hb at least 3 to 6 gm/dL below the baseline. Patients present with severe fatigue, anemia, shortness of breath, and even syncope. Blood counts show severely low hemoglobin with near-absent reticulocytes. Bone marrow biopsy shows arrest in the pro-normoblast stage in patients with acute parvovirus infections. [9]

Acute intrahepatic cholestasis (AIC):  Presents with sudden onset right upper quadrant pain. Physical exam shows worsening jaundice, enlarging and tender liver, and clay-colored stools. Labs show very high bilirubin levels, elevated alkaline phosphatase, and coagulopathy. The hemolysis parameters may be normal. AIC is a medical emergency.

Infections in patients with SCA can be a harbinger of infection with Streptococcus pneumoniae infection or osteomyelitis.

• The use of prophylactic antibiotics and pneumococcal vaccinations has reduced their incidence. However, loss of splenic function in SCA patients puts them at risk of invasive bacterial species.
• Osteomyelitis can be unifocal or multifocal- Staphylococcus aureus , Salmonella , and other enteric organisms can cause osteomyelitis in SCA patients. 

Priapism  is defined as a sustained, unwanted painful erection lasting more than 4 hours. It is a common condition among patients with SCA, affecting 35% of all men/boys. 

Acute Ocular Complications

• The complication presents similarly in patients with SCA and sickle cell trait.
• The low oxygen pressure and acidotic nature of the aqueous humor promote sickling of the RBC, leading to blockage of the trabecular network leading to an acute rise in intraocular pressure (IOP). 
• High IOP is poorly handled in patients with SCA - which can lead to CRAO and secondary hemorrhages. 
• Central Retinal Artery Occlusion (CRAO)- Results from thrombus formation in the retinal artery leading to infarction of the retina, macular ischemia, or macular infarction. CRAO can occur spontaneously or secondary to increased IOP (from hyphema), Moyamoya syndrome, or ACS in patients with SCA. 
• Patients present with proptosis, local pain, and edema of the lid or orbit.
• The exam shows reduced extraocular motility and decreased visual acuity.
• CT scan helps in distinguishing this from orbital cellulitis/ infection. 
• Orbital Compression Syndrome (OCS) - also called orbital apex syndrome, is characterized by ophthalmoplegia and vision loss secondary to events occurring at the orbital apex. Cranial nerves II, III, IV, VI, and the first division of CN V can be involved. MRI of the orbits is the best modality for diagnosis. 

Chronic Complications in Patients with SCA

Iron Overload:  Iron (Fe) overload is a common problem in SCA patients due to repeated transfusions and chronic hemolysis. Each unit of packed RBC contains 200 to 250 mg of iron. Excessive iron mainly affects the heart, lungs, and endocrine glands. [10]  Hepatic cirrhosis from excessive iron is a major cause of death in patients with SCA. Clinical trials in patients with thalassemia have shown that systemic iron load correlates directly with survival and cardiac incidents. [11]

Avascular Necrosis (AVN) of Joints:  AVN of the femoral head is a common cause of chronic pain and disability in SCA patients. Although the hip joint is the most common joint to be involved, other joints can also be affected. AVN occurs at the distal portion of the bone, where collateral circulation is poor. The capillaries get occluded by sickle RBCs leading to hypoxia and bone death. Risk factors for AVN of the femoral head include age, frequency of painful episodes, hemoglobin level, and alpha-gene deletion. In patients with HbSS, the overall prevalence is 50 percent by age 33. HbSS-alpha thalassemia and HbSS-Beta-0 thalassemia are at higher risk of developing AVN early in life. 

Leg Ulcers : More common in SCA compared to other SCD genotypes. Approximately 2.5% of patients with SCA above ten years of age have leg ulcers. Leg ulcers are more common in men and older people and less common in people with high total hemoglobin, alpha-gene deletion, and high levels of HbF. Trauma, infections, and severe anemia also increase the risk of leg ulcers. The ulcers occur more commonly on the medial and lateral surfaces of the ankles. They vary in size and depth, and chronic ulcers may lead to osteomyelitis, especially if they are deep enough to expose the bone.

Pulmonary Artery Hypertension (PAH) : Affects 6 to 11% of patients with SCA. PAH in SCA is classified under World Health Organization (WHO) group V. However; chronic hemolysis leads to pulmonary vascular changes classified under WHO group 1 in up to 10% of all SCA patients. PAH in SCA can also occur due to left heart dysfunction (Group II), chronic lung disease from SCA (Group III), chronic thromboembolism (Group IV), or extrathoracic causes (Group V). 

The patient may complain of dyspnea on exertion, swelling in the legs, or present with symptoms of underlying disease (like a history of thrombosis, heart failure, etc.). An echocardiogram helps in estimating the tricuspid regurgitant jet velocity (TRV). Elevated TRV is associated with increased mortality in adults. However, TRV can be transiently elevated during acute chest syndrome. Serum NT-pro-BNP is directly correlated with mortality as well. The final diagnosis is made with a right heart catheterization.  

Renal complications: Chronic kidney disease (CKD) occurs in approximately 30% of adult patients with SCA. The acidotic, osmotic, and hypoxic environment of the kidney increases the risk of polymerization of HbS, leading to the sickling of RBC. SCA patients secrete excessive creatinine in their proximal tubules. Hence, it becomes challenging to identify early signs of kidney disease, as creatinine takes a longer time to rise. Microalbuminuria (30-300mg albumin in 24-hour urine collection) is often the first manifestation of CKD. Spot urine-creatinine ratio is not validated in SCA patients due to hypersecretion of creatinine.

• Hypoesthenuria- Inability to concentrate urine due to loss of deep juxtamedullary nephrons. It is the most common complication in SCA patients. It leads to frequent urination and increases the risk of dehydration. It also increases the risk of enuresis in children.
• Renal papillary necrosis occurs due to obstruction of the vessels supplying the vasa recta resulting in medullary infarction. It presents with hematuria. It is more common in patients with HbSC disease.
• Asymptomatic Proteinuria: It is present in 15 to 50% of patients. It develops early in life due to hyperfiltration and loss of selectivity for albumin.

Ophthalmologic Complications: Chronic eye complications are more common in patients with HbSC and HbSS disease. They are found in up to 50% of patients.

• Proliferative Sickle Retinopathy occurs due to vaso-occlusion of vitreal arterioles leading to ischemia which leads to neovascularization. Neovascular tissue is predisposed to hemorrhage and vitreal traction forces resulting in vitreal hemorrhage (the most severe complication of proliferative sickle retinopathy). 
• Treatment / Management

Patients with SCA present with acute and chronic complications. 

Management of Acute Complications

Pain management is a critical part of SCA. It is challenging for clinicians to accurately assess patients' needs, especially if they meet them for the first time. Patients with SCA often suffer from the stigma of requiring high doses of opioids for pain control, which leads to them being labeled as 'opioid abusers,' 'manipulators,' or even' drug seekers.'  [12]

• Analgesic administration starts simultaneous with evaluating the cause, ideally within 30 minutes of triage and 60 minutes of registration.
• Develop individualized pain management plans - this should be made available to the emergency room and should be implemented each time the patient presents with VOC and pain.
• NSAIDs are used in patients with mild to moderate pain who report prior episodes of relief with NSAIDs
• Any patient presenting with severe pain- preferably used parenteral opioids. An intravenous route is preferred; however, if access is difficult, use the subcutaneous route.
• The dose of parenteral opioids is calculated based on the total dose of short-acting oral opioids taken at home.
• Pain should be reassessed every 15 to 30 minutes, and readminister opioids if needed. The escalation of opioids is done in 25% increments.
• Patient-controlled analgesia (PCA) is preferred. If an "on-demand" setting is used in PCA, then continue long-acting analgesia.
• When pain control is achieved, "wean off" parenteral opioids before converting to oral medications.
• Calculate the inpatient analgesic requirement at discharge and adjust home doses of short and long-acting opioids accordingly.
• Meperidine is not used in managing VOC-related pain unless this is the only medication that controls the pain.
• Antihistamines only help in controlling opioid-related itching. When required, use oral formulations only—readminister every 4 to 6 hours as needed.
• Incentive spirometry
• Intravenous hydration
• Supplemental oxygen is needed only if saturation drops below 95% on the room air.

Management of Chronic Pain

Chronic pain management in SCA patients focuses on the safe and adequate use of pain medications, particularly opioids. A comprehensive assessment of the patient's ailment, the kind and doses of pain medicine required to control pain, and the functional outcomes of using these medications are made at each encounter. The process involves collaboration with multiple specialties, like psychiatry, social work, etc., to administer the right pain medicine in the proper doses. 

The strategy adopted in the clinic to prescribe pain medicine involves:

• One person must be assigned to prescribe long-term opioids. They should document all encounters extensively involving the physical exam, lab work, etc. 
• Assess each patient for non-SCA-related pain and treat/refer to the appropriate specialty for managing this pain.
• Limit prescribing pain medicines without meeting the patient- every patient must be physically assessed every 2 to 3 months or sooner.
• Develop an individualized pain management plan for each patient, reassess this plan annually, and modify it accordingly.
• Encourage patients to explore alternative methods of controlling pain, like direct massage, self-hypnosis, and music therapy.

Acute Chest Syndrome (ACS):  It is an emergency regardless of the sickle cell disease phenotype. It can lead to respiratory failure and death if not managed as an emergency.

• All patients must be hospitalized-
• Upon admission, start treatment with antibiotics, including coverage for atypical bacteria.
• Supplemental oxygen is provided to those with oxygen saturation of less than 95% at room air.
• "Early" administration of simple blood transfusion is recommended for hypoxic patients. However, exchange transfusion is recommended at the earliest opportunity.
• Close monitoring for worsening respiratory status, increasing oxygen requirement, worsening anemia, and bronchospasm (use of beta-adrenergic dilators is encouraged in asthmatics) must be done. Intensive care units must be on standby to receive such patients who experience worsening respiratory status.
• Closely monitor predictors of severity- increasing respiratory rate, worsening hypoxia, decreasing hemoglobin or platelet count, multilobar involvement on chest X-ray, and developing neurological complications.
• Incentive spirometry and hydration (intravenous or oral) must always be encouraged. 
• ACS is a strong indicator for initiating disease-modifying therapy (hydroxyurea, etc.) or starting the patient on a chronic blood transfusion program.

Sequestration Crises

• Intravenous fluids for hydration, pain control, and simple/exchange blood transfusion are central to managing sequestration crises.
• Never correct anemia completely- when the crises resolve, and the organs shrink, the sequestered blood re-enters the circulation, leading to increased hematocrit and viscosity, increasing the risk of thrombotic and ischemic events.
• Splenectomy is recommended for patients with life-threatening episode splenic sequestration crises or with recurrent splenic sequestration. It is also offered to those who have baseline hypersplenism.
• Instruct patients and parents in monitoring the size of the liver and spleen regularly.

Acute Stroke:  Urgent neurology and transfusion medicine consultation are needed to provide optimal care and prevent long-term damage.

• Simple or exchange blood transfusion emergently.
• Start a program of chronic exchanges or blood transfusion. 
• Where blood transfusion cannot be used (iron overload, excessive alloantibodies) or is unavailable, start on long-term disease-modifying therapy. SWiTCH trial demonstrated that chronic transfusions are a better way to manage patients with stroke.

Aplastic Crises:  Parvovirus infections cause a transient drop in hemoglobin. Humoral immunity develops within 7 to 10 days that stays for life. The patient is extremely susceptible to developing ACS or stroke during the acute period. Initiate exchange/simple transfusion to bring Hb to a safe level, not necessarily to normal/baseline level.

Infections presenting with fever:  Oral empiric antibiotics are given promptly while evaluating the reason for the fever. For ill-appearing patients, admit them and administer intravenous antibiotics.

Priapism: Early recognition is the key to management. Delayed management can lead to impotence. Urologists need to be involved early on in the care of such patients. 

• Conservative measures include using analgesics, hydration, and sedation - which usually leads to detumescence and retains potency. Most experts would call for upfront urologic management rather than losing time trying conservative measures. [13]
• Urologists can perform penile aspiration or irrigation of corpora cavernosa with alpha-adrenergic drugs.
• Blood transfusion/ exchange transfusion is not useful - few authors have reported neurological complications with the use of blood transfusion (ASPEN syndrome). Hence it is best to avoid blood transfusion.

Acute ocular Complications:  All ocular complications must be managed in consultation with ophthalmologists and hematologists to prevent vision loss. 

• Hyphema- Anterior chamber paracentesis or surgical intervention to manage the thrombus must be done promptly.
• Reducing intraocular pressure helps prevent CRAO and other compression issues. 
• Infections are managed with prompt administration of antibiotics. 
• Corticosteroids are used to relieve excessive pressure in patients with OCS.

Chronic Complications

Avascular Necrosis:  About 40 to 80% of cases of hip joint AVN are bilateral; therefore, both joints should be investigated simultaneously. Pain management and physical therapy are to be initiated as early as possible. Advanced cases may require hip arthroplasty.

Leg Ulcer: Conservative measures involve wound care, wet-to-dry dressings, and pain control. Hydroxyurea is avoided in patients with open leg ulcers, as it may prevent healing. Frequent evaluation for the stage of healing or lack of infection, osteomyelitis must be done. Local and systemic antibiotics are used for infected ulcers.

Pulmonary Hypertension:  Patients with higher TRV are referred to pulmonologists for management. Small studies have shown increased mortality with sildenafil.

Renal Complications: Refer SCA patients with micro- or microalbuminuria to nephrologists for detailed workup and consideration of angiotensin-converting enzyme inhibitor (ACE-inhibitor). Follow patients closely who have modest elevation in creatinine (>0.7 mg/dL in children, >1.0 mg/dL in adults), and refer to a nephrologist at the earliest sign of worsening creatinine.

Ophthalmologic Complications: Refer SCA patients regularly for ophthalmologic evaluation, especially if they complain of slow vision changes. Direct and indirect ophthalmoscopy, slit-lamp biomicroscopy, and fluorescein angiography are used to evaluate SCA patients. Laser photocoagulation therapy is used to manage proliferative sickle retinopathy. A vitrectomy or retinal repair may be needed in the rare event of vitreal hemorrhage or retinal detachment. 

Iron Overload

Unlike hemochromatosis, phlebotomy is not an option in patients with SCA. Preventing iron overload with good transfusion practices is the best way to deal with iron overload. Patients with SCA need not follow the rule of having hemoglobin close to 7gm/dL. Packed RBC transfusion should be restricted to the management of symptoms. Choosing exchange transfusion over simple transfusion also helps to reduce/prevent iron overload.

Indications to start iron chelation therapy

• A liver iron concentration (LIC) greater than 3 mg iron (Fe)/gm dry weight
• Cardiac T2* < 20 milliseconds
• Serum ferritin greater than 1000 on two different occasions 15 days apart
• Age greater than two years
• Expected survival beyond one year
• Number of transfusion of Packed RBC in 1 year- > 10 in pediatric patients OR > 20 in adults. 

Goals of therapy

• Serum ferritin < 1000 mcg/L,
• LIC <7mg Fe/gm dry weight
• Cardiac T2* > 20 milliseconds

When do patients need modification of treatment?

• Treatment needs to be intensified if LIC > 15 mg Fe/gm dry weight and deescalated when LIC < 3 mg Fe/gm dry weight.
• Treatment needs to be intensified if serum ferritin > 2500 IU/L and deescalated when serum ferritin < 300 IU/L
• Treatment needs to be intensified when cardiac MRI shows T2* < 15 milliseconds or when cardiac symptoms occur (like heart failure, arrhythmias)

Iron Chelators

• Disperse tab formulation: Initial dose: 10mg/kg/day. Maximum dose: 20mg/kg/day
• Tablet or granule formulation: Initial dose: 7mg/kg/day. Maximum dose: 14mg/kg/day
• It does not interfere with the pharmacodynamics of hydroxyurea; hence it can be used simultaneously.
• Adverse effects- gastrointestinal intolerance, dose-dependent rise in serum creatinine, liver dysfunction.
• Daily subcutaneous infusions via portable infusion pump given over 8 to 24 hours; 1 to 2 gm/day 
• It can be given as a daily IV infusion also. 40 to 50 mg/kg/day (max dose 60 mg/kg/day) over 8 to 12 hours (max rate 15 mg/kg/hour) 
• IM route is acceptable for children but not preferred for adults. 0.5 to 1mg/day
• Adverse effects- Injection site reactions, cardiovascular shock (if administered too fast), blood dyscrasias, growth retardation.  
• Adverse effects - agranulocytosis, hepatotoxicity, gastrointestinal symptoms, and arthralgia.

Blood transfusion:  Blood transfusions form an integral part of the management of SCA. The goal of transfusion is to increase the oxygen-carrying capacity of blood and reduce the HbS component. A blood transfusion (simple or exchange) is given to keep the HbS level below 30% (STOP 1 and 2 trials). [14]  In patients receiving regular exchange transfusions (history of stroke, intolerance, or contraindication to hydroxyurea), a more practical target for HbS is 25% to prevent a rise of HbS beyond 30%.

What types of blood transfusion are used in SCA?

• Simple transfusion: Transfusion of matched packed red blood cells (PRBC)
• Exchange transfusion: Transfusion of PRBC while removing blood from the patient at the same time.

Who should receive blood transfusions?

• Hb < 7gm/dL or drop of >2 gm/dL from baseline- consider simple or exchange transfusion. 
• Twin pregnancy- consider prophylactic exchange transfusion
• Hb less than 9 gm/dL- Simple transfusion
• Hb more than 9gm/dL- Partial exchange transfusion

What kind of transfusion practice should be followed?

• Severe ACS - oxygen saturation less than 90% even when started on supplemental oxygen. 
• Multiorgan Failure
• Acute ischemic stroke
• Splenic sequestration - never corrects the anemia completely.
• Acute anemia

Complications from Chronic Transfusions

• Alloimmunization- increases the risk of transfusion reactions, especially delayed hemolytic transfusion reactions. 
• Iron overload
• Transmission of blood-borne diseases like hepatitis B, C, and HIV; extremely low risk due to intensive screening of donors and blood products.
• Differential Diagnosis

In general, globin gene mutations affecting hemoglobin are common and affect 7% of the entire world population. [15]  Over 1000 variations of hemoglobin exist. However, only a handful of variations are significant clinically. 

Common Variants of SCA or HbSS Disease

• Hemoglobin S-beta-0 thalassemia (Clinically behaves exactly like HbSS disease)
• Hemoglobin SC (a milder variant of SCD) - can have a phenotypic presentation of sickle cell anemia
• Hemoglobin S-beta+ thalassemia (a milder variant of SCD)

Several other hemoglobin variants are present that can mimic SCA if they are inherited along with HbS.

• Hemoglobin Jamaica-Plain (beta-68 [E12] Leu -> Phe)
• Hemoglobin Quebec-Chori (beta-87 [F3] Thr > Ile)
• Hemoglobin D-Punjab (beta-globin, codon 121, glutamine to glutamic acid)
• Hemoglobin O-Arab
• Hemoglobin E

Other conditions that can present with hemolysis, where SCA can be ruled out with history, examination, hemoglobin electrophoresis, and study of the peripheral smear

• Antibody-mediated autoimmune hemolytic anemia (both warm and cold antibodies)
• Other hemoglobinopathies- alpha or beta-thalassemia
• Paroxysmal nocturnal hemoglobinuria
• RBC-membrane defects (hereditary spherocytosis, hereditary elliptocytosis)
• Enzyme defects (pyruvate kinase deficiency, glucose-6-phosphate deficiency)
• Drug-induced hemolysis
• Transfusion-related hemolysis (acute or delayed hemolytic reaction)
• Microangiopathic hemolytic anemia (atypical or typical hemolytic uremic syndrome, thrombotic thrombocytopenic purpura)
• Infectious causes (malaria, babesiosis, Rickettsia , Clostridia , Bartonella )
• Vasculitis-induced hemolysis
• Medical Oncology

The goal of disease-modifying therapy in sickle cell anemia is to reduce the frequency of vaso-occlusive crises (VOC) and pain crises and prevent organ damage. These medications usually do not have a role "during" acute crises. Hydroxycarbamide, or hydroxyurea, was the first drug approved by the FDA for use in patients with SCA. However, the USFDA approved hydroxyurea for pediatric patients two years and above only in 2017 (based on the ESCORT HU trial).   

Disease-Modifying Drugs/Therapy

The goal of disease-modifying therapy in patients with SCA is to alter the kinetics of sickle erythrocytes. Hydroxyurea does this by increasing the concentration of fetal hemoglobin (HbF).

Hydroxyurea:  This is a ribonucleotide reductase inhibitor that increases the concentration of HbF in patients with SCD. It not only increases the intracellular concentration of HbF but also increases the number of erythrocytes containing HbF. In addition to this, hydroxyurea also reduces the number of circulating reticulocytes and leukocytes, raises the volume of an RBC (high MCV is noted in patients receiving hydroxyurea), reduces the deformability of RBC, improves the flow of blood through capillaries, and alters the expression of adhesion molecules hence preventing vaso-occlusive crises. The initial trials with hydroxyurea (Phase-III Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH)) demonstrated a clear benefit over placebo in reducing the incidence of pain crises and the cost of care. Long term, the MSH study also showed a mortality benefit. In the pediatric age group, two seminal trials (HUG-KIDS-Phase I/II and BABY HUG-phase III) demonstrated good tolerability and led to the drug's approval. [16] [17]  

• Having three or more sickle cell-associated moderate to severe pain crises within a 12-month period; treat with hydroxyurea
• Those with sickle cell-associated pain that interferes with daily activities of living and quality of life
• History of severe and/or recurrent ACS
• Severe symptomatic chronic anemia that interferes with daily activities or quality of life
• Infants 9 months of age and older, children, and adolescents with SCA, offer hydroxyurea regardless of clinical severity to reduce SCA-related complications (e.g., pain, dactylitis, ACS, anemia)
• For those with chronic kidney disease taking erythropoietin and hydroxyurea can be added to improve anemia
• DO NOT give hydroxyurea to pregnant women and lactating mothers who choose to breastfeed their babies
• Dosing for adults: Start with 15 mg/kg/day. Round up to the closest 500 mg. For patients with CKD- start at 5 to 10 mg/kg/day. 
• Dosing for infants and children: start at 20 mg/kg/day
• Target absolute neutrophil count (ANC) of above 2000/microL and platelet count above 80,000/microL. In younger patients, an ANC of 1250/microL is allowed if baseline counts are low.
• Monitor blood counts every four weeks when increasing the dose of hydroxyurea.
• Clinical response takes 3 to 6 months to come. Hence a minimal trial of 6 months of daily continued use of hydroxyurea is done before considering alternative therapies. 
• Daily adherence is a must. It must be emphasized to the patient.
• If a positive response is seen, then hydroxyurea must be continued indefinitely. 
• Myelotoxicity is the most common and most substantiated adverse effect of hydroxyurea. The rest of the adverse effects reported in the literature, especially carcinogenesis and leukemia, have never been demonstrated in large studies. 
• Avoid the use of hydroxyurea in patients with leg ulcers.

Voxelotor:  Voxelotor acts by inhibiting the polymerization of HbS and increasing the affinity for oxygen. It is dosed at 1500 mg by mouth daily and is approved for SCA treatment in patients 12 years of age and older. Voxelotor can be given with or without hydroxyurea. USFDA approved it in 2019 based on the results of the phase 3 HOPE trial (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization) evaluating voxelotor (1500 mg versus 900 mg versus placebo in 1:1:1 design). [18] [19]  

The most common adverse reactions are headache, diarrhea, abdominal pain, nausea, fatigue, rash, and pyrexia. Voxelotor interferes with high-performance liquid chromatography (HPLC). Hence the hemoglobin quantification is not accurate when the patient is on voxelotor. HPLC should be done when the patient is off therapy. Also, the use of voxelotor may increase the Hb, but there is no evidence to suggest discontinuation of exchange transfusion in patients receiving this for stroke prophylaxis.

Crizanlizumab:  A humanized immunoglobulin G2-Kappa monoclonal antibody inhibits P-selectin, thereby blocking its interaction with P-selecting glycoprotein-1. This leads to reduced interaction between activated endothelium, platelets, leukocytes, and sickled RBCs, leading to reduced VOC. [20]  The phase II SUSTAIN trial demonstrated a clinical benefit of Crizanlizumab by demonstrating a reduction in pain crises, VOC, emergency room visits, and increased median time to first crises. Although the hospitalization rate was numerically lower in the intervention group, the difference was not statistically significant compared to the placebo group. [21]

It is approved for the treatment of SCA in patients 16 years of age and older. It is dosed as a 5mg/kg intravenous infusion administered over 30 minutes at weeks 0, 2, and then every four weeks. The most common adverse reactions are nausea, arthralgia, back pain, and pyrexia. Infusion-related reactions can occur. Crizanlizumab can interfere with platelet counts; send the blood immediately before administration or send blood in citrated tubes. 

L-Glutamine:  Glutamine is the most abundant amino acid in the body. It is not an essential amino acid under normal circumstances, but in patients with SCA, a high hemolysis rate increases the demand for glutamine. L-glutamine is available in a medical formulation. The exact mechanism of action of L-glutamine remains anecdotal. It is believed to work by scavenging for reactive oxygen species and acting as a substrate for the regeneration of nitrous oxide, NAD, and NADH. [22]  The USFDA approved L-glutamine in 2017 after positive results from the phase III trial. The authors demonstrated a statistically lower number of pain crises, fewer hospitalizations, fewer cumulative days in the hospital, prolonged time to first and second pain crises, and a reduced number of ACS. [23]  Adverse events include constipation, nausea, headache, abdominal pain, cough, extremity pain, back pain, and chest pain. There is an additional concern that L-glutamine may increase mortality and the rate of multiorgan failure. However, these are yet exploratory. 

Hematopoietic Stem Cell Transplant

Allogeneic hematopoietic stem cell transplant (HSCT) is a potentially curative option in SCA patients where cure rates approach approximately 90%. Improving the quality of life and reducing the cost of managing long-term complications trumps the cost of performing allogeneic HSC. Pre-school age is considered the best time to perform HSCT, with increased mortality recorded in older patients. A myeloablative or a non-myeloablative regimen can be used; however, myeloablative regimens are not recommended for adults. Matched sibling donor is preferred for performing allogeneic HSCT. Due to the lack of matched sibling donors, other approaches like a matched unrelated donor, umbilical cord blood transplant, and haploidentical transplant are also being explored. [24] [25]

Potential barriers to performing allogeneic HSCT

• Alloimmunization due to repetitive transfusions (exchange of blood)
• Organ dysfunction due to SCA (possibly a reason why younger patients do better)
• Lack of matched sibling donors/ insurance.

Indications for performing allogeneic HSCT

• Stroke (most common and strongest indication to perform allogeneic HSCT.
• Abnormal transcranial doppler
• Acute chest syndrome
• Recurrent VOC not controlled with medical therapy or chronic transfusions

The complications with allogeneic HSCT:

• Transplant-related mortality approaches 7 to 10%, comparable with SCD-related mortality
• Graft rejection OR graft failure - less with myeloablative regimens (7 to 11%) compared to non-myeloablative regimens (11 to 50%)
• Graft-versus-host disease and related morbidity
• Transplant-related complications like lung injury, endocrine, and metabolic adverse events

The recent approvals of newer agents and the emergence of gene-editing techniques have expanded the options for SCA patients. Also, extending the benefit of HSCT to low-income countries remains a significant challenge. 

Future Perspectives

Gene editing is a new therapy focus whereby researchers attempt to increase the HbF level in patients with SCA. This technique is being developed alongside HSCT. Many approaches to gene editing are in clinical trials right now. [26] [27]

• Viral gene addition using lentivirus: The technique aims to add a modified beta or gamma-globin gene to reduce the HbS component and increase the HbA (beta-globin gene) or the HbF (gamma-globin gene).
• CRISPR (Clustered regularly interspaced short palindromic repeats): Targets the expression of BCL11A, which normally downregulates gamma-globin expression. By introducing insertions and deletions in the BCL11A erythroid lineage-specific enhancer on chromosome 2, BCL11A is downregulated, resulting in increased expression of the gamma-globin gene, which subsequently increases HbF.

Cost Factor

The annual cost of the voxelotor is approximately $125,000. Each vial of crizanlizumab costs approximately $2400, with a yearly cost of $84,852 and $113,136 per year for most patients. The monthly cost of the L-glutamine formulation is $3000 for adults and up to $1000 for the pediatric age group. A myeloablative regimen for HSCT can lead to a cost of approximately $280,000 at 100 days of care/admission. [28]  In addition, the advanced level of expertise and dedicated infrastructure required to deliver such care also comes at a considerably high cost. Considering such high costs for the newer therapies, bringing them to lower-income regions like sub-Saharan Africa is a challenge, where approximately 6 million suffer from sickle cell anemia. 

Most of the survival data in patients with SCA does not factor in the advent of new medications. The Cooperative Study of Sickle Cell Disease (CSSCD) (between 1978-88) reported the median age of death for women and men as 42 and 48 years, respectively. This study also showed that acute chest syndrome, renal failure, seizures, high leukocyte count, and low levels of HbF were associated with an increased risk of early death in patients with SCA. [29]  More recent studies have shown that elevated tricuspid regurgitant jet velocity on echocardiography, prolonged QTc interval, pulmonary hypertension, high N-terminal pro-brain natriuretic peptide, history of asthma and/or wheezing, history of end-stage renal disease requiring dialysis, and the severity of hemolysis are independent risk factors towards early death in patients with SCA. [30]

More recent data combining nine studies from Europe and North America (evaluating 3257 patients) listed the following as predictors of mortality:

• Age (per 10-year increase in age)
• Tricuspid regurgitant jet velocity 2.5 m/s or more
• Reticulocyte count
• Log(N-terminal-pro-brain natriuretic peptide)
• Fetal hemoglobin [30]

With the approval of newer drugs in 2019 (voxelotor and crizanlizumab), increased use of hematopoietic stem cell transplant, and exploring newer techniques like gene therapy, survival is bound to increase along with the quality of life. 

• Complications

SCA can lead to acute complications and chronic complications

Acute complications: Most acute complications are associated with occlusion of the small to medium-sized vessels (sometimes large-sized vessels) due to polymerization of HbS and hemolysis. 

• Sequestration crises: splenic or hepatic sequestration
• Fat embolism
• Bone infarction/necrosis
• Coagulopathy: increases the risk of both arterial and venous clots- stroke, myocardial infarction, venous thrombosis
• Ophthalmic: vitreous hemorrhage, retinal detachment, retinal artery/vein occlusion
• Aplastic crises: in association with parvovirus infection
• Papillary necrosis
• Delayed growth and development and growth retardation
• Cardiac: cardiomegaly, cardiomyopathy, left ventricular hypertrophy, arrhythmia, congestive heart failure
• Pulmonary: pulmonary edema, sickle cell lung disease, pulmonary hypertension
• Hepatobiliary: Hepatomegaly, intrahepatic cholestasis, cholelithiasis, viral hepatitis
• Splenic complications: splenomegaly, hyposplenia, asplenia
• Renal: acute and chronic renal failure, pyelonephritis, renal medullary carcinoma
• Musculoskeletal: degenerative changes, osteomyelitis, septic arthritis, osteonecrosis, osteopenia/osteoporosis
• Neurologic: aneurysm, mental retardation
• Ophthalmic: proliferative sickle retinopathy, vitreous hemorrhage, retinal detachment, nonproliferative retinal changes
• Endocrine: primary hypogonadism, hypopituitarism, hypothalamic insufficiency
• Iron overload due to repeated transfusions and chronic hemolysis
• Deterrence and Patient Education

SCA is a debilitating disease that affects a patient physically and has significant emotional and psychiatric consequences. The stigma of being diagnosed with SCA has been well documented. Many SCA patients are inaccurately labeled as drug seekers and opioid abusers due to the need for an inordinately high amount of opioids for pain control. In addition, frequent interactions with different providers (in the emergency rooms, hospital admissions, etc.) can lead to inconsistent care. In such a scenario, the patients need to be an advocate for themselves. The following points can act as a guide for patient education.

• Show consistency in outpatient clinics and show up for your appointments. Regularity in visits to your providers helps to build trust within the system.
• Discuss pain requirements for pain medications with your provider with an open mindset- They may appear restrictive in prescribing pain medications, especially opioids. Still, they are trying to help you by protecting you against overdosing. 
• Try and use the same emergency room, or at least the ER within the same hospital system. It is useful and helps in developing familiarity with the people who work in that ER. It also allows easy access to your individualized plan of care, which your provider develops for such situations. 
• Adherence to disease-modifying therapy will help reduce the events of pain crises and prevent long-term organ damage. 
• Always be receptive to alternative ways of getting control over pain - including music therapy, self-hypnosis, and deep muscle relaxation. 
• Patients can adopt protective measures- stay warm and avoid exposure to extreme temperatures, adequate hydration, and breathing exercises at home. 
• Enhancing Healthcare Team Outcomes

SCA is a systemic disorder that affects the entire body. The disease not only manifests with physical symptoms (pain crises, organ damage, etc.) but also has numerous psycho-social implications. Most patients with SCA belong to the African-American community and a minority to Hispanic and other communities, which makes them prone to certain prejudices. Besides, the high demand for opioids to manage chronic pain makes the situation even more challenging. [31]  All providers must keep aside their inherent prejudice when caring for a patient with SCA, working collaboratively as an interprofessional team. Almost all specialties need to be involved in managing patients with SCA. However, the hematology team dedicated to taking care of SCA patients must be the primary physicians for these patients.

Specialties like ophthalmology, orthopedics, psychiatry, gastroenterology, and cardiovascular medicine interact closely with SCA patients. However, this does not diminish the importance of other specialties. Pharmacy and nursing also play a vital role. With the advent of newer drugs and infusions and SCA affecting liver and kidney function, pharmacists and nursing experts are required to ensure safe dosage and medication delivery to the patient. 

The data presented here is derived mostly from large and small randomized clinical trials. [Level 1 and 2] Few aspects of care presented here are from cohort and case-control studies. [Level 3]

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Sickle Cell Anemia, Hemoglobin C Contributed by Ed Uthman (CC BY 2.0 https://creativecommons.org/licenses/by/2.0)

Disclosure: Ankit Mangla declares no relevant financial relationships with ineligible companies.

Disclosure: Moavia Ehsan declares no relevant financial relationships with ineligible companies.

Disclosure: Nikki Agarwal declares no relevant financial relationships with ineligible companies.

Disclosure: Smita Maruvada declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Mangla A, Ehsan M, Agarwal N, et al. Sickle Cell Anemia. [Updated 2023 Sep 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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About Sickle Cell Disease

• Sickle cell disease (SCD) is a group of inherited blood disorders. Abnormal hemoglobin is produced.
• Red blood cells become hard and sticky and get stuck in small blood vessels, resulting in pain and other serious complications.
• There are several types of SCD, some more severe than others.
• In the United States, SCD is often found at birth through routine newborn screening.

Sickle cell disease (SCD) is a group of inherited red blood cell disorders. Red blood cells contain hemoglobin, a protein that carries oxygen. Healthy red blood cells are round, and they move through small blood vessels to carry oxygen to all parts of the body.

In someone who has SCD, the hemoglobin is abnormal, which causes the red blood cells to become hard and sticky and look like a C-shaped farm tool called a sickle. The sickle cells die early, which causes a constant shortage of red blood cells. Also, when they travel through small blood vessels, sickle cells get stuck and clog the blood flow. This can cause pain and other serious complications (health problems) such as infection, acute chest syndrome, and stroke.

There are several types of SCD. The specific type of SCD a person has depends on the genes they inherited from their parents. People with SCD inherit genes that contain instructions, or code, for abnormal hemoglobin.

Below are the most common types of SCD:

HbSS­­­­

People who have this form of SCD inherit two genes, one from each parent, that code for hemoglobin "S." Hemoglobin S is an abnormal form of hemoglobin that causes the red cells to become rigid, and sickle shaped. This is commonly called sickle cell anemia and is usually the most severe form of the disease.

People who have this form of SCD inherit a hemoglobin S gene from one parent and a gene for a different type of abnormal hemoglobin called "C" from the other parent. This is usually a milder form of SCD.

HbS beta thalassemia

People who have this form of SCD inherit a hemoglobin S gene from one parent and a gene for beta thalassemia, another type of hemoglobin abnormality, from the other parent. There are two types of beta thalassemia: "zero" (HbS beta 0 ) and "plus" (HbS beta + ). Those with HbS beta 0 -thalassemia usually have a severe form of SCD. People with HbS beta + -thalassemia tend to have a milder form of SCD.

There also are a few rare types of SCD, such as the following:

HbSD, HbSE, and HbSO

People who have these forms of SCD inherit one hemoglobin S gene and one gene that codes for another abnormal type of hemoglobin ("D," "E," or "O"). The severity of these rarer types of SCD varies.

5 Facts You Should Know About Sickle Cell Disease

Sickle cell trait (SCT)

People who have sickle cell trait (SCT) inherit a hemoglobin S gene from one parent and a normal gene (one that codes for hemoglobin "A") from the other parent. People with SCT usually do not have any of the signs of the disease. However, in rare cases, a person with SCT may develop health problems; this occurs most often when there are other stresses on the body, such as when a person becomes dehydrated or exercises strenuously. Additionally, people who have SCT can pass the abnormal hemoglobin S gene on to their children.

SCD is a genetic condition that is present at birth. It is inherited when a child receives two genes—one from each parent—that code for abnormal hemoglobin.

SCD is diagnosed with a simple blood test. In children born in the United States, it most often is found at birth during routine newborn screening tests at the hospital. In addition, SCD can be diagnosed while the baby is in the womb. Diagnostic tests before the baby is born, such as chorionic villus sampling and amniocentesis , can check for chromosomal or genetic abnormalities in the baby. Chorionic villus sampling tests a tiny piece of the placenta called chorionic villus. Amniocentesis tests a small sample of amniotic fluid surrounding the baby.

Because children with SCD are at an increased risk of infection and other health problems, early diagnosis and treatment are important.

Talk to your doctor to find out how to get tested and to learn about the results after testing.

Complications

People with SCD may start to have signs of the disease during the first year of life, usually around 5 months of age. Symptoms and complications of SCD are different for each person and can range from mild to severe.

Prevention and treatment of SCD complications

Management of SCD is focused on preventing and treating pain episodes and complications. Prevention strategies include lifestyle behaviors such as maintaining adequate fluid intake and avoiding extreme temperatures and medical screenings such as transcranial Doppler (TCD) ultrasound screenings to identify children at increased risk of stroke.

Prevention measures also include medical interventions such as vaccines to prevent infections and blood transfusions to reduce the occurrence of stroke in persons identified to be at risk. When pain crises occur, they can be managed through various clinical strategies include medication and intravenous fluids. Additionally, several medications are available that can be taken regularly to prevent or reduce the occurrence of pain crises and other complications. Bone marrow transplants and newly developed gene therapies are also potential treatment options for some patients.

Below is a list of key organizations of interest to people living with SCD and their families.

American Society of Hematology

• SCD Initiative : An initiative to improve outcomes for people with SCD
• Build Your Own SCD School Binder : Resources to support students with SCD

American College of Emergency Physician's Emergency Department Sickle Cell Care Coalition Information about emergency care for people with SCD

Children's Hospital of Philadelphia Sickle Cell Center Sickle cell school outreach tools and educational resources

ClinicalTrials.gov Up-to-date information on sickle cell disease clinical research trials

Foundation for Women & Girls + with Blood Disorders (FWGBD) An organization dedicated to ensuring all women and girls with blood disorders are correctly diagnosed and optimally treated and managed at every stage of life

National Heart, Lung, and Blood Institute Sickle cell information, tips for healthy living, and resources

National Human Resource Genome Institute Gene therapy education materials for the sickle cell disease community

Sickle Cell Disease Association of America Information, news, research, and resources

Sickle Cell Information Center Information about SCD; resources for patients, families, and healthcare providers; research; clinical trials; news; and books

Sickle Cell Reproductive Health Education Directive Resources on reproductive health care for people living with all types of SCD

• + This includes persons with, or have had, the ability to menstruate.

Sickle Cell Disease (SCD)

Sickle cell disease (SCD) is a group of inherited red blood cell disorders. In SCD, the red blood cells become hard and sticky and look like a C-shaped farm tool called a “sickle.”

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Sickle Cell Disease Research & Care

The NHLBI and Sickle Cell Disease

• The NHLBI has researched sickle cell disease since its founding as the National Heart Institute in 1948.
• Since 1972, when the National Sickle Cell Anemia Control act was passed, the NHLBI has spent more than $1 billion researching the condition.
• The NHLBI funds basic research and large clinical trials and conducts scientific workshops and consensus meetings.
• The NHLBI has convened an expert panel to develop sickle cell disease clinical practice guidelines to help providers give the best care to patients. The guidelines are expected to be released in 2011. A related public education campaign will also be launched in 2011.
• The NIH hosted the James B. Herrick Symposium on Nov. 16-17, 2010 in Bethesda, MD to celebrate research progress and look ahead to remaining challenges.
• More information on sickle cell disease is available.

What is Sickle Cell Disease?

• Sickle cell disease is inherited. People who have the disease inherit two copies of the sickle globin gene—one from each parent. The gene codes for production of an abnormal hemoglobin.
• Persons affected with this condition produce abnormal red blood cells containing hemoglobin S instead of normal hemoglobin A. When red cells with Hemoglobin S lose their oxygen, they become distorted and shaped like crescents or sickles. These cells are sticky and can block blood vessels, leading to organ damage, and severe episodes of pain known as crises.
• Sickle cell disease causes life-long anemia.
• Damage to the spleen causes an increased risk of serious infection. Persons with sickle cell disease are also at risk of pneumonia, bone infections, and other infections.
• Some people have mild symptoms, while others have very severe symptoms and are hospitalized frequently for treatment.
• Most people in the US with sickle cell disease can expect to live at least into middle age. Some of these people have few symptoms, but some live with a considerable burden of disease, including recurrent and chronic pain, lung disease, leg ulcers, and other complications.

Why Sickle Cell Disease Matters

• Sickle cell disease lowers quality of life for thousands of American families.
• The genetic blood disorder affects 70,000–100,000 Americans, the majority of whom are African American or Hispanic.
• Sickle cell disease is most common in people whose families come from Africa, South or Central America, Caribbean islands, Mediterranean countries, India, and Saudi Arabia.
• Sickle cell disease occurs in approximately one out of every 500 African American births and one out of every 36,000 Hispanic American births.
• About 2.5 million people in the United States have sickle cell trait, which occurs when a person inherits one copy of the globin gene.
• Today’s sickle cell disease treatment options, which include the drug hydroxyurea and blood transfusions, help many. Bone marrow transplants offer a cure for sickle cell disease for some patients, but due to a scarcity of matched donors, it is not a cure for everyone. Researchers are working on ways to make this cure more widely available.

Progress from Research

• Research has helped patients live longer. In the 1970s, life expectancy for individuals with sickle cell disease was about 14 years. Today, many individuals live into their 40s and longer.
• FDA approval in the 1990s of the drug hydroxyurea to treat adults with the disease was a major advance. Daily oral therapy with hydroxyurea reduces pain crises and hospital visits by more than 50 percent in most patients.
• Antibiotics to prevent and treat infections have reduced childhood deaths from the disease by more than 80 percent.
• A blood screening test done on newborns is now performed in all U.S. states.
• When both parents have sickle cell trait, each of their children has a 1 in 4 chance of having sickle cell disease. Tests can be performed early in pregnancy to determine if a child is affected.
• Bone marrow transplants can cure sickle cell disease in some patients.
• Research on the condition has advanced other areas of medicine including genetics and molecular biology.
• Researchers have learned that periodic blood transfusions in children at high risk of stroke help reduce the risk of having a first stroke.
• Research on damage to blood vessels is increasing understanding of why some people develop damage to the vessels in their lungs and brains.

Sickle Cell Disease Bench to Bedside

• Some of the medical benefits coming out of sickle cell disease research are not reaching enough people. We must educate providers and patients about current advances in diagnosis and treatments.
• Many individuals who could benefit from hydroxyurea are not prescribed the drug.
• Volunteers are critical to conducting clinical trials and have helped advance the field. More volunteers are needed to continue our progress.

The Future of Sickle Cell Disease

• The NHLBI is supporting research on more and better treatments to ease the burden of sickle cell disease on those affected.
• Trials using new bone marrow and stem-cell transplant procedures have cured a small number of some adults with sickle cell disease.
• More research is needed to understand possible health implications of sickle cell trait.
• A new gene finding could lead to breakthrough therapies. This gene impacts production of a form of hemoglobin that directly influences the severity of the condition.
• Current research is exploring ways to reduce the risks of serious complications, including stroke, hypertension, respiratory problems, and vulnerability to overwhelming bacterial infections.

Last Updated: April 12, 2012

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