Hello, everybody, and welcome to HCPLive® Peer Exchange titled “Extra Perspectives on the Optimal Management of Sickle Cell Disease.” My name is Dr Ify Osunkwo, and I’m a hematologist and a professor of medicine in pediatrics at Atrium Health in Charlotte, North Carolina. I take care of a sickle cell [SC] disease population of about 1400 living with sickle cell disease in ages 18 and older. Today I have a few of my peers, and I would love to have them introduce themselves, starting with Dr Abdullah Kutlar. 

Thank you, Ify. I’m Abdullah Kutlar, a hematologist and the director of the Sickle Cell Center at the Medical College of Georgia at Augusta University. I’m looking forward to this exchange.

Hi, I’m Wally Smith. I’m a general internist by training, but I’ve been taking care of patients with sickle cell disease since 1984 at 2 institutions. Since 1991, I’ve been at Virginia Commonwealth University, where I direct the Adult Sickle Cell Center.

 Our next panelist is Dr Pat McGann. Pat?

 I’m Pat McGann. I’m an associate professor of pediatrics and a sickle cell doctor at Cincinnati Children’s Hospital. I take care of many children with sickle cell disease in the United States and have lots of partnerships across the world, so I’m helping to improve outcomes globally as well.

Welcome, everybody. Our discussion is going to focus on providing an overview of sickle cell disease and discussing available standards of care using treatments of sickle cell disease. We’re also going to take a deep dive into the new treatments that were actually approved over the past 4 or 5 years, and our long-standing treatment for sickle cell disease that we’ve had for the past 20 years. Welcome, everybody. Let’s get started. Our first question is going to Wally. How do you define sickle cell disease to the medical audience and even the patient audience?

 First, you must understand what hemoglobin is. Hemoglobin is a molecule inside your red blood cells that carries oxygen. You need hemoglobin to pick up the oxygen and deliver it to the tissues. Patients with sickle cell disease have a problem with that because they have a deficient hemoglobin. The hemoglobin doesn’t pick up oxygen well and doesn’t hold on to it well, and when it doesn’t hold on to oxygen, it tends to form funny red blood cells, like a garden sickle. The hemoglobin inside forms little crystals or polymers and stretches the cell from what normally is a doughnut into funny shapes, including the garden sickle. When you look at somebody’s blood who has sickle cell disease, you don’t see a bunch of doughnuts, you see these funny shaped cells.

There are 4 genetic kinds of sickle cell. It’s a genetic disease; mom and pop have to have the trait in order for Junior to get the disease. It’s not an every-time thing. Every time mom and pop have a child, there’s a 1 in 4 chance for Junior to get the disease. Some families are unlucky, 3 or 4 children in the family will have the disease because every time there’s a 1 in 4 chance. 

There are 4 genotypes prevalent in the United States. Some would say 5, some would say 6 if you go worldwide. The more severe genotypes are SS [sickle cell anemia]. That’s where mom and pop have the same hemoglobin S [sickle] gene. And then S beta plus thalassemia, where mom or dad has the hemoglobin S gene and dad has the thalassemia gene that passes on. If you draw all those things out, the complications get significant, but the main thing to take away is it’s genetic and there’s a bad hemoglobin. People with this disease do not do well. They die early, they’re anemic, they’re in pain, they have infections, and they have strokes. It’s a miserable life, and until recently it was a childhood killer. Only recently have we been able to stretch the length of life past the childhood stage.

 That is interesting, Dr Smith. Abdullah, can you highlight the differences in the genotypes? Many patients say they have a touch of sickle cell or the milder form. Can you explain to us what it means to have the different types of sickle cell disease that Wally had mentioned? There are 4 to 5 common types. Can you talk about that?

Wally made a great introduction and made it easy by mentioning the different genotypes of sickle cell disease. If you have 2 copies of the hemoglobin S gene, 1 from each parent, you have with hemoglobin S or sickle cell anemia. Then there are other mutations or variant hemoglobins, such as beta-thalassemia and hemoglobin C, which can interact with sickle hemoglobin to generate a phenotype of sickle cell disease. 

If you look at the US population, I can cite some of the statistics from our adult population. This is about the same, give or take a few percentage points. About 69% of our patient population is hemoglobin S, followed by SC disease in about 20%, and S beta plus thalassemia in 6%. S beta zero thalassemia is in 3% of our patient population. There’s a 1% to 2% of those rarer genotypes, such as SD Los Angeles, SE, SOR1. The interesting thing is that for all practical purposes, the phenotypes of SS and S beta zero are similar, and they run a similar clinical course, as do SC and S beta plus thalassemia.

The Cooperative Study of Sickle Cell Disease [CSSCD], which is the largest natural history study conducted in upward of 20 centers in the United States between the late 1970s and early to mid-1990s, shows that if you look at the clinical features, SS and S beta zero cluster together, whereas SC and S beta plus cluster together. This was a 1994 publication in the New England Journal of Medicine by Ora Platt and other investigators from the CSSCD. The crisis or VOC [vaso-occlusive crisis] rate is twice in the SS, S beta zero group compared with SCS beta plus. The same applies for an acute chest, and retinopathy seems to be more common in SC, which is a viscosity-related pathology, so vascular necrosis. There are distinct differences, although these can be grouped into SS, S beta zero vs S beta plus, and SC. 


There can still be some mild differences among these genotypes. It’s safe to say that SS and S beta zero are more severe phenotypes of the disease than SC and S beta plus.

Understanding Sickle Cell Disease 

Pat, can you discuss the prevalence of sickle cell disease? Not just in the United States but also around the world. Give us insight into the burden of sickle disease: economically, socially, and medically in these different populations.

Many people think of this as an uncommon or rare condition. It’s really not, in this country and across the world. As some people probably know, most patients in the United States who have sickle cell disease are Black or African American because the genetic mutation happened in Africa and places where malaria is highly prevalent. In Africa at least 300,000 babies are born every year with sickle cell disease. Most don’t get diagnosed because they don’t have screening as we do here in the United States. I just saw a statistic that 150,000 children are diagnosed with HIV every year. Twice as many children are born with sickle cell disease and considered the global recognition of both conditions. It is not uncommon at all.

In the United States it also is not uncommon. There are about 3000 babies born with sickle cell disease in the United States. Depending on which state you live in, there is newborn screening and there are tests for 30 or 40 conditions—sickle cell disease is among them—no matter what your race or ethnicity. Everyone gets tested for sickle cell. Of the things that are tested in this country, sickle cell disease is by far the most commonly detected condition by newborn screening. It’s more common than hypothyroidism or PKU [phenylketonuria] or cystic fibrosis or anything else. This is not often recognized because it’s a problem of racial minorities. Along with any other health problem in this country, those who are in a racial minority, like Black or African American, are affected by social determinants of health even more profoundly, so patients with sickle cell, on top of having a chronic medical condition, must face those challenges too. There are lots of comparisons to be made between sickle cell and other diseases. Sickle cell disease was detected, or first described, in 1910, but there were no drugs available for it until the 1980s. It was described as the first molecular disease in 1949, and we still have only a few treatments available. It’s a big problem, way bigger than people recognize both here and across the world.

Thank you so much, Pat. It’s important for people to realize the profound impact sickle cell has on the individuals affected, not just those individuals but their family members, society in general, the economics of health care, and the economics of society.

Prevalence and Burden of SCD 

Wally, can you talk a little about the acute sickle cell complications and how these differ from the chronic complications? It’s important to highlight that no matter what type of sickle cell disease you have, you are at risk of both acute and chronic complications.

That’s right. You know, the acute complication that doctors and hospitals know the best is called a vaso-occlusive crisis, or crisis for short. We’ve messed around with terminology to try to better describe it, and I keep coming back to crisis. It is a crisis in the life of the patient because they’re in pain, they want treatment early, and they want treatment immediately. If you intervene sooner, you likely can prevent some of the downstream complications. It’s seen in the emergency departments of many hospitals and in hospital wards around the country. But as you said, the size of vaso-occlusive crises are painful and may cause all kinds of disability and acute organ dysfunction on top of that.

Besides that, there’s this chronic low-level hum of sickling going on all the time in all the blood vessels, in all the organs of every patient with sickle cell disease. Some more than others. And it’s that low-level hum that ongoing crises like complication that you can’t even feel, because it’s the same vaso-occlusive phenomena. That destroys your organs. That causes eventually either liver, lung, eye, brain, heart, kidney, or other failure. Failure of your joints. You get basically rotten hips, rotten shoulders, rotten knees, all due to lack of oxygen getting to those organs and organ death over time. The spleen in most children is gone by the time they’re adults because they’ve been either ischemic or they’ve been trying to filter out those abnormal red cells that I discussed earlier. The spleen is like a trash can, and it’s overworked. By the time they get to be adults, it’s a nub; it’s gone.

 Patients cannot handle this low-level hum, and their organs 1 by 1 begin to fail. Sometimes they don’t even know their organs are failing.

 That’s a question that I wanted to pose to Abdullah and to Pat. Sometimes patients say, “I’m not having a pain crisis, so I don’t need to see the hematologist. I don’t need to go to the doctor.” I think you see that with pediatric, young adults, teenagers. When they’re not having pain, they’re like, “See you later.” How do you convince them that what Wally says is true? They have this long-standing chronic stuff happening all the time.

 It’s an excellent point, especially in adolescents and young adults who feel well and who—by luck, by high fetal hemoglobin, or whatever you say—don’t have a lot of acute pain episodes. It’s very difficult. I used to try to persuade patients to be on a disease-modifying therapy, mainly hydroxyurea. Wally, there are some very nice points that we came up with at the end of the MSH [Multicenter Study of Hydroxyurea] follow-up. That shows very nicely that people who have been taking hydroxyurea for most of the time have much lower incidents of death, and that is an eye-opener for many of them. Then you go over different chronic complications. You may not feel pain, but as Wally pointed out, the organ damage is ongoing at that time. It’s still progressing.

 And we still have young adults who have strokes who have never had a pain crisis?

Yes, and the paradigm of the disease is really changing as we have these new therapies, which we’ll get into. Wally said that by adulthood your spleen is broken, basically by the time you’re 2 years old your spleen has been shown to be significantly damaged. When I talk to newly diagnosed babies, I talk to them with a much greater sense of optimism than families a decade ago. We start hydroxyurea early and try to protect their organs. It’s a long haul. It’s like a vitamin to keep them healthy. They might hear about pain, but it’s more than pain. For older patients, I try to think of what they might want to do when they get older, whether it’s playing sports or the job that they want to do. If they want to do those effectively, then protecting their organs is an important thing. We try to bring those things up.

 Excellent. This highlights the next comment I’m trying to make here. When you look over years of sickle cell disease, the life expectancy has improved, as you guys mentioned. However, we still have a 3-decade gap between a sickle cell individual and the regular African American who lives in the United States. The median age of sickle cell disease in Africa is 17 years old. That’s dismal. To think the adults in Africa with sickle cell disease are 17 years old, that’s almost embarrassing. In America, they’re still between the 40s and the 50s. You may have some people who live to be 60, 70, and 80, but they’re fewer and far between compared with what we want to see and compared with the general population. 

Dr Kenneth Ataga and some colleagues did a minute analysis several years ago. They looked at 41 studies to see the impact of a lower or a dropping of hemoglobin on long-term outcomes of sickle cell disease. It was a very interesting study. This is a little more complex than we can get into in this broadcast, but they showed that a drop in hemoglobin of 0.4 g/dL is enough to increase your risk of having a stroke. A drop in hemoglobin of 0.6 g/dL has an increased risk of kidney problems, pulmonary hypertension, and even the risk of death. And the drop in hemoglobin of 0.9 g/dL increases pulmonary hypertension. It’s really important to remember that it’s not just pain. The hemodynamic changes that are associated with having sickle cell disease cause long-term chronic damage to your organs, as Wally Abdullah, and Pat had mentioned, so we cautiously pay attention. We have a more futuristic way of looking at the patients: How do we protect organs as well as damage control and treat pain as a primary focus of sickle cell disease management?

Acute and Chronic Complications in SCD 

Abdullah, can you discuss the recently published NHLBI [National Heart, Lung, and Blood Institute] recommendations for screening and monitoring of sickle cell disease complications, including anemia regarding stroke, pulmonary adrenal dysfunction, and retinopathy? What do we know that we should be doing in the year 2021?

As was pointed out by Wally, you, and Pat, we are having an increasing recognition that sickle cell [SC] disease is not just pain crisis, and when the pain crisis is gone, they are fine. No. The organ damage starts very early. Based on a long period of accumulation of data from clinical trials and everything, the National Heart, Lung, and Blood Institute and more recently ASH [American Society of Hematology] have come up with guidelines on how to identify and prevent or treat organ damage. 

Let’s take stroke, for example. Stroke is another complication. The natural history study, the CSSCD [Cooperative Study of Sickle Cell Disease], identified that about 11% of patients with sickle cell up to age 20 suffer from stroke; it’s a little higher in SS [sickle cell anemia] and a little lower in SC. We have no way of identifying stroke, but in the landmark trials STOP 1 and STOP 2, done by my colleague Dr Robert Adams, transcranial doppler was a very useful predictor of cerebrovascular disease. If you have high velocities in major intercranial arteries, such as the carotid, anterior cerebral, and middle cerebral, that presents a highly increased risk of stroke. With the STOP studies, screening with TCD [transcranial Doppler ultrasound] was established as a means of detecting stroke risk. The current recommendation in the guidelines is to start screening everybody at age 2, and at least until age 16 or 17, a window with the highest frequency of cerebrovascular disease. 

Normal velocities are less than 170 cm/s. Those who have velocities over 200 cm/s have a significantly higher risk of stroke, like 10-fold or so, over the next 4 years. The standard has been established to identify these individuals and put them on transfusion. That’s why it’s important in prevention. There is a category of 170 to 200 cm/s, which is called conditional. Conditionals can be treated with transfusion, but now we have evidence that hydroxyurea is effective in reducing velocities. We could use those. In secondhand prevention, transfusions are necessary. That’s for stroke risk. In terms of cardiopulmonary, it’s very important—and this has been shown in many studies—to screen the patients clinically and symptomatically for the presence of pulmonary complications like asthma… 

 And restrictive lung disease and so forth. As you become older, the issue of pulmonary hypertension becomes significant. The recent recommendations for monitoring include echocardiograms on all adults and looking at the tricuspid regurgitant velocity. Normally, it should be 2.5 m/s. If anybody is at 2.5 m/s, repeat that and optimize the sickle therapy, whether it’s hydroxyurea or any other disease-modifying agent. But if the velocity is over 3 cm/s, then they must be referred for a right heart catherization to identify pulmonary hypertension. This has been proven to have pulmonary arterial hypertension, which requires treatment. Those are the recommendations in a nutshell. 

Sickle cell involves kidneys from a very early age. I’m not going to talk about the hyposthenuria, which some people say starts in the intrauterine life. The more clinically significant aspect of sickle nephropathy is the sickle cell of high penetration, microalbuminuria, albuminuria, and then chronic kidney disease, end-stage renal failure. It’s a sequence that is very similar to the evolution of diabetic nephropathy. These 2 diseases have a lot in common. 

The microalbuminuria can be seen in children but sharply increases with increased age. The recommendation…is to start screening for microalbuminuria at age 10. Any albumin or creatinine ratio of 30 mg/g or over should be taken seriously. In children, there are some studies that have shown hydroxyurea to be effective in reducing nephropathy. In adults, you must start either an ACE inhibitor or an ARB therapy in patients with microalbuminuria. The guidelines also recommend that anybody with albuminuria that is greater than 300 mg protein excretion in 24 hours should be referred for a nephrology evaluation and work-up and likely be put on ACE inhibitors and ARBs. For retinopathy, recently it has been found to be a little more common in SS than originally thought. The recommendation is again starting at age 10, do a dilated retinal exam. If it’s normal, repeat it every year or 2. If that’s abnormal, then they should be followed by a retinal specialist, and necessary treatment should be instituted.

Anemia-Related SCD Manifestation: Monitoring and Screening  

 One thing I’d like to point out that you said is to screen for symptoms. A lot of times patients show up to their clinic appointments, and let me know if you think this is true, we ask, “How are you doing?” They say, “I’m fine.” “Have you had any pain crises?” “Absolutely none.” They’re like, “I’m doing great.” But then they can’t walk a block, they can’t climb the stairs, they’re getting dizzy when they get out of bed too quickly, they’re lethargic all the time. They can’t do any type of sports, or any kind of physical activity, they don’t have a job. And they’re “fine” because they’re not in the hospital, but they really are not fine, they have shortness of breath, they have…on exertion, they have all the symptoms that would suggest either cardiac pulmonary or chronic anemia complications, and it slides under the radar. What are your thoughts about that? I’ll start with Pat and Wally; I want to get your thoughts.

 Yes, in sickle cell disease the pain crises are so predominant, in your face, and this patient’s quality of life is so poor that they’re just used to it. Unless you dig in and get to it, they may not recognize that they could do things that they ought to do. It’s partly on us as health care providers to ask these important questions because it’s not about the pain at all, it’s about organ function, it’s about quality of life, it’s about doing stuff. These things often go under the radar, and when they go under the radar, it’s hard to do anything about them when pulmonary hypertension or chronic kidney disease are too far along.

 Absolutely, Wally what are your thoughts? This whole idea of caring for sickle cell disease being more of an early detection and prevention philosophy vs damage control and acute intervention. What are your thoughts on this?

We study patients to determine their health-related quality of life, Ify. And we looked at battered women, patients on dialysis, patients with asthma, and the like. And sickle cell is competing for bad quality of life with those diseases, and we published that because both in children and adults, quality of life in sickle cell disease is impaired. It’s impaired in people who don’t have a lot of crises, and it’s even more impaired in people who have a lot of crises. It is important to say to the patient, “The way you feel now may be normal for you, but it’s not normal for life.” What we’re learning, now that we have medications that can improve the hemoglobin, is patients are suddenly going, “I’ve been missing all of this, all my life?” Their quality of life is improving because they’re on medications that help them, and they didn’t realize they could do better than what they were doing. It is important to say to patients, “What’s your fatigue level?” If you run a sickle cell clinic for adults, don’t expect any patient to show up before 10 am.

They are not getting out of bed at 8 o’clock in the morning and doing nothing for nobody, because they’re anemic.

Can I share an anecdotal report on a patient of ours to the effect that Wally reported? This is a 56-year-old female who I have followed for over 2 decades, almost 3 decades. She was on hydroxyurea and had a great response, fetal hemoglobin around 30%. But over the years her hemoglobin declined from 8 to about 6 [g/dL]. In August we started her on voxelotor. I saw her last week. I said, “How are you doing?” She said, “I’ve never felt this good in my life.” Her hemoglobin, which was 6, was now 10 [g/dL]. To Wally’s point, we have some success stories with some of the new disease-modifying agents like that.

 That quality-of-life matters. They get used to being so poor with their quality of life. 

They grew to expect a poor quality of life and they adjust, and they use the word “fine” to describe their current quality of life, when what they really mean is, “As good as I can be in the condition that I’m in.”

 Impact of SCD on Quality of Life 

 I want to switch to treatment options available for sickle cell disease. We’ve had 1 drug available from the mid-1990s, and thankfully we have a couple more. Pat, can you discuss the mechanism of action and the use of hydroxyurea in targeting the pathophysiology of sickle cell disease and its history, how it works, why we use it, and what the outcomes were?

 Yes. It’s a really old medication. It’s been used since the 1950s, primarily to treat cancers, and part of the notoriety of hydroxyurea as a chemotherapy agent is because of that. It was found through some nice experiments in the 1980s to induce fetal hemoglobin. We know that babies express fetal hemoglobin, and it is a type of hemoglobin that binds oxygen more tightly so that fetuses can extract oxygen from the mother’s circulation. Then when the baby is born, they no longer need that, and they make adult hemoglobin. If you have sickle cell disease, you make sickle hemoglobin. And we know from the experiment of nature that babies don’t have sickle cell symptoms until that fetal hemoglobin goes away, which usually happens by 6 months of age, though in varying degrees with different people.

There are also some people who inherit a high fetal hemoglobin, hereditary persistence of fetal hemoglobin. And if you have that with sickle hemoglobin, you have no symptoms. Fetal hemoglobin is a great target. Hydroxyurea was a medicine found to induce that in 1980s, and a multicenter study of hydroxyurea in adults showed that it was highly effective in reducing pain, time to pain events, and many studies thereafter have proven those benefits. There’s always been a bit of a concern because of its label as a chemotherapy medicine that it will suppress your blood counts, that it will have long-term effects, and we now have 35 years of data with hydroxyurea basically that it shows it’s safe. The primary possible adverse effect is that it might reduce your blood counts, your white blood cells or your neutrophils, your reticulocyte count, especially in some older patients whose kidneys might not work well or whose bone marrow might be tired. But you can modulate that and adjust the dose. The other effects that are suggested sometimes have not panned out with 30 years of evidence so far.

Now in pediatrics, and I’m a pediatric hematologist, we use it routinely starting in the first year of life. These babies, when I talk to the parents at diagnosis, I tell them we’re going to start hydroxyurea and keep their baby healthy and let them grow up and live an essentially normal life. So far we have about 50 or 60 patients for whom we’ve done this in the last 5 or 6 years, and they’re doing quite well, with fetal hemoglobin levels of 30% to 40%. In adults, especially older patients who have chronic organ damage, it’s often a bit more challenging, and sometimes patients don’t tolerate it as well. Medication adherence becomes a concern obviously with many oral medications. It is once a day, but that once a day is quite a bugaboo for some. But it is a good medicine, and we have lots of new exciting medicines. It’s important not to forget about hydroxyurea, and it still should be the foundation to these other therapies until we have new evidence.

I like that you mentioned it’s been around for a while. We have new medicines coming, but this is a foundational medication that works only if you take it. The medicine must get from the bottle into the body for it to work.

Hydroxyurea in Sickle Cell Disease 

Expert Perspectives on the Optimal Management of Sickle Cell Disease

Experts discuss challenges in sickle cell disease along with the available standard of care and newer FDA-approved agents used in the management of the disease. 

Expert Perspectives on the Optimal Management of Sickle Cell Disease

EP 1: Understanding Sickle Cell Disease

EP 2: Prevalence and Burden of SCD

EP 3: Acute and Chronic Complications in SCD

EP 4: Anemia-Related SCD Manifestation: Monitoring and Screening

EP 5: Impact of SCD on Quality of Life

EP 6: Hydroxyurea in Sickle Cell Disease