AN OVERVIEW OF SICKLE CELL DISEASE (SCD) AND THE IMPACT OF HEMOGLOBIN S (HbS) POLYMERIZATION, ANEMIA, AND HEMOLYSIS1-5

The following video segments give greater insight into the complications of SCD, and how HbS polymerization is the root cause of hemolysis and anemia, leading to further damage and vasculopathy.

Living with Sickle Cell Disease

Learn about the prevalence, symptoms, and burden that SCD-associated complications can impose on patient care and quality of life.

Hello everybody. My name is Dr. Andrew Campbell and I’m Director of the Comprehensive Sickle Cell Program at Children’s National Hospital in Washington, D.C. I’ll be your host today.

This program is sponsored by Global Blood Therapeutics. I am presenting this program on behalf of GBT. The program has been reviewed consistent with GBT’s internal review policies.

Let’s start by reviewing the overall prevalence of sickle cell disease, the toll that the disease takes on their patient, and the impact on the quality of life of an individual living with sickle cell disease.

According to data from the CDC, in the United States, sickle cell disease affects an estimated 100,000 people. It disproportionately affects Black and Hispanic Americans.1,2

In fact, 1 out of 365 births among Black Americans are affected with sickle cell disease.

And 1 out of 16,300 births among Hispanic Americans are also affected.

The prevalence is highest in the Eastern and Southern United States and in parts of the Midwest.1

The states with the highest prevalence of sickle cell disease are Florida, New York, and Texas.1

Sickle cell disease is a group of inherited disorders caused by mutations in the gene that encode for hemoglobin subunit beta.1

A specific sickle nucleotide substitution results in sickle cell allele hemoglobin.

Sickle cell disease occurs when a person inherits a sickle cell gene from each parent.

On the other hand, individuals with one hemoglobin S allele and one unaffected , hemoglobin A, have sickle cell trait, but not sickle cell disease.

According to the CDC, approximately 1 in 12 African Americans in the United States are carriers, which is also known as sickle cell trait.

This diagram illustrates inheritance patterns for the most common sickle cell disease, genotype sickle cell anemia hemoglobin SS,1 but there are other genotypes as well.2

Such as hemoglobin SC disease,HbSβ0-thalassemia, HbSβ+-thalassemia, and others.

People with sickle cell disease have significantly reduced life expectancy1 While the life expectancy was poor in 1979, the data shown here depict what has changed from 1979 to 2006.

One thing to point out here is that between 1979 and 2006, survival for children with sickle cell disease in the US improved significantly due to universal newborn screening, infection prevention, and comprehensive care.1,2

However, during the same period of time, survival for adults with sickle cell disease did not improve dramatically.1,2 In fact, it is far from where it needs to be.

In 2006, the mean age of death among people with sickle cell disease was only 39 years of age.1

Symptoms of sickle cell disease begin to appear as early as 6 months of age.1

We’ve all seen these acute, life-threatening events that can happen at any age throughout the pediatric journey.1

We see complications related to organ damage may occur in childhood, including overt stroke, silent cerebral infarct, neurocognitive impairment, or retinopathy. Another important complication is hearing impairment. The heart and lungs are also affected in acute chest syndrome and left ventricular hypertrophy. We also see splenic dysfunction, renal impairment, avascular necrosis, and priapism.1-3

When we look at the complications through adulthood, adults with sickle cell disease experience many of the same symptoms as children, but disease manifestations may worsen with age.1

Progressive organ damage may manifest in adults as overt stroke, silent cerebral infarct, hearing loss, neurocognitive impairment, progressive retinopathy, pulmonary hypertension, heart failure, kidney failure, liver dysfunction, leg ulcers, avascular necrosis, reduced bone density, as well as reproductive issues such as priapism, erectile dysfunction, male infertility, and pregnancy-related complications.1-5

Strokes tend to be more severe in the adult population and often lead to physical and cognitive disabilities, and mortality.1

This figure here shows that complications over time from a retrospective of claims analysis that tracked 3,208 patients with sickle cell disease. Sickle cell complications examined in this study include stroke, renal complications, leg ulcers, congestive heart failure, and pain, among others.1

We see that the complications of sickle cell disease begin in childhood and increase with age.1

Complication frequency begins to increase sharply during the period in which patients transition from pediatric to adult care for couple of reasons. First, the chronic, progressive nature of the disease start to manifest in patients, and this leads to worsening complications.2

Secondly, following the transition from children to adulthood, there is reduced access to medical follow-up and preventive care (such as hydroxyurea and transfusions) due to inadequate transition care planning, and limited availability of specialized providers. Patients may also have changes in coverage that complicate the transition process.1,2

In addition to cognitive impairments, people with sickle cell disease suffer from somatic, psycho-social and general function impairments and report significantly reduced health-related quality of life on many domains. These quality-of-life impacts may include depression and anxiety. They may also include pain, fatigue and weakness, and cognitive impairments; limitations in activities of daily living, and others shown here.1-3

These quality of life impairments illustrate the toll that the disease has on patients’ well-being and their ability to function on a day-to-day basis.

This study by Kato and others examined physical functioning scores measured using the SF-36 and the Pediatric Quality of Life Inventory generic core scales in healthy individuals, and individuals with chronic disease. Scores range from 100 to 0 with 100 representing the best health-related quality of life.

The study was conducted in both adults and children with sickle cell disease and found that they were substantially impaired with health-related quality of life.

As you can see on diagram here, compared with individuals with other chronic illnesses such as cancer and cystic fibrosis, many of the individuals with sickle cell disease was worse or comparable to those individuals.

This data is powerful in that it allows you to see a bigger picture of the impact of sickle cell disease on patients’ lives, beyond the hospital and clinic visits.

Underlying Pathophysiology of Sickle Cell Disease Leading to Organ Damage

Discover the molecular and cellular processes that contribute to red blood cell sickling in SCD, and how these processes drive the vascular and systemic changes observed in individuals with SCD.

Hello everybody. My name is Dr. Andrew Campbell and I’m Director of the Comprehensive Sickle Cell Program at Children’s National Hospital in Washington, D.C.I’ll be your host today.

This program is sponsored by Global Blood Therapeutics. I am presenting this program on behalf of GBT. The program has been reviewed consistent with GBT’s internal review policies.

We’re now going to dive deeper into the pathophysiology of sickle cell disease, and how it can lead to organ damage.

Sickle cell disease occurs due to a mutation in hemoglobin that causes it to polymerize.

The inherited mutation and the beta-globin gene results in a single amino acid substitution at the sixth position in the beta-globin chain of the hemoglobin protein, hemoglobin S, changing it from glutamine to valine, causing it to polymerize.

Here on this slide, we see a hemoglobin with two alpha-globin chains and two beta-globin chains, along with the heme group with its iron core.

Hemoglobin S polymerization and red blood cell sickling are the root causes of pathology in sickle cell disease.1,2

As the oxygen gets off-loaded from the hemoglobin molecules, the hemoglobin S molecules polymerizes. These polymers form long, rigid rods within a red blood cell that causes it to take an elongated crescent or “sickle” shape.1,2

Hemoglobin S polymerization and sickling lead to cellular abnormalities in red blood cells, that promote hemolysis of their cells.1,2

Hemolysis releases red blood cell contents, including free heme, free hemoglobin, ATP, ADP and others. These substances promote oxidative damage, activation of neutrophils, platelets and endothelial cells, and scavenge nitric oxide, which impairs vasodilation.1,2

These abnormal red blood cells, platelets and neutrophils adhere to each other and to activated endothelium, contributing to the formation of vaso-occlusions that block blood flow. This blockage of blood flow can ultimately lead to organ damage.2

Hemolysis of sickle red blood cells also leads to anemia, impairing oxygen delivery.3

We know that vaso-occlusions can restrict blood flow, leading to crisis, which is characterized by sudden onset of severe pain.1-3

Vaso-occlusions most often occur in the bones, the back, the chest, and the extremities.1

Vaso-occlusion triggers are unpredictable and include cold, dehydration, infection, and stress.4,5

As these cellular clusters form within the blood vessel, this can lead to hypoxia and may lead to tissue injury and tissue death if blood flow remains restricted.2,3,5

In a 7-year follow-up study of 104 adults with sickle cell disease who were monitored for organ damage and vaso-occlusive crises we see that regardless of whether a patient experiences vaso-occlusive crises, they are at risk of organ damage.

In this study, as you can see, regardless of whether a patient had 0-1 vaso-occlusive crises per year or >1 vaso-occlusive crises per year, there was no significant association of vaso-occlusive crisis frequency and organ damage, as seen on this slide, from microalbuminuria, renal failure, pulmonary hypertension, leg ulcers or stroke, to name a few.

In summary, hemoglobin polymerization and red blood cell sickling are the root cause of pathology in sickle cell disease, which leads to anemia, hemolysis, and vaso-occlusive crises.1

The Role of Anemia and Hemolysis in Sickle Cell Disease Leading to Organ Damage

Learn how anemia and hemolysis play an important role in causing organ damage in SCD patients.

Hello everybody. My name is Dr. Andrew Campbell and I’m Director of the Comprehensive Sickle Cell Program at Children’s National Hospital in Washington, D.C.I’ll be your host today.

This program is sponsored by Global Blood Therapeutics. I am presenting this program on behalf of GBT. The program has been reviewed consistent with GBT’s internal review policies.

We will now discuss in more detail how anemia and hemolysis in sickle cell disease contribute to organ damage.

Well, we know that anemia and hemolysis are associated with progressive damage to organs. Damage can occur to many organs including brain, lungs, heart, liver, spleen, kidneys, gallbladder, penis, skin.1,2

Additionally, progressive organ damage is common and irreversible in roughly half of the people with sickle cell disease by age 50.3,a

This was based on a 4-decade observational study of 1,056 people with sickle cell disease.

In order to examine the association between anemia and severity and the risk of clinical outcomes, a meta-analysis was performed by Dr. Ataga and colleagues, on the studies that report on the association of hemoglobin levels, with 5 clinical outcomes of interest. These include elevated pulmonary artery systolic pressure; albuminuria; abnormal transcranial doppler velocity; stroke/silent infarct, and mortality.

The analysis compared hemoglobin levels in patients with and without these outcomes, across 41 studies in over 9,000 patients.

These results suggest that a correlation may exist between hemoglobin magnitude and morbidity and mortality-associated measures, and that mild-to-moderate reductions in hemoglobin may be associated with morbidity and mortality.

To understand how hemolysis severity is associated with increased risk of death in children with sickle cell disease, we can learn from the Cooperative Study of Sickle Cell Disease.

This figure represents an analysis of the relationship between the absolute reticulocyte count in children and time to death.

There were 354 children diagnosed with sickle cell anemia who had their first visit within 196 days of birth, and this study used the highest absolute reticulocyte count recorded between 2 and 6 months of age.

The most abrupt rise in death occurred before 2 years of age in the group with the highest absolute retic count.

We also see the death rate rose in a largely stepwise fashion with absolute reticulocyte count.

We see similar results in adults. In this study, hemolysis severity appears to be associated with the risk of some clinical outcomes.

A study of 213 patients with sickle cell disease found a statistically significant difference in survival between patients with high and low levels of LDH, which is a marker of hemolysis.

We know that anemia and hemolysis cause damage to the brain, specifically contributing to increased risk of stroke and neurocognitive impairment in sickle cell disease.1,2

Anemia reduces oxygen delivery to the brain, and decreases cerebrovascular reserve.1

Anemia severity correlates with abnormal TCD velocity.3

Hemolysis releases cell-free hemoglobin, which scavenges nitric oxide, facilitates oxidative damage and damages vessels.4,5

All in all, there is an environment where vasculopathy increases risk of stroke, silent cerebral infarct and neurocognitive problems.1-4

Let’s dive into that a little bit deeper on the next slide.

Shown here are four datasets that show how hemoglobin level is associated with risk of stroke and silent cerebral infarct.

The graphs on the left show 2 studies by Belisario and Domingos demonstrating that lower levels of hemoglobin were associated with increased risk of stroke.1,2

The graphs on the right show 2 studies by Kwiatkowski and DeBaun, demonstrating that lower levels of hemoglobin were associated with increased risk of silent cerebral infarct.3,4

Going back to the Cooperative Study of Sickle Cell Disease that we discussed earlier, we show here an analysis of the relationship between absolute reticulocyte count in children and time to stroke.

There were 354 children diagnosed with sickle cell anemia who had their first visit within 196 days of birth. This study used the highest absolute reticulocyte count recorded between 2 and 6 months of age.

We see that the stroke rate rose in a largely stepwise fashion with absolute reticulocyte count.

Here we take a look more specifically at the role of anemia and hemolysis in the development of pulmonary hypertension in sickle cell disease.1-3

Pulmonary vasoconstriction and increased cardiac flow associated with anemia contribute to elevated pulmonary artery pressure.1-3

Increased cardiac output secondary to anemia may also play a role in pulmonary hypertension.1,2

With regards to hemolysis, impaired vasodilatory responses to nitric oxide are correlated with free plasma hemoglobin and LDH, contribute to pulmonary and systemic vasoconstriction.1,3

When we look at this prospective multicenter study of 310 children aged 3 to 20 years of age, in the United States with sickle cell disease from Minniti and others, we see that anemia and hemolysis are directly correlated with the risk of pulmonary hypertension in children.

Lower hemoglobin levels and higher LDH and reticulocyte levels in children with sickle cell disease were associated with elevated tricuspid regurgitant velocity, which is a surrogate marker of pulmonary hypertension.

This perfective study of 195 adult patients with sickle cell disease, which included patients with hemoglobin SS, hemoglobin SC , HbSβ0-thalassemia or HbSβ+-thalassemia by Gladwin and others show that anemia and hemolysis are directly correlated with the risk of pulmonary hypertension.

Lower hemoglobin levels and higher bilirubin levels in adults with sickle cell disease are associated with elevated TRV, a surrogate marker of pulmonary hypertension.

When we discuss anemia and hemolysis in the context of kidney disease in sickle cell disease, we know the following:

Anemia leads to compensatory increase in cardiac output, resulting in renal vasculopathy.2

Hemolysis releases heme, which facilitates oxidative damage and defects in renal vasoregulation.1

Overall, these factors lead to renal vasculopathy and progressive kidney disease.1,2

A retrospective chart review by Lebensburger and others, of children with hemoglobin SS and HbSβ0-thalassemia were performed on 4 years of data to identify children with microalbuminuria, along with the risk factors associated with microalbuminuria.

Data shown here illustrates that anemia and hemolysis are associated with kidney damage in children with sickle cell disease.

Lower hemoglobin levels and higher LDH levels in children with sickle cell disease are associated with microalbuminuria, a marker of glomerular damage.

In a perspective longitudinal follow-up study of 189 adults with sickle cell disease with a mean age of 34.8 years, we see that the anemia and hemolysis are associated with kidney damage in adults with sickle cell disease.

As shown in the data seen here, lower hemoglobin and higher bilirubin levels in adults with sickle cell disease are associated with microalbuminuria, a marker of glomerular damage.

Let’s talk about Kayla, a hypothetical patient with sickle cell disease.

She’s a 12-year-old African American female with hemoglobin SS sickle cell disease.

She experiences pain and fatigue that require her to limit participation in extracurricular sports and social activities.

She’s had no recent hospitalizations for a vaso-occlusive crisis.

However, she’s had difficulty concentrating in school; her academic performance is declining. She also has a abnormal neurocognitive testing.

Kayla has also been taking hydroxyurea at the maximum tolerated dose since the age of 6.

When you look at her laboratory values, we see what we would expect in a 12 year old, on her maximum tolerated dose of hydroxyurea.

Her white blood cell count is 5,000, Her ANC is 3,100. She has a hemoglobin level of 7.4 and a fetal hemoglobin level of 15%. Her MCV is 100. Platelet count 121,000. We also see markers associated with hemolysis, specifically. Her absolute retic count of 200,000. LDH of 621 and her indirect bilirubin of 3.5.

Kayla is clearly manifesting quality-of-life issues, and also showing abnormal neurocognitive performance in spite of doing everything her physician is asking her to do. However, she still suffers from anemia and hemolysis.

As Kayla enters adulthood, at 33 years of age, she has discontinued hydroxyurea due to family planning.

She has infrequent pain crisis, and when we look at her workup, some of her lab values have changed.

We see that her renal function testing is starting to show the damage that sickle cell disease has occurred over the past 20 years:

We see her urine albumin to creatinine ratio is elevated at 225. Her creatinine 1.2. eGFR 69.

Her white blood cell count 9,500 with an ANC of 5000. She continues to be anemic, with a hemoglobin of 6.5. Her hemoglobin F decreased at 3.0%. Her MCV decreased at 90 and her platelet count has increased to 276,000. Her hemolytic markers also show an increase in hemolysis. Specifically, absolute reticulocyte count that is increased to 450,000 and her LDH to 900. Her indirect bili 5.5.

So this is a story that many of us have seen unfold in our clinics. Although Kayla did everything that she … was asked of her, her outcome was still predictable. She’s an example of how anemia and hemolysis can contribute to the progression of organ damage in patients with sickle cell disease.

We’ve shown in this presentation multiple studies that have found that chronic anemia and hemolysis are associated with progressive sickle cell complication.2-4 These studies include data on the following:

Stroke and silent cerebral infarct. Kidney damage. Pulmonary hypertension.

Studies have demonstrated that anemia and hemolysis are associated with organ damage, which is a major cause of death in people with sickle cell disease5,6

After seeing this data and hearing Kayla's story, I hope I was able to better convey the underlying effect of anemia and hemolysis have on organ damage and outcomes of patients with sickle cell disease.

The Impact of Polymerization on SCD Morbidity3

See the impact HbS polymerization has on SCD progression.

Just a single point mutation in the beta globin gene leads to the debilitating damage of sickle cell disease.

This inherited change drives a complex, unrelenting condition characterized by vaso-occlusion, chronic hemolysis, and chronic anemia.

Hemoglobin S polymerization is the root cause of sickle cell disease pathology and its long-term sequelae.

In low oxygen environments, hemoglobin S molecules coalesce and begin to polymerize.

The polymers coalesce into long fibers that distort red blood cells into the characteristic sickle shape.

Hemoglobin S polymerization is the key event that leads to drastic changes in the integrity and function of red blood cells.

The polymers deform red blood cell membrane structure, making the cells much more rigid and adhesive.

This slows or obstructs blood flow, resulting in vaso-occlusion and diminished oxygen delivery.

Lower local oxygen levels induce further sickling, vaso-occlusion, reperfusion injuries, and inflammatory responses.

Additionally, membrane changes caused by hemoglobin S polymers lead to cellular dehydration, chronic hemolysis, and early cell death.

Sickled cells only survive for about 10-20 days versus 120 days for healthy red blood cells, which stresses the bone marrow and increases reticulocyte production.

When red blood cells become fragile and lyse, they release hemoglobin and other cellular contents that contribute to vasculopathy and further inflammation.

Free hemoglobin is broken down, decreasing the amount of active hemoglobin in circulation and leading to chronic anemia and its clinical complications.

Left unchecked, the pathologic effects of vaso-occlusion, chronic hemolysis, and chronic anemia can lead to progressive tissue damage and end-organ damage.

Organs that may be affected by long-term chronic damage include: the brain, eyes, lungs, heart, kidneys, and gallbladder.

In summary, a single nucleic acid substitution in the beta globin gene causes hemoglobin S polymerization that initiates extensive pathological changes leading to vaso-occlusion, chronic hemolysis, and chronic anemia.

There is an ongoing need for improved management of patients with sickle cell disease and related end organ damage.

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References: 1. Telen MJ, Malik P, Vercellotti GM. Therapeutic strategies for sickle cell disease: towards a multi‐agent approach. Nat Rev Drug Discov. 2019;18(2):139-158. 2. Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4(article 18010). doi:10.1038/nrdp.2018.10. 3. Kato GJ, McGowan V, Machado RF, et al. Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood. 2006;107(6):2279-2285. 4. Damanhouri GA, Jarullah J, Marouf S, Hindawi SI, Mushtaq G, Kamal MA. Clinical biomarkers in sickle cell disease. Saudi J Biol Sci. 2015;22(1):24-31. doi:10.1016/j.sjbs.2014.09.005. 5. Kato GJ, Steinberg MH, Gladwin MT. Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin Invest. 2017;127(3):750-760.

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