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 SCD2,6-9

Learn about the symptoms, complications, and impact SCD can have on a patient's quality of life, organ function, and life expectancy.

To the people that are at home, in the audience and the-my fellow healthcare providers, I thank you very much for taking the time out of your very busy schedule to talk about what I think is a pretty important topic. I hope that you find this slide deck and presentation both informative and that it positively impacts how we manage and care for children and adults with sickle cell disease. But, without further ado, let’s just kind of get into the slide deck. So, it’s important to understand why sickle cell disease is screened for and the-why they need comprehensive care.

And, the main reason is people with sickle cell disease have significantly reduced life expectancy. So, this figure shows data from a publication from 2006 that reported that the mean age of death among individuals with sickle cell disease in the United States was 39 years of age. Now, this has changed somewhat in the last several years. Between 1979 and 2006, survival for young children with sickle cell disease, particularly those under six, improved significantly due to universal newborn screening. This allows for infection prevention with the advent of penicillin prophylaxis and with immunization schedules and we’ve developed comprehensive pediatric care.

However, during this time, survival for adults with sickle cell disease has not improved dramatically with the mean age of death still being in the mid to late 30s to early 40s. So, the complications with sickle cell disease begin in early childhood. This figure shows data from a retrospective claims analysis that tracked 3,208 patients with sickle cell disease and it shows that the complications both begin in early childhood and, importantly, they tend to increase with age. The complication frequency begins to increase sharply during the time to transition from pediatric to adult care and this is due to several important factors.

First, sickle cell disease is a chronic and progressive disease leading to worsening complications as individuals age. The second is there tends to be reduced access to medical follow-up and preventative care for adults with sickle cell disease and this leads to reductions in availability to therapeutic regimens such as hydroxyurea and transfusion therapy. A third is that there tends to be a limited availability of some specialized providers for adults with sickle cell disease. And finally, there are changes in insurance coverage that are associated with aging out of pediatrics and off of parental insurance coverage and into an individual’s own coverage.

Now, the complications for sickle cell disease begin very early on in life and we start seeing them as early as six months of age. As a pediatric hematologist and somebody that does mostly very young children, this is the population that I care for. We tend to see acute life-threatening events within the first six months of life. Complications related to organ damage occur very early on, including overt strokes, silent cerebral infarcts, neurocognitive impairment, retinopathy, acute chest syndrome, left ventricular hypertrophy and dysfunction, splenic dysfunction, renal impairment, avascular necrosis and priapism in our male patients.

Now, in adults with sickle cell disease, many of them experience the same exact symptoms as children with respect to organ involvement but the disease manifest-manifestations are typically worse with age and progressive. For example, progressive organ damage may manifest as, in adults, as an overt stroke, progressive silent cerebral infarcts, neurocognitive impairment, progressive retinopathy that can lead to blindness, pulmonary hypertension, heart failure and kidney failure that are all associated with very high mortality rates for individuals with sickle cell disease, liver dysfunction, reduced bone mineral density and priapism in males with sickle cell that can be related to difficulties with fertility later in life.

Of note, overt strokes tend to be much more severe in adults than they are in the pediatric population and these are associated with a high degree of mortality. And, even in individuals who survive they are associated with significant physical and cognitive disabilities that substantially impact their health-related quality of life. But, in addition to the cognitive impairments, individuals with sickle cell disease report significantly reduced health-related quality of life in many domains, including pain, fatigue, weakness, cognitive impairments, limitation in activities of daily living and other activities that are shown here.

But, ultimately, the lives of individuals with sickle cell disease are cut short by the progressive insidious complications of the disease, most notably end-organ dysfunction. On the screen, you see data from a single center that reported clinical and autopsy findings at the time of death in 141 cases of individuals with sickle cell disease from 1975 to 2001. What you will note is the primary cause of death in this cohort was cardiopulmonary disease with 37-percent of participants succumbing directly as a result of cardiopulmonary failure.

Renal failure accounted for almost a quarter of sickle cell-related deaths in this institution. And, these results have been seen in multiple studies and multiple cohorts throughout the United States over the past several years.

The Role of VOCs, Hemolysis, and Anemia in SCD6-8,10

Discover how VOCs, anemia, and hemolysis can lead to vasculopathy and organ damage.

To the people that are at home, in the audience and my fellow healthcare providers, I thank you very much for taking the time out of your very busy schedule to talk about what I think is a pretty important topic. I hope that you find this slide deck and presentation both informative and that it positively impacts how we manage and care for children and adults with sickle cell disease. But, without further ado, let’s just kind of get into the slide deck.

Vaso-occlusive crises are characterized by sudden acute onset of extreme severe pain. Vaso-occlusion most often occurs in the bones, back, chest and extremities and the triggers are individualized.

And, although pain is considered a hallmark of sickle cell disease, the frequency of acute care visits for pain are not necessarily correlated to the overall disease severity in organ damage.

Now, it’s important to note that people with sickle cell disease are at risk for organ damage regardless of the vaso-occlusive crisis frequency in people with sickle cell disease monitored for organ damage and vaso-occlusion over a seven-year period. The data shown on the screen shows that there was no significant association observed between the frequency of vaso-occlusion crisis in any of the events listed on the screen, many of which are direct measurements of end-organ damage, specifically renal failure, pulmonary hypertension, stroke, microalbuminuria, retinopathy and osteonecrosis in addition to leg ulcers, cholelithiasis and priapism.

We’re going to talk about the role of hemolysis and anemia, specifically in sickle cell disease.

Anemia and hemolysis are associated with the progressive damage to organs that can be observed in brain, lungs, heart, liver, kidneys, gallbladder, penis and skin of individuals with the disease. Progressive organ damage, in fact, is very common and irreversible in the majority of people with sickle cell disease and can be identified by age 40 to 50.

In order to examine the association between the severity of anemia and risk of clinical outcomes, Dr. Ken Ataga performed a meta-analysis on the studies that reported the association of hemoglobin level with five clinical outcomes of clinical importance.

The first outcome was stroke or silent cerebral infarct. The second outcome was abnormal TCD velocity which is a biomarker predictor of overall stroke risk. The third was albuminuria. The fourth was tricuspid regurgitant velocities or pulmonary arterial systemic pressures which look at pulmonary hypertension and the final was looking at overall mortality in patients with sickle cell disease.

This analysis compared hemoglobin levels in patients who had the outcome of interest and those who did not have the outcome of interest across 45 studies and represents 9,637 patients.

The results suggest that a correlation exists between hemoglobin magnitude and morbidity and mortality, specifically when looking at the associated measures. So, if you look at the figure, for example, a 0.9 decrease in hemoglobin was associated with higher increase in individuals having potential markers of pulmonary hypertension, a reduction in 0.6 g/dL of hemoglobin was associated with a higher risk of albuminuria, similar with death, and similar reductions in 0.5 and 0.4 were associated with abnormal TCD velocity which is a stroke predictor and overt stroke or silent cerebral infarct itself.

Now, this data suggests that even mild to moderate reductions in overall chronic hemoglobin levels may be of clinical significance with respect to acquisition of end-organ dysfunction as individuals age.

Hemolysis severity also appears to be associated with the risk of some clinical outcomes. For example, data on your screen was published by Greg Kato and is a study of 213 patients with sickle cell disease and what he found was a statistically significant difference in the overall survival between individuals with high and low LDH, a marker of hemolysis, specifically, high LDH was defined as 315 IU/L and low was less than that.

But, how do hemolysis and anemia contribute to increased risk of end-organ dysfunction? So, specifically for stroke and neurocognitive impairment, hemolysis releases cell-free hemoglobin which scavenges nitric oxide, facilitates oxidative damage and damages blood vessels. Anemia reduces oxygen delivery to the brain and decreases cerebrovascular reserve in the time of acute stresses. The anemia severity also correlates very tightly with cerebrovascular blood flow. These combined can lead to vasculopathy and vasculopathy in and of itself increases the risk of stroke, silent cerebral infarct and overall neurocognitive problems.

So, here is data showing an association between hemoglobin level and risk of stroke and silent cerebral infarct.

Hemoglobin levels are associated with the risk of stroke and silent cerebral infarct. The graph on the left shows two studies that demonstrate that lower levels of hemoglobin were associated with an increased overall risk of stroke and, again, highlighting that the difference between those two values are not huge. So, the difference in the Belisario cohort being 7.5 g/dL were the patients that had a stroke versus 7.9 in the patients that did not have a stroke with a similar relationship in the other study. On the right, you will see that a lower hemoglobin was also associated with an increased risk of silent cerebral infarcts with the purple being the individuals that had silent cerebral infarcts and the light purple without.

In the Debaun Study, the average hemoglobin for individuals with a silent cerebral infarct were 8 g/dL compared to only 8.3 in those that did not have a silent cerebral infarct.

But, how does anemia and hemolysis potentially contribute to the development of pulmonary hypertension? Impaired vasodilator response to nitric oxide is correlated with free plasma hemoglobin and LDH and these contribute to pulmonary and systemic vasoconstriction. Increased cardiac output secondary to chronic longstanding anemia may also play a role in pulmonary hypertension. Together, pulmonary vasoconstriction and increased cardiac flow contribute to the elevated pulmonary pressure and pulmonary hypertension that can evolve in individuals with sickle cell disease.

So, hemolysis and anemia have been reported to be directly correlated with the risk of pulmonary hypertension. So, higher LDH levels and lower hemoglobin levels, shown respectively in the figure on the left and on the right, have been shown to be associated with increased risk of elevated TR jet velocities which are a surrogate marker of pulmonary hypertension in sickle cell disease.

Hemolysis and anemia also potentially contribute to kidney disease in sickle cell. Hemolysis releases heme which facilitates oxidative damage and defects in renal vasoregulation. Anemia leads to a compensatory increase in the cardiac output and it results in renal hyperperfusion and glomerular vascular injury. Combined, these factors lead to renal vasculopathy and progressive renal disease.

So, in this slide, hemolysis and anemia have been correlated with kidney damage in sickle cell disease.

On the left, higher LDH in people with sickle cell disease have been associated with increased risk of microalbuminuria and, on the right, lower hemoglobin levels have been associated with microalbuminuria, with microalbuminuria being a marker of early glomerular damage.

Sickle Cell Patient Profile5,11-13

Damage from SCD can begin early in childhood and go unnoticed. This damage may be progressive and lead to organ damage later in life.

So, here we present a hypothetical typical case of a 12-year-old African American female that I think many pediatric hematologists would know. This is Kayla. Kayla has sickle cell anemia (HbSS). She comes to clinic on a routine basis. Her family is involved and she experiences pain and fatigue that require her to limit her participation in extracurricular sports and social activities but she is able to maintain not being hospitalized with the use of typical at-home regimens with increasing hydration, heat packs and nonsteroidals. And, she doesn’t have any recent hospitalization for vaso-occlusive crises. She does, however, report that she has difficulty concentrating in school and, because of that, over the last several years her academic performance has declined. And, because of that academic decline, neurocognitive testing was performed, and she has some abnormalities that have been identified. Now, she’s currently taking hydroxyurea at a maximum tolerated dose and has been doing so since six years of age. And her laboratory values in clinic are as follows:

She has a fetal hemoglobin of 15-percent which is relatively stable. Her last hemoglobin was 7.4 g/dL. She has a relatively brisk reticulocytosis of 8-percent, but she has a good change in her mean corpuscular volume with a 120 fl. She is within the goal range of neutrophil count with an ANC of 3100 and her total white blood cell count is 5. However, she continues to have some markers of elevated hemolysis with a lactate dehydrogenase level of 621 and an indirect bilirubin of 3.5. She has no signs of platelet toxicity with a platelet count of 121.

Fast forward to today. Now, Kayla is 33 years old. She has discontinued hydroxyurea due to her family planning issues. She has infrequent pain crisis as she has gotten older, but her laboratory values are as follows: She has a fetal hemoglobin of 3-percent. She has a hemoglobin of 6.5. Her reticulocytosis has markedly increased, which is now at 15-percent. Her mean corpuscular volume has dropped to 90. Her absolute neutrophil count is 5000 with a total white count of 9.5 and her markers of hemolysis have dramatically increased with an LDH of 740 and an indirect bilirubin of 5.5. She continues to have a normal platelet count. But, importantly, on organ testing her renal function is beginning to decline. On a urine albumin to creatinine ratio, her urinalysis has 225 mg/gm within the sample. Her serum creatinine is now 1.2 mg/dL and her estimated GFR is calculated to be 69 mL/min.

This shows the natural progression currently of individuals with sickle cell disease and it highlights that you don’t have to have multiple acute vaso-occlusive complications.

In fact, it’s actually quite common for adults to develop not one marker of end-organ dysfunction but multiple organs affected in sickle cell disease by the second, third or fourth decades of life.

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. 6. Gladwin MT. Cardiovascular complications and risk of death in sickle-cell disease. Lancet. 2016;387(10037):2565-2574. 7. Nath KA, Hebbel RP. Sickle cell disease: renal manifestations and mechanisms. Nat Rev Nephrol. 2015;11(3):161-171. 8. Guasch A, Navarrete J, Nass K, Zayas CF. Glomerular involvement in adults with sickle cell hemoglobinopathies: prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol. 2006;17(8):2228-2235. 9. Bush AM, Borzage MT, Choi S, et al. Determinants of resting cerebral blood flow in sickle cell disease. Am J Hematol. 2016;91(9):912-917. 10. Olaniran KO, Eneanya ND, Nigwekar SU, et al. Sickle cell nephropathy in the pediatric population. Blood Purif. 2019;47(1-3):205-213. 11. Manci AE, Culberson DE, Yang YM, et al. Causes of death in sickle cell disease: an autopsy study. Br J Haematol. 2003;123(2):359-365. 12. Vichinsky EP. Chronic organ failure in adult sickle cell disease. Hematology Am Soc Hematol Educ Program. 2017;2017(1):435-439. doi:10.1182/asheducation-2017.1.435. 13. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376(9757):2018‐2031.

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