In sickle cell disease (SCD),
HBB MUTATION AND HbS POLYMERIZATION ARE KEY DRIVERS OF SCD PATHOPHYSIOLOGY1-3

SCD is characterized by red blood cell (RBC) dysfunction1-3

In SCD, a single point mutation in the HBB gene that encodes hemoglobin subunit β, or beta-globin, leads to the production of hemoglobin S (HbS).1 In low-oxygen environments, HbS can polymerize, causing RBCs to distort into a characteristic crescent or sickle shape.1,4 Sickled RBCs can slow or obstruct blood flow, resulting in vaso-occlusion and diminished oxygen delivery to surrounding tissues and organs. Membrane changes caused by HbS polymers can lead to RBC dehydration, chronic hemolysis, and early cell death, causing anemia.1 Over time, this dysfunction may contribute to progressive tissue and organ damage.5

The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6

Thumbnail of link to the "Impact of Hemoglobin S Polymerization" video

See the impact that a mutation in HBB and polymerization of HbS have on RBC function

SCD AND END-ORGAN DAMAGE

The pathophysiology of SCD is complex and involves dysregulation of molecular, cellular, and biophysical processes in a multitude of cell types and organ systems.5,7

The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6

HbS polymerization can cause RBC sickling, which may trigger
hemolysis, as well as
anemia and vaso-occlusion8,9

Sickled cells often die prematurely3,10

HbS polymerization damages the cell membrane and results in fragile RBCs that can die prematurely due to hemolysis.

AVERAGE RBC LIFESPAN

Graph of average lifespan of sickled (10-20 days) and healthy (120 days) RBCs Graph of average lifespan of sickled (10-20 days) and healthy (120 days) RBCs

HEMOLYSIS AND VASCULOPATHY

When an RBC hemolyzes, hemoglobin and arginase are expelled into the vasculature, where they act to decrease nitric oxide bioavailability. A vicious cycle of arginine dysregulation and continuing hemolysis leads to a further reduction in nitric oxide, causing oxidative stress and endothelial dysfunction. Free heme acts as an inflammatory mediator and can further compound the vascular damage.11-13

The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6

Chart of hemolysis path to damage

Chronic hemolytic anemia can contribute to long-term organ damage in SCD14-17

Anemia can impact the daily lives of people with SCD

Clinically, anemia can manifest in many ways that affect day-to-day life.14-21

Moderate to severe anemia can lead to:

  • Fatigue
  • Weakness
  • Reduced physical performance
  • Impaired cognitive function

The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6

ANEMIA AND THE CARDIOVASCULAR SYSTEM

In SCD, the heart responds to anemia by increasing stroke volume. This increase in cardiac output, along with vascular stiffness, results in raised systolic blood pressure. High systolic systemic blood pressure is an independent risk factor for the development of multiple cardiovascular morbidities.14

The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6

Diagram of anemia's impact on the cardiovascular system

ANEMIA AND CEREBROVASCULAR RISK

In response to anemia in patients with SCD, cerebral blood flow is increased to maintain oxygen supply. The ability to increase blood flow under stress, known as cerebrovascular reserve, is diminished in patients with SCD. A high resting blood flow and reduced vascular reserve increase the risk of stroke and silent cerebral infarction (SCI). Multiple factors, including male sex, lower baseline hemoglobin level, higher baseline systolic blood pressure, and history of previous seizures, may also influence risk of SCI.15,16,21

The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6

Diagram of anemia's impact on the cerebrovascular system

ANEMIA AND KIDNEY DAMAGE

In SCD, anemia can affect the kidney by causing an increase in systolic pressure, which results in renal hyperperfusion and an increase in glomerular filtration rate (GFR). As a result, renal damage such as glomerular hypertrophy may occur, and those with SCD remain at high risk for progressive renal insufficiency. As renal damage progresses, the kidney is unable to produce appropriate levels of erythropoietin, which, in addition to other factors, can exacerbate the anemia.14,17-19,22

The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6

Diagram of anemia's impact on the kidney

Vaso-occlusive crises9,11

For many patients, debilitating pain is a significant complication caused by their SCD.9,10 Acute vaso-occlusive pain is thought to be caused by vascular obstruction and tissue ischemia that occur when sickled RBCs and other cells become trapped in the microvasculature.9 Pain symptoms can resolve in a few days. However, vaso-occlusion can continue silently beyond these discrete pain events.7,23

The degree to which SCD pathophysiology contributes to end-organ damage is not known, as multiple factors—including age, sex, genotype/genogroup, treatment status, and other patient-specific variables—may also affect its etiology.6

VAS0-OCCLUSION AND END-ORGAN DAMAGE

Vaso-occlusion can result in damage to multiple organ systems, including the renal and cardiovascular systems.5,14,18

Occlusion of postcapillary venules (vaso-occlusion)9,11

Sickled RBCs can interact with leukocytes, platelets, and the vascular endothelium to develop a vaso-occlusion, which can independently lead to hemolysis, inflammation, and painful infarction. Inflammation also increases the expression of adhesion molecules, trapping more cells and worsening vaso-occlusion.

Vaso-occlusion
Vaso-occlusion

Ischemia-reperfusion9,11

Reperfusion of ischemic tissue generates free radicals and causes oxidative damage, all of which is worsened with the presence of free hemoglobin from ongoing hemolysis.

Ischemia-reperfusion
Ischemia-reperfusion

Vasculopathy and endothelial dysfunction9,11

Inflammation and chronic down-regulation of nitric oxide lead to additional endothelial damage and advanced vasculopathy.

Vasculopathy and endothelial dysfunction
Vasculopathy and endothelial dysfunction
Person with body organs highlighted

Silent damage can occur even during periods of subclinical disease3,9

See what may happen between pain crises

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References: 1. Stuart MJ, Nagel RL. Sickle-cell disease. Lancet. 2004;364(9442):1343-1360. 2. Kato GJ, Steinberg MH, Gladwin MT. Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin Invest. 2017;127(3):750-760. 3. Kato GJ, Piel FB, Reid CD. Sickle cell disease. Nat Rev Dis Primers. 2018;4:(article 18010). doi:10.1038/nrdp.2018.10. 4. Kapoor S, Little JA, Pecker LH. Advances in the treatment of sickle cell. Mayo Clin Proc. 2018;93(12):1810-1824. 5. Sundd P, Gladwin MT, Novelli EM. Pathophysiology of sickle cell disease. Annu Rev Pathol. 2019;14:263‐292. 6. Buchanan G, Vichinsky E, Krishnamurti L, Shenoy S. Severe sickle cell disease—pathophysiology and therapy. Biol Blood Marrow Transplant. 2010;16(1 suppl):S64-S67. doi:10.1016/j.bbmt.2009.10.001 7. 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. 8. Gordeuk VR, Castro OL, Machado RF. Pathophysiology and treatment of pulmonary hypertension in sickle cell disease. Blood. 2016;127(7):820‐828. 9. Rees DC, Williams TN, Gladwin MT. Sickle cell disease. Lancet. 2010;376(9757):2018‐2031. 10. Kanter J, Kruse‐Jarres R. Management of sickle cell disease from childhood through adulthood. Blood Rev. 2013;27(6):279‐287. 11. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005;293(13):1653-1662. 12. Damanhouri GA, Jarullah J, Marouf S, Hindawi SI, Mustaq G, Kamal MA. Clinical biomarkers in sickle cell disease. Saudi J Biol Sci. 2014;22(1):24-31. 13. Morris CR. Vascular risk assessment in patients with sickle cell disease. Haematologica. 2011;96(1):1-5. 14. Gladwin MT. Cardiovascular complications and risk of death in sickle-cell disease. Lancet. 2016;387(10037):2565-2574. 15. 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. 16. DeBaun MR, Armstrong FD, McKinstry RC, Ware RE, Vichinsky E, Kirkham FJ. Silent cerebral infarcts: a review on a prevalent and progressive cause of neurologic injury in sickle cell anemia. Blood. 2012;119(20):4587-4596. 17. 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. 18. Nath KA, Hebbel RP. Sickle cell disease: renal manifestations and mechanisms. Nat Rev Nephrol. 2015;11(3):161-171. 19. Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;23(10):1631-1634. 20. Swanson MD, Grosse SD, Kulkami R. Disability among individuals with sickle cell disease: literature review from a public health perspective. Am J Prev Med. 2011;41(6)(suppl 4):S390-S397. 21. Vichinsky WP, Neumayr LD, Gold JI, et al. Neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adults with sickle cell anemia. JAMA. 2010;303(18):1823-1831. 22. Olaniran KO, Eneanya ND, Nigwekar SU, et al. Sickle cell nephropathy in the pediatric population. Blood Purif. 2019;47(1-3):205-213. 23. Qari MH, Aljaouni SK, Alardawi MS, et al. Reduction of painful vaso-occlusive crisis of sickle cell anaemia by tinzaparin in a double-blind randomized trial. Thromb Haemost. 2007;98(2):392-396.