In sickle cell disease (SCD),
HEMOGLOBIN S (HbS)
POLYMERIZATION IS THE
ROOT CAUSE OF SCD DAMAGE1-3

The core mechanism that drives SCD pathology

In low-oxygen environments, HbS can polymerize, causing red blood cells (RBCs) to distort into a characteristic sickle shape.1,4 This slows or obstructs blood flow, resulting in vaso-occlusion and diminished oxygen delivery to surrounding tissues and organs. Membrane changes caused by HbS polymers lead to cellular dehydration, chronic hemolysis, and early cell death, causing anemia.1 Over time, this chronic dysfunction leads to progressive tissue and end-organ damage.5

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

Damage starts with HbS polymerization3

Click here to see its impact on SCD progression.

Picture of Hemoglobin S Units in RBC

HbS units in oxygenated RBC

SCD pathologic manifestations begin here
Picture of Hemoglobin S polymers forming in deoxygenated RBC and damage to RBC beginning

Damage Initiated

HbS polymers form in deoxygenated RBC

Picture of a sickled red blood cell

Distorted, sickled RBC

Diagram of 3 SCD pathologies (hemolysis, anemia, and vaso-occlusion)
Picture of person with impacted organs
ORGAN DAMAGE1,4

Three pathologies driving sickle cell damage

SCD pathophysiology involves multiple biologic processes that radically affect the structure and function of RBCs, other blood cells, and the vasculature.6

HbS polymerization causes RBC sickling,
which can trigger
hemolysis, as well as
anemia and vaso-occlusion7,8

Sickled cells die prematurely3,9

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

AVERAGE RBC LIFESPAN

Hemolysis leads to vasculopathy and progressive
organ damage10-12

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.

Chart of hemolysis path to damage

Chronic hemolytic anemia is a major contributor to SCD damage13

The burden of anemia was quantified (difference in hemoglobin levels) in a meta-analysis of 36 studies that looked at cardiovascular morbidities in patients with SCD.19*

Hemoglobin levels were significantly lower in patients with SCD who had a negative clinical outcome19

Clinical outcome

Mean difference in
hemoglobin levels (g/dL)

 0.0
-0.2
-0.4
-0.6
-0.8
-1.0
  • Elevated
    ePASP
    (Heart/lung)
  • Albuminuria
    (Kidney)
  • Death
  • Abnormal
    TCD velocity
    (Brain)
  • Stroke/SCI
    history
    (Brain)

ePASP = estimated pulmonary artery systolic pressure (heart/lung); Albuminuria (kidney); TCD = transcranial doppler (brain);
SCI = silent cerebral infarction (brain)

*Meta-analysis of 36 studies (N=9,637) was conducted of relevant peer-reviewed literature from 1998 to 2017. From these data, the difference in hemoglobin between those with and without negative clinical outcomes was quantified.19

Anemia can adversely impact the daily lives of people with SCD13-18,20,21

Clinically, anemia can manifest in many ways that affect day-to-day life. Moderate to severe anemia can lead to:

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

Over time, chronic anemia can progress into increasingly severe complications.

Anemia places significant stress on the
cardiovascular system13

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.

Diagram of anemia's impact on the cardiovascular system

Anemia and cerebrovascular risk14,15

Chronic anemia is one of the strongest risk factors for cerebral vascular injury. In response to anemia, 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).

Diagram of anemia's impact on the brain

Anemia contributes to kidney damage in SCD13,16-18,22

Kidney damage can occur through several SCD-mediated pathways. 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, contributes to exacerbating anemia.

Diagram of anemia's impact on the kidney

Acute pain and chronic vasculopathy8,10

For many patients, debilitating pain is the most significant complication caused by their SCD.8,9 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.8 Pain symptoms can resolve in a few days. However, vaso-occlusion can continue silently beyond these discrete pain events6,23

Occlusion of postcapillary venules (vaso-occlusion)

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.

Image of vaso-occlusion
Image of vaso-occlusion

Ischemia-reperfusion

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.

Image of ischemia-reperfusion
Image of ischemia-reperfusion

Vasculopathy and endothelial dysfunction

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

Image of vasculopathy and endothelial dysfunction
Image of vasculopathy and endothelial dysfunction
Image of person with body organs highlighted

Silent damage occurs even during periods of subclinical disease3,8

View what happens 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. 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. 7. Gordeuk VR, Castro OL, Machado RF. Pathophysiology and treatment of pulmonary hypertension in sickle cell disease. Blood. 2016;127(7):820‐828. 8. Rees DC, Williams TN, Gladwin MT. Sickle cell disease. Lancet. 2010;376(9757):2018‐2031. 9. Kanter J, Kruse‐Jarres R. Management of sickle cell disease from childhood through adulthood. Blood Rev. 2013;27(6):279‐287. 10. 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. 11. 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. doi: 10.1016/j.sjbs.2014.09.005. 12. Morris CR. Vascular risk assessment in patients with sickle cell disease. Haematologica. 2011;96(1):1-5. 13. Gladwin MT. Cardiovascular complications and risk of death in sickle-cell disease. Lancet. 2016;387(10037):2565-2574. 14. 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. 15. 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. 16. 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. 17. Nath KA, Hebbel RP. Sickle cell disease: renal manifestations and mechanisms. Nat Rev Nephrol. 2015;11(3):161-171. 18. Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;23(10):1631-1634. 19. Ataga KI, Gordeuk VR, Allen IE, Colby JA, Gittings K, Agodoa I. Low hemoglobin increases risk for stroke, kidney disease, elevated pulmonary artery systolic pressure, and premature death in sickle cell disease: a systematic literature review and meta-analysis. Blood. 2018;132(suppl 12):1-12. 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.

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