SCD Pathophysiology

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The Pathophysiology of Sickle Cell Disease

Sickle cell disease (SCD) is a complex genetic disorder that goes beyond red blood cells and early on progresses to a chronic vascular disease.1

Silent, ongoing vaso-occlusion that drives the chronic nature of the disease is caused by multicellular adhesion among endothelial cells, red blood cells, white blood cells, and platelets. This multicellular adhesion occurs as a result of endothelial damage and inflammation, which cause chronic upregulation of specific adhesion mediators, including selectins.1,2

Ongoing vaso-occlusion can culminate in vaso-occulsive crises (VOCs)—the clinical hallmark of sickle cell disease—which are unpredictable and extremely painful events that can lead to medical intervention.4,5 VOCs are associated with decreased quality of life and increased risk of organ damage and death.1,6,7

The Pathophysiology of Sickle Cell Disease

WATCH THIS VIDEO TO LEARN MORE ABOUT SCD AND THE CAUSE OF VASO‑OCCLUSION AND VOCs.

The Pathophysiology of Sickle Cell Disease

WATCH THIS VIDEO TO LEARN MORE ABOUT SCD AND THE CAUSE OF VASO‑OCCLUSION AND VOCs.

Background on Sickle Cell Disease

Sickle cell disease is a complex genetic blood disorder that comprises multiple genotypes. These genotypes are characterized by a mutation in the β-globin gene that results in an abnormal hemoglobin variant called HbS. HbS causes red blood cells to become rigid and crescent-shaped upon deoxygenation.8


 

Two interlinked mechanisms contribute to the clinical picture of sickle cell disease. First, repeated cycles of red blood cell sickling lead to hemolysis and anemia.7,9

 

 

Second, a multicellular adhesion process involves red blood cells, white blood cells, and platelets that aggregate and adhere to endothelial cells of the vessel wall. As a result, this process promotes vaso-occlusion that leads to chronic vascular damage, which begins early in childhood.10,11

 

Multicellular Adhesion Drives
Vaso-occlusion

Vaso-occlusion and vaso-occlusive crises (VOCs) are the result of a multicellular adhesion process involving multiple cells and adhesion mediators. Blood cells and endothelium are chronically activated as a result of inflammation, resulting in upregulation of specific adhesion mediators.1

 

Multi-cellular adhesion process

The Cycle of Vaso-occlusion and VOCs

The cycle of vaso-occlusion


1. INFLAMMATION & CELL ACTIVATION

The blood vessels of patients with sickle cell disease are in a chronic state of inflammation, caused by the release of inflammatory cytokines from activated endothelial cells2,18

  • Chronic vascular inflammation and cell activation happen over time and both are exacerbated by hemolysis19
    • The activation of blood cells and endothelial cells lead to increased expression of adhesion mediators, resulting in multicellular adhesion2

2. MULTICELLULAR ADHESION

Adhesion mediators drive multicellular adhesion among endothelial cells, red blood cells, white blood cells, and platelets, promoting vaso-occlusion.2,3

  • The multicellular adhesion process begins with the overexpression of several adhesion mediators on the surface of platelets, leukocytes, and endothelial cells2
  • Activated cells and the endothelium initiate a complex cascade of cell interactions that may lead to multicellular adhesion and ongoing vaso-occlusion2

3. VASO-OCCLUSION & VOCs

Ongoing, silent vaso-occlusion can result in VOCs, also known as sickle cell pain crises, the clinical hallmark of sickle cell disease4,5

  • VOCs are unpredictable, extremely painful events that last on average 10 days and can require medical intervention5,7
  • VOCs, and associated complications, account for much of the burden of sickle cell disease and are the primary reason for up to 95% of hospital admissions among patients with the disease5,20

4. TISSUE & ORGAN DAMAGE

Ongoing, silent vaso-occlusion and VOCs are associated with increased risk of organ damage and death.21-24

  • Vaso-occlusion and VOCs are associated with decreased organ function and can result in life-threatening complications such as chronic lung disease, cardiopulmonary disease, and stroke5,7
  • The chronic nature of sickle cell disease is the result of a self-perpetuating cycle of inflammation, cell activation, multicellular adhesion, vaso-occlusion, and tissue damage. This may lead to future VOCs, which are associated with an increased risk of organ damage, multi-organ failure and death

 

 

References: 1. Conran N, Franco-Penteado CF, Costa FF. Newer aspects of the pathophysiology of sickle cell disease vaso-occlusion. Hemoglobin. 2009;33(1):1-16. 2. Zhang D, Xu C, Manwani D, Frenette PS. Sickle cell disease: Challenges and progress. Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. Blood. 2016;127(7):801-809. 3. Habara A, Steinberg MH. Genetic basis of heterogeneity and severity in sickle cell disease. Exp Biol Med (Maywood). 2016;241(7):689-696. 4. Puri L, Nottage KA, Hankins JS, Anghelescu DL. State of the art management of acute vaso-occlusive pain in sickle cell disease. Paediatr Drugs. 2018;20(1):29-42. 5. Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood. 2012;120(18):3647-3656. 6. American Society of Hematology. State of Sickle Cell Disease: 2016 Report. Washington, DC: 2016. Available at: http://www.scdcoalition.org/report.html. 7. Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med. 2017;376(16):1561-1573. 8. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376(9757):2018-2031. 9. Aleluia MM, Fonseca TC, Souza RQ, et al. Comparative study of sickle cell anemia and hemoglobin SC disease: clinical characterization, laboratory biomarkers and genetic profiles. BMC Hematol. 2017;17:15. doi:10.1186/s12878-017-0087-7. 10. Solovey A, Lin Y, Browne P, et al. Circulating activated endothelial cells in sickle cell anemia. N Engl J Med. 1997;337(22):1584-1590. 11. Schimmel M, Zeerleder SS, Biemond BJ. Inflammatory and endothelial markers during vaso-occlusive crisis and acute chest syndrome in sickle cell disease. Am J Hematol. 2017;92(11):E634-E636. 12. Kappelmayer J, Nagy B. The interaction of selectins and PSGL-1 as a key component in thrombus formation and cancer progression. Biomed Res. 2017;2017(6138145):1-18. doi: 10.1155/2017/6138145. 13. Manwani D, Frenette PS. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood. 2013;122(24):3892-3898. 14. Matsui NM, Borsig L, Rosen SD, Yaghmai M, Varki A, Embury SH. P-selectin mediates the adhesion of sickle erythrocytes to the endothelium. Blood. 2001;98(6):1955-1962. 15. Polanowska-Grabowska R, Wallace K, Field JJ, et al. P-selectin-mediated platelet-neutrophil aggregate formation activates neutrophils in mouse and human sickle cell disease. Arterioscler Thromb Vasc Biol. 2010;30(12):2392-2399. doi:10.1161/ATVBAHA.110.211615. 16. Wagner DD, Frenette PS. The vessel wall and its interactions. Blood. 2008;111(11):5271-5281. doi:10.1182/blood-2008-01-078204. 17. Hebbel RP, Yamada O, Moldow CF, Jacob HS, White JG, Eaton JW. Abnormal adherence of sickle erythrocytes to cultured vascular endothelium. J Clin Invest. 1980;65(1):154-160. 18. Kanter J, Kruse-Jarres R. Management of sickle cell disease from childhood through adulthood. Blood Rev. 2013;27(6):279-287. 19. Merle NS, Grunenwald A, Rajaratnam H, et al. Intravascular hemolysis activates complement via cell-free heme and heme-loaded microvesicles. JCI Insights. 2018;3(12):1-17. 20. Ballas SK, Lusardi M. Hospital readmission for adult acute sickle cell painful episodes: frequency, etiology, and prognostic significance. Am J Hematol. 2005;79(1):17-25. 21. Belcher JD, Mahaseth H, Welch TE, et al. Critical role of endothelial cell activation in hypoxia-induced vasoocclusion in transgenic sickle mice. Am J Physiol Heart Circ Physiol. 2005;288:H2715-H2725. 22. Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C. Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients. Medicine (Baltimore). 2005;84(6):363-376. 23. Elmariah H, Garrett ME, De Castro LM, et al. Factors Associated with Survival in a Contemporary Adult Sickle Cell Disease Cohort. Am J Hematol. 2014;89(5):530-535. 24. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330(23):1639-1644.

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