Complex Genetic Disorder Common SCD Genotypes Underlying SCD Mechanism Multicellular Adhesion

The Pathophysiology of Sickle Cell Disease

Sickle Cell Disease–Complex Genetic Disorder

Sickle cell disease (SCD) is a complex genetic blood disorder that affects the structure and function of hemoglobin, reduces the ability of red blood cells (RBCs) to transport oxygen efficiently and, early on, progresses to a chronic vascular disease.1

SCD Is a Disorder Arising From Mutations in the Hb Beta Gene

In patients with SCD, mutations in both β-globin alleles alter the structure of hemoglobin.2

2 ß-globin chains
Hb Beta Gene Mutation
2 α-globin chains

Normal hemoglobin (HbA) comprises 2 β-globin and 2 α-globin chains2

When deoxygenated, abnormal hemoglobin (HbS) undergoes polymerization resulting in the sickling of RBCs2

Fetal hemoglobin (HbF) is another normal type of hemoglobin, but is expressed only until ~6 months of age.3

 

Sickle Cell Disease Is a Monogenic yet Pleiotropic Disease

SCD is caused by a single point mutation in the Hb gene, but results in diverse clinical manifestations (eg, chronic vascular damage, vaso-occlusion, anemia, and organ damage).3-5

Chronic vascular damage
Chronic Vascular Damage
Vaso-occlusion
Vaso-Occlusion
Anemia
Anemia
Organ Damage
Organ Damage
(Acute and Chronic Complications)

Sickle Cell Trait vs Sickle Cell Disease Genotypes

SCD 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.2

 

Sickle Cell Trait2
Sickle Cell Trait
HbA HbS
Individuals with sickle cell trait inherit 1 mutant allele (Hbs)
Sickle Cell Anemia6
Sickle Cell Anemia
HbS HbS
Individuals with sickle cell anemia inherit 2 HbS alleles
Other SCD Genotypes6
Other Sickle Cell Disease Genotypes
HbS Other Hb Mutation
Individuals inherit 1 HbS allele and another mutant Hb allele
Monogenic=single point mutation, caused by 1 gene.
Pleiotropic=1 gene that causes multiple, seemingly unrelated effects/complications.

Common Sickle Cell Disease Genotypes

SCD is a complex, heterogenous disease affected by environmental factors and genetic variability. The most common and severe form of SCD usually presents in patients with the homozygous HbSS genotype.2,3

SCD Type Depends on the Mutation in the Hemoglobin Gene5

Genotype% of SCDpopulation% of affected ethnicities
HbSS
(sickle cell anemia)7,8
~74%-76% ~70% of patients of African ancestry
HbSC7,8 ~18%-24% ~25%-30% of patients of African ancestry
HbSβ-thalassemia7,8 ~1%-6% Most prevalent in people of Eastern Mediterranean or Indian descent
HbSβ-thalassemia7,8 ~1%-6% Most prevalent in people of Eastern Mediterranean or Indian descent
HbSD7 <1% Most prevalent in northern India but occurs worldwide
HbSα-thalassemia2,3,7 N/A ~30% of patients of African region
~50% of people of Middle Eastern or Indian descent
   
HbAS
(sickle cell trait)2
None
(not a form of SCD)
~8% of African Americans are sickle cell trait carriers
  • aBased on 3 large multicenter cohorts of patients with SCD of predominantly African descent in the Americas and the United Kingdom.
Sickle cell disease demographics

In the United States, the majority of patients with SCD are of African ancestry. Patients of Hispanic, South Asian, South European, and Middle Eastern descent are also affected.9,10

Facts About Sickle Cell Disease

SCD is one of the most common inherited blood disorders with about 100,000 people affected in the United States. Did you know more than 55% of people with SCD reside in just 10 states?9,11,12

 

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Mechanism of sickle cell disease

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HbS Polymerization

Under hypoxic conditions, HbS undergoes polymerization1

Sickling

HbS polymers distort the shape of the RBCs, causing them to become dense and sickle shaped1

Hemolysis

The inflexibility of sickled RBCs contributes to their premature destruction13

Anemia

A decrease in the number of RBCs, due to premature destruction, leads to lower hemoglobin levels and subsequent anemia13

Chronic Vascular Damage

Ongoing vascular damage and repeated injury to the blood vessel wall over time result in activation of endothelial cells1,13

Inflammation and Cell Activation

The chronic inflammatory environment within blood vessels leads to increased expression of adhesion mediators, resulting in multicellular adhesion1,13

Multicellular Adhesion

Activated endothelial cells initiate a complex cascade of interactions with RBCs, white blood cells (WBCs), and platelets that leads to multicellular adhesion and ongoing vaso-occlusion6,13

Vaso-Occlusion

Multicellular adhesion reduces and blocks blood flow to organs1

Vaso-Occlusive Crises

Ongoing, silent, vaso-occlusion may result in vaso-occlusive crises (VOCs)-the clinical hallmark of SCD15,16

Vaso-occlusion and VOCs are the result of a multicellular adhesion process involving WBCS, RBCs, and platelets that aggregate and adhere to endothelial cells of the vessel wall.13

Ongoing, silent, vaso-occlusion may result in VOCs—the clinical hallmark of SCD.15,16

Endothelial cells1,13

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 cells

White blood cells1

adhere to the inflamed endothelium of the blood vessel wall and RBCs, and promote further inflammation

Platelets1

are continually activated in SCD and bind to WBCs, endothelial cells, and RBCs

Red blood cells1

can adhere directly to activated endothelial cells, as well as to platelets and WBCs


Vaso-occlusive crises

Adhesion Mediators1,13*

  • • Activated endothelial cells, platelets, WBCs, and RBCs adhere to each other to form a multicellular adhesion cluster. This occurs through proteins called adhesion mediators, including P-, E-, and L-selectin and results in vaso-occlusion and VOCs

P-selectin on activated endothelial cells and platelets17-19

  • • Mediates the capture and tethering of WBCs and sickled RBCs to the activated endothelium
  • • Expressed on platelets causing them to bind to WBCs that are clustered together

E-selectin on activated endothelial cells17,18

  • • Binds WBCs to activated endothelial cells and promotes the capture of sickled RBCs

L-selectin on the surface of WBCs18

  • • Mediates the recruitment and adhesion of additional WBCs to endothelial cells

*Based on preclinical studies.

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. Steinberg MH. Sickle cell disease and associated hemoglobinopathies. In: Goldman L, Ausiello D, eds, Cecil Medicine, 23rd ed. Philadelphia, PA; Saunders Elsevier; 1991:Chap 167. 3. Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med. 2017;376(16):1561-1573. 4. Kalpatthi R, Novelli EM. Measuring success: utility of biomarkers in sickle cell disease clinical trials and care. Hematology Am Soc Hematol Educ Program. 2018. 2018;2018(1):482-492. 5. Ballas SK, Kesen MR, Goldberg ME, et al. Beyond the definitions of the phenotypic complications of sickle cell disease: an update on management. ScientificWorldJournal. 2012; 2012;2012:949535. doi: 10.1100/2012/949535. 6. Habara A, Steinberg MH. Genetic basis of heterogeneity and severity in sickle cell disease. Exp Biol Med (Maywood). 2016;241(7):689-696. 7. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376(9757):2018-2031. 8. Saraf SL, Molokie RE, Nouraie M, et al. Differences in the clinical and genotypic presentation of sickle cell disease around the world. Paediatr Respir Rev. 2014;15(1):4-12. 9. Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med. 2010;38(4 Suppl):S512-S521. 10. Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review. Am J Epidemiol. 2000;151(9):839-845. 11. Brousseau DC, Panepinto JA, Nimmer M, Hoffmann RG. The number of people with sickle-cell disease in the United States: national and state estimates. Am J Hematol. 2010;85(1):77-78. 12. Centers for Disease Control and Prevention. Data and Statistics: Sickle Cell Disease. https://www.cdc.gov/ncbddd/sicklecell/data.html. Accessed March 11, 2019. 13. 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. 14. Chirico EN, Pialoux V. Role of oxidative stress in the pathogenesis of sickle cell disease. IUBMB Life. 2012;64(1):72-80. 15. 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. 16. Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood. 2012;120(18):3647-3656. 17. Field JJ. Can selectin and iNKT cell therapies meet the needs of people with sickle cell disease? Hematology Am Soc Hematol Educ Program. 2015;2015:426-432. 18. Kappelmayer J, Nagy B. The interaction of selectins and PSGL-1 as a key component in thrombus formation and cancer progression. Biomed Res Int. 2017;2017(6138145):1-18. doi: 10.1155/2017/6138145. 19. 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.

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