Sickle Cell Disease (SCD)


Sickle cell disease (SCD) is caused by a mutation in the gene that encodes the beta-globin chain of the hemoglobin molecule. The mutation results in the formation of sickle hemoglobin (HbS), which has the unique feature of polymerizing on deoxygenation.1 Because of a single base-pair point mutation (GAG to GTG) in the beta-globin gene, the amino acid glutamic acid (which is hydrophilic) is replaced by valine (which is hydrophobic) at position 6 of the beta-globin molecule, resulting in the formation of HbS.2 HbS polymerization causes erythrocyte sickling, leading to vaso-occlusion and episodes of ischemia, referred to as crises. Organs including the brain, bones, lungs, spleen, and liver can be severely damaged during crises, with substantial morbidity and mortality.3 

Pathophysiology

Vaso-occlusive pain crises are the most characteristic complication of sickle cell anemia (SCA). Although vaso-occlusion is a complex process, the polymerization of HbS is a critical event in the pathophysiology of SCA.4 HbS polymerization alters the form and physicochemical features of red cells, leading to hemolytic anemia and the obstruction of blood flow (vaso-occlusion), which can harm any organ.4 Three key pathophysiological mechanisms—polymerization of HbS, vaso-occlusive phenomena, and endothelial dysfunction mediated by hemolysis—have been found to drive the clinical picture of SCA. Sterile inflammation has recently been characterized as a fourth mechanism.5

HbS Polymerization

HbS polymerization is an exceptionally dynamic process.6 The affinity of HbS for oxygen is lower than that of HbA. HbS polymerization is exacerbated by the reduced affinity of HbS for oxygen, and polymerization in turn further diminishes the oxygen affinity of HbS.4

The deoxygenation process that accelerates HbS polymerization occurs as a result of mechanisms such as physiologically high levels of 2,3-diphosphoglycerate (2,3-DPG) and enhanced sphingokinase-1 activity. Furthermore, excessive concentrations of HbS, aberrant Gados channel activity resulting in dehydration, and recurrent injury to erythrocyte membranes all enhance HbS polymerization.7 HbS polymers form long strands very quickly. The lengthening polymer fibers deform red cells, reducing their flexibility and affecting rheology, finally resulting in vaso-occlusion.4,5

HbS polymerization disrupts the normal lipid bilayer and proteins of red cell membranes. The result is a decrease in cellular hydration and accelerated hemolysis, which romotes the early apoptosis of red blood cells. The permanent sickling of red cells is caused by further deformation of their membranes and dehydration.4

The lifespan of sickled red blood cells is reduced by 75%, and the cells are extremely unstable. Hemolysis is primarily extravascular, caused by macrophage phagocytosis; however, approximately one-third is intravascular. Oxidative stress, which causes hemolysis via the auto-oxidation of HbS, can result in damage to the erythrocyte cell membranes, which is both a cause and an effect.4

Cell Adhesion and Vaso-occlusion 

Vaso-occlusion resulting in ischemia is the primary mechanism underlying acute systemic painful vaso-occlusive crisis (VOC) requiring emergency medical care.5 VOC is a complex process based on interactions among red blood cells and endothelial cells, white blood cells, and platelets. Direct contact with sickled red cells, free heme and hemoglobin, and hypoxia-induced reactive oxygen species (ROS) is believed to activate endothelial cells.4 Increased erythrocyte adherence results in the formation of heterocellular aggregates that block small vessels and ultimately cause local hypoxia.8 

Endothelial dysfunction and sterile inflammation, which are characteristic of SCD, play a major role in upregulating selectins, vascular cell adhesion molecule 1, and major leukocyte chemoattractants on endothelial cells, causing adhesion of red blood cells and white blood cells.4,5

Endothelial Dysfunction 

Cell-free hemoglobin causes significant oxidative stress in the cells and blood vessels of patients with SCD.4 It also promotes the generation of reactive oxygen species (ROS). Cell-free hemoglobin in plasma causes nitric oxide (NO) scavenging, resulting in impaired endothelial function, and enhances proliferative vasculopathy in the respiratory and systemic vasculature.5

Sterile Inflammation

Heme and its oxidized form, hemin (ferric protoporphyrin IX), which are released after hemoglobin is oxidized, play an important role in the pro-inflammatory and procoagulant milieu of SCD, marked by the activation of leukocytes, platelets, endothelial cells, tissue factor, cytokine storm, NO depletion, and ROS generation.5 Studies of mouse models of SCA indicate a role of neutrophils in vaso-occlusion. In addition to neutrophils and erythrocytes, platelets have been identified in circulating heterocellular aggregates in the blood of individuals with SCA. The adhesion of platelets to heterocellular aggregates occurs via P-selectin.4 Thrombocytopenia is a strong predictor of the development of VOC in patients with SCD, indicating platelet sequestration at sites of vaso-occlusion.5 

Conclusion

The pathophysiology of SCD is based on genetics, HbS polymerization–dependent hemolysis and sickling, vaso-occlusion–dependent ischemia-reperfusion injury, endothelial dysfunction–dependent vasculopathy, and sterile inflammation. These factors lead to multiorgan complications.5 

References

  1. Steinberg MH. Pathophysiology of sickle cell disease. Baillière’s Clinical Haematology. 1998;11(1):163-184.
  2. Inusa BPD, Hsu LL, Kohli N, et al. Sickle cell disease—genetics, pathophysiology, clinical presentation and treatment. Int J Neonatal Screen. 2019;5(2):20. doi:10.3390/ijns5020020
  3. Piccin A, Murphy C, Eakins E, et al. Insight into the complex pathophysiology of sickle cell anaemia and possible treatment. Eur J Haematol. 2019;102(4):319-330. doi:10.1111/ejh.13212
  4. Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010. doi:10.1038/nrdp.2018.10
  5. Sundd P, Gladwin MT, Novelli EM. Pathophysiology of sickle cell disease. Annu Rev Pathol. 2019;14:263-292. doi:10.1146/annurev-pathmechdis-012418-012838
  6. Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med. 1997;337(11):762-769. doi:10.1056/NEJM199709113371107
  7. Mangla A, Ehsan M, Agarwal N, Maruvada S. Sickle cell anemia. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2021.
  8. Sedrak A, Kondamudi NP. Sickle cell disease. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2021.

Reviewed by Debjyoti Talukdar, MD, on 11/13/2021.

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