Sikkelcelziekte
The Molecular Basis of Sickle Cell Disease
The term sickle cell disease (SCD) describes a clinical syndrome caused by the presence of HbS, due to a sinble base change (A>T) at codon 6 (rs334) = een puntmutatie op codon 6 van het bètaglobinegen, autosomale recessieve mutatie.
The genetic causes of SCD include homozygosity for the rs334 mutation (HbSS) (generally known as SCA) and compound heterozygosity between rs334 and mutations that lead to either other structural variants of β-globin (such as HbC) or reduced levels of β-globin production (β-thalassemia).
The heterozygous status of rs334 (coding for HbS) results in the sickle cell trait (HbAS), in which erythrocytes contain a mixture of both normal HbA and HbS molecules. Through mechanisms that have not been completely elucidated, such heterozygotes have a substantial survival advantage in malaria-endemic environments.
Link: Williams and Thein, 2018
The most important of processes of SCD pathophysiology are summarized in this Figure and described in further detail below.
Vasooclusion: Sickled erythrocytes have difficulty negotiating the microvasculature and cause logjams that result in local tissue hypoxemia
Hemolysis: While steady-state hemolysis involves both an intravascular and an extravascular component , the intravascular element has been the main focus from a pathophysiological perspective. It has been proposed that the release of both free hemoglobin and arginase is directly responsible for a chain of events that results in vascular pathology.
Pathophysiology
The fundamental event that underlies the manifold pathophysiological consequences of SCA is the polymerization of HbS under conditions of low oxygen tension. HbS polymerization alters both the structure and function of erythrocytes, initiating a cascade of events that ultimately affect a wide range of tissues, with far-reaching clinical and pathological consequences.
Polymerization of deoxy-HbS eventually leads to the formation of dehydrated and misshapen erythrocytes, typically with a sickled shape. The sickled cells trigger microvascular occlusion through interactions with activated neutrophils and platelets and adhesion to vascular endothelium, leading to ischemia and tissue hypoxia followed by vasodilation and reperfusion injury. The damaged erythrocytes are short lived, continuously releasing hemoglobin, and oxidized hemoglobin releases heme. Heme functions as a damage-associated molecular pattern that activates endothelial cells, macrophages, and neutrophils and promotes the formation of NETs (NETosis) via TLR4 binding. Abbreviations: HbS, hemoglobin S; NET, neutrophil extracellular trap; NO, nitric oxide; RBC, red blood cell; ROS, reactive oxygen species; SCA, sickle cell anemia; sRBC, sickle red blood cell; VWF, von Willebrand factor.
Clinical Course and Complications
Acute complications
Chronic complications
Common complications of SCA that add to morbidities
While many complications are related to age, it is also clear that some patients are genetically predisposed to some complications. Predisposing or protective genetic variants have been identified for some complications, such as bilirubin levels and gallstones, as well as sickle nephropathy. Clearly some patients are also predisposed to stroke, avascular necrosis, and pulmonary complications, but genetic variants for these complications need genetic and functional validation. Abbreviation: SCA, sickle cell anemia