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Clinical variability in sickle cell anemia

Martin H Steinberg, MD
Section Editor
Stanley L Schrier, MD
Deputy Editor
Jennifer S Tirnauer, MD


Homozygosity for a unique hemoglobin gene mutation (HBB glu6val, GAG —> GTG, sickle hemoglobin, HbS), located on chromosome 11, causes sickle cell anemia (SCA). Upon deoxygenation, HbS molecules polymerize into intracellular fibers, forming a high molecular weight gel and causing the sickle cell deformity. This process initiates an elaborate and incompletely understood pathophysiological cascade that includes injury to the sickle red cell; intravascular and extravascular hemolysis; adhesive interactions among sickle cells, endothelial cells, other blood cells, and plasma factors; reperfusion injury; and inflammation. As a result of this cascade, vital tissues are injured, impairing their function, causing localized pain (ie, the sickle cell vasoocclusive crisis) and, in many cases, premature death for the affected individual.

The clinical features of SCA are exceptionally heterogeneous. As in most "single-gene" disorders, clinical heterogeneity is influenced by other genes that shape its intermediate phenotypes. The products of modifier genes, sometimes called epistatic genes, are also likely to interact, thus determining the specific phenotype within each affected family and patient (eg, stroke risk, other vasoocclusive events, HbF level, response to hydroxyurea) [1-4]. (See "Genetic association studies: Principles and applications".)

The clinical variability of SCA will be discussed here [5-7]. Other features of the HbS molecule and the clinical features of SCA are discussed separately. (See "Sickle hemoglobin polymer: Structure and functional properties" and "Overview of the clinical manifestations of sickle cell disease".)

Clinical heterogeneity is also present among the different genotypes of sickle cell disease (SCD; eg, HbSC disease, HbS-beta thalassemia) and is often accounted for by the presence and nature of the hemoglobin molecule that accompanies HbS (eg, HbD, HbC, HbE). The variability of sickle cell disorders due to the simultaneous inheritance of the gene for HbS from one parent and a different beta chain variant or beta thalassemia from the other (ie, a compound heterozygous genotype) is discussed separately. (See "Overview of variant sickle cell syndromes".)


Before discussing the individual factors affecting the sickle cell anemia (SCA) phenotype, it is useful to briefly review those processes that are involved from initiation of HbS polymerization through sickle vasoocclusion and hemolysis.


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