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Mechanisms of vaso-occlusion in sickle cell disease

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


Sickle cell disease (SCD; this designation includes homozygosity for hemoglobin S, compound heterozygosity for hemoglobins S and C, compound heterozygosity for hemoglobin S and beta thalassemia, plus other less common genotypes) is a typical Mendelian disorder. It is associated with hypoxia-induced polymerization of the abnormal hemoglobin S (HbS) molecule, followed by red blood cell injury and sickling, with resultant microvascular occlusion (vaso-occlusion) clinically manifested most often as an acute painful episode or "crisis", but with many other acute and chronic complications.

However, numerous features of SCD are not accounted for by polymerization-based explanations alone, including the high degree of clinical heterogeneity among patients with identical hemoglobin genotypes, the unpredictable occurrence of acute vaso-occlusive episodes, the variable rate of hemolysis among patients, and the different frequencies of the many chronic complications. This variance in phenotypic expression is due partly to the modulating effects of numerous modifier genes such as those that control fetal hemoglobin (HbF) expression or cause alpha thalassemia, other less well documented disease modifying genes, and environmental and psychosocial factors. Recognition of these polymerization-independent mechanisms has placed the sickle cell disorders into the broader area of vascular disease, in which the interaction between sickle cells and the vascular endothelium assumes pathogenetic importance. Interrupting such interactions may provide a worthwhile therapeutic strategy. (See "The endothelium: A primer".)

This topic review will discuss factors underlying the process of sickle vaso-occlusion. Discussions of the overall process of hemoglobin S polymer formation and the effects of modulatory genes are presented separately. (See "Sickle hemoglobin polymer: Structure and functional properties" and "Clinical variability in sickle cell anemia".)

Evaluation and treatment of vaso-occlusive pain episodes and the role of hydroxyurea and red blood cell transfusion in prevention vaso-occlusive complications of SCD are presented in detail separately. (See "Evaluation of acute pain in sickle cell disease" and "Vaso-occlusive pain management in sickle cell disease" and "Hydroxyurea use in sickle cell disease" and "Red blood cell transfusion in sickle cell disease".)


It is reasonable to conclude that deoxy-hemoglobin S (HbS) polymerization is a primary event and central to the pathophysiology of SCD, and that lacking this, the full phenotype of the disease is unlikely to be expressed. The attribution of all aspects of SCD to hemoglobin polymerization-related events evolved to a great extent from circumstantial evidence linking the peculiar shape of sickle red cells, abnormal HbS solubility, blood viscosity, structure of the HbS polymer, and impaired rheologic properties of sickle cell suspensions. The relationships among these abnormalities is complex and not totally reflective of the clinical realities of the disease. Previous reviews include references to these primary studies [1,2].

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Literature review current through: Sep 2017. | This topic last updated: Oct 05, 2017.
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