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Sickle hemoglobin polymer: Structure and functional properties

Martin H Steinberg, MD
Section Editor
Donald H Mahoney, Jr, MD
Deputy Editor
Jennifer S Tirnauer, MD


In sickle hemoglobin (Hb S), a missense mutation (GAG to GTG) causes a valine to be substituted for glutamic acid on the surface of the Hb S molecule in the sixth position of the beta globin chain (HBB glu6val). This change endows Hb S when deoxygenated with a new property: the capacity to polymerize. Hb S polymer injures the sickle erythrocyte, increases its density, reduces its deformability, increases its adhesivity, and shortens its life span.

The polymerization of deoxy Hb S is the primary and indispensable event in the molecular pathogenesis of sickle cell disease [1,2]. The polymer has the form of an elongated rope-like fiber, which usually aligns with other fibers, forming a fascicle, and distorting the red cell into the classic crescent or sickle shape, among many other abnormal shapes, and resulting in a marked decrease in cell deformability. Hb S can undergo innumerable cycles of deoxygenation-induced polymerization and reoxygenation-induced depolymerization; however, the sickle erythrocyte membrane can withstand only a finite number of these cycles before it is irreversibly injured and recognized via the many abnormal "sickle" shapes that circulate in patients.

Polymerization alone does not account for the pathophysiology of sickle cell disease. Subsequent changes in red cell membrane structure and function, disordered red cell volume control, increased red cell adherence to vascular endothelium [3,4], misregulation of vasoactivity, and inflammation also contribute to sickle vasoocclusion and hemolysis that are the hallmarks of sickle cell disease. In genetics these are called pleiotropic effects, because they go beyond the immediate consequences of the abnormal gene.

The polymerization process and the modulating factors will be reviewed here. Other issues relating to the sickling process and an overview of structure and function of hemoglobin are discussed separately. (See "Structure and function of normal hemoglobins".)


Following deoxygenation, sickle hemoglobin (Hb S) containing cells assume a variety of distorted shapes readily appreciated by light microscopy (picture 1) and even more clearly by scanning electron microscopy (diagnostic image 1 and picture 2) [5]. Studies at higher resolution using transmission electron microscopy have provided information concerning the structure and packing of the sickle fiber. X-ray diffraction studies subsequently refined the structure at a resolution of 0.2 nm (2.0 Å) and provided information on molecular orientation and contacts [6-8].


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Literature review current through: Sep 2016. | This topic last updated: Jun 1, 2015.
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