The distinct pathobiology of sickle cell-hemoglobin C disease. Therapeutic implications.
The data available clearly establish that the hyperconcentration of hemoglobin C and S inside SC cells is the main and driving mechanism for the pathologic behavior of these cells. It facilitates the polymerization of Hb S, but it also favors the tendency of Hb C to induce the formation of crystals and aggregates, abnormal morphologic shapes, and abnormally dense reticulocytes, through a particularly active K:Cl cotransport. Why these cells are endowed with a particularly active K:Cl cotransport is still a mystery; it is disproportionate with the extent of the hemolysis and the number of young cells. Is there an abnormal interaction between Hb C and the K:Cl cotransport protein in the inner aspect of the membrane? Are there abnormal interactions between Hb C and the other transport mechanisms that balance the shrinking capacity of K:Cl cotransport (as Na/H exchange)? Only future work will tell. In any case, SC disease is unique among the hemoglobinopathies in that a single intervention could correct all abnormalities: the restitution of the normal MCHC, as proven experimentally by Fabry et al. Hence, effort should be centered on looking for compounds that increase red cell volume, because in SC cells, increases in volume will not distort the cell, but restore it to the normal red cell volume and the normal red cell shape. This luxury is not available for cells with normal MCHC (the majority of the red cells in SS blood), because increasing their volume will progressively turn them into spheres, a rheologically disadvantaged shape.
Nagel
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Division of Hematology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York.
Lawrence
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C
D000818:Animals; D002352:Carrier Proteins / Q000097:blood; D004913:Erythrocytes, Abnormal / Q000378:metabolism / Q000473:pathology; D006444:Hemoglobin C / Q000378:metabolism; D006450:Hemoglobin SC Disease / Q000097:blood / Q000235:genetics; D006451:Hemoglobin, Sickle / Q000378:metabolism; D006801:Humans; D027981:Symporters; D000096922:K Cl- Cotransporters
D002352:Carrier Proteins; D006444:Hemoglobin C; D006451:Hemoglobin, Sickle; D027981:Symporters; D000096922:K Cl- Cotransporters