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The distinct pathobiology of sickle cell-hemoglobin C disease. Therapeutic implications
1Division of Hematology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York.
Insights
Hyperconcentration of hemoglobin C and S in red blood cells drives SC disease pathology. Increasing red blood cell volume can correct these abnormalities, offering a unique therapeutic avenue.
Area of Science:
- Hematology
- Molecular Biology
- Cell Biology
Background:
- Sickle cell (SC) disease is characterized by abnormal red blood cell morphology and function.
- The hyperconcentration of hemoglobin C (Hb C) and hemoglobin S (Hb S) within SC cells is a key factor in their pathologic behavior.
Purpose of the Study:
- To elucidate the mechanisms underlying the pathologic behavior of SC cells.
- To identify potential therapeutic strategies for SC disease.
Main Methods:
- Analysis of red blood cell physiology, focusing on hemoglobin concentration and transport mechanisms.
- Review of existing data on SC cell behavior and experimental interventions.
Main Results:
- Hyperconcentration of Hb C and Hb S directly causes Hb S polymerization and Hb C aggregation, leading to abnormal cell shape and density.
- Active K:Cl cotransport contributes to cell shrinkage, but its hyperactivity in SC cells remains unexplained.
- Restoring normal mean corpuscular hemoglobin concentration (MCHC) has been shown to correct SC cell abnormalities.
Conclusions:
- Targeting red blood cell volume by increasing MCHC represents a promising therapeutic strategy for SC disease.
- Further research is needed to understand the role of K:Cl cotransport and its interaction with Hb C.
Abstract:
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.