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The polymerization of sickle cell hemoglobin (HbS) in the erythrocytes of sickle cell anemia patients is the primary event in the pathophysiology of this debilitating and deadly disease. Correspondingly, the majority of the current clinical treatments rely on delaying HbS polymerization. In search of pathways towards novel, more efficient treatment strategies, we explore the mechanism of nucleation of the HbS polymers. Previous work has shown that this nucleation follows a two-step mechanism, whereby the polymers nucleate inside dense liquid clusters suspended in the solution and occupying about 10−5 of the solution volume. We show that free hematin, which is spontaneously released by HbS due to its intrinsic instability to autoxidation, accelerates by 100× the rates of both nucleation and growth of the polymers and that its removal leads to complete arrest of HbS polymerization. Exploring the mechanism underlying these hematin effects, we show that hematin enhances the attraction between the hemoglobin molecules in the solution and this yields 100× higher volume of the dense liquid clusters in which nucleation occurs. These findings suggest that the nucleation of sickle cell hemoglobin polymers and the ensuing pathology can be suppressed by controlling the release and concentration of hematin in the red blood cells.
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