That Platelet Fv Plays in Promoting Thrombin 754 2 8 J a N U a R Y 2 0 1 0 I V O L U M E 1 1 5 , N U M B E R 4 Blood

generation at the activated platelet surface. What remains uncertain, however, is whether residual platelet FV levels correlate with the severity of bleeding in severe FV-deficient patients. Although there has been speculation on this correlation,8 no systematic study has been done. Furthermore, mechanistic studies are needed to investigate some remaining questions. The first relates to the origin of residual platelet FV in these severe FVdeficient patients. Are megakaryocytes able to synthesize a very small amount of FV that is protected in the platelet environment or, alternatively, do megakaryocytes have an extremely efficient system to endocytose most of the FV that is being synthesized form the liver in these patients? Recent studies have shown that the majority of platelet FV is endocytosed from the plasma pool by megakaryocytes via a specific receptor-mediated process.5 However, this system has yet to be evaluated in sufficient detail to know whether it is efficient enough to take up FV in the context of plasma levels less than 1%. A final area that needs further investigation is an understanding of why TFPI levels are decreased in severe FV deficiency. Although FV was shown to bind to TFPI, it is currently unknown whether FV actually protects TFPI from proteases or other clearance mechanisms. Overall, the quality work of Duckers et al underscores the complexity of a seemingly simple deficiency of one clotting factor and reminds us that a balance of multiple components ultimately contribute to the clinical phenotype. Conflict-of-interest disclosure: The author declares no competing financial interests. ■