Despite longstanding evidence for increased activation of coagulation in hemolytic anemias, its pathophysiology and its role in the vaso-occlusive crises of sickle disease remain unclear. Here Dr. Ataga reviews the latest evidence on this topic, emphasizing the likely multifactorial origin of the activation and the increasing evidence for the importance of cellular elements or their derived microparticles. See related articles on pages 1513 and 1520