Thrombospondin 1 was first identified as a thrombin-sensitive protein (TSP) that was released in response to activation of platelets by thrombin, hence its name. Upon release from activated platelets, TSP1 binds to the platelet surface in a Ca2+-dependent manner. Platelet-bound TSP1 interacts with integrins αIIbβ3 and αvβ3, with CD36 and the integrin-associated protein (IAP), and with integrin-bound fibrinogen and fibronectin. Early antibody inhibition experiments indicated that TSP1 was required for the secondary secretion-dependent phase of platelet aggregation. More recently, TSP1 was shown to activate αIIbβ3 by its binding to IAP (11). This interaction results in spreading of platelets on fibronectincoated surfaces and assembly of a signaling complex containing the integrin, IAP, c-Src, FAK, and Syk protein kinase, and culminates in platelet aggregation. However, these findings must now be reconciled with the report that TSP1-null mice are free of bleeding defects and show normal thrombin-induced platelet aggregation (5). Possibly, compensatory changes in these mice maintain a normal potential for platelet aggregation. TSP1 may also perform other functions in blood, since it is incorporated into fibrin clots and binds to a number of plasma proteins including fibrinogen, plasminogen, and histidine-rich glycoprotein. On the other hand, platelet TSP1 could function primarily at sites of injury and bleeding to influence macrophages, fibroblasts, and endothelial cells that participate in wound healing. Paradoxically, although TSP1 is present in platelets and TSP2 is not, it is TSP2-null mice that display a bleeding diathesis (4). Kyriakides et al.(12) have recently reported that megakaryocytes contain abundant TSP2, most of which is probably produced by marrow stromal cells and is taken up by megakaryocytes from the extracellular milieu. Just how TSP2 is lost from megakaryocytes as they fragment to form platelets is not understood. Platelets from TSP2-null animals show a reduced ability to aggregate in vitro in response to ADP and are also compromised in the formation of aggregates on the denuded subendothelium of the common carotid artery of mice in vivo (12). TSP2 therefore seems to be required for the generation of normal platelets from megakaryocytes, but the resulting biochemical defect in TSP2-null platelets is not known. It is also possible, in view of the abnormal collagen fibrillogenesis observed in TSP2-null mice, that abnormalities in the subendothelium could contribute to the defective aggregation of platelets in vivo.