Thrombospondin: a modular adhesive glycoprotein of platelets and nucleated cells

Platelet adhesion to the subendothelial matrix and the subsequent aggregation of the activated platelets is a special case of intercellular adhesion that is highly regulated and for which multiple, possibly redundant adhesive systems exist. The large "adhesive glycoproteins" such as fibrinogen, von Willebrand factor, and fibronectin and their receptors, which participate in platelet adhesion and aggregation, are not unique to platelets, and probably serve analogous functions in a variety of cell types and locations. Thrombospondin (TS)/ the most abundant protein of platelet alpha-granules, has been recognized as a new member of this class of adhesive glycoproteins. Whereas other adhesive glycoproteins are contained within alpha-granules and secreted upon platelet activation, they also exist in plasma at high concentrations. Hence TS is the only member of the group that is unique to alpha-granules and whose expression in quantity at sites of platelet aggregation is absolutely dependent on platelet activation. Since its discovery in 1971, TS has been thought to have a role in platelet aggregation (3, 4). This suspicion has recently been confirmed by the fnding that both monoclonal (14) and polyclonal (22, 37) antibodies against platelet TS can block the secondary or secretion-dependent phase of platelet aggregation. This result in itself, however, does not speak directly to the mechanism of TS involvement in this complex process, since antibodies against fibrinogen (62), fibronectin (13), and the platelet glycoprotein IIb/IIIa (43), the receptor on platelets for fibrinogen and fibronectin, will all block platelet aggregation. Other agents that block aggregation are short peptide sequences related either to RGDS, the cellbinding sequence of fibronectin and fibrinogen (21), or to the COOH-terminal segment of the fibrinogen gamma chain (27). Both interfere with the binding of fibrinogen, fibronectin (58), and presumably yon Willebrand factor (61) to IIb/IIIa. In addition to its localization in platelets and its presumed synthesis in megakaryocytes (42), TS has been found, using