Control of von Willebrand factor multimer size by thrombospondin-1

Plasma von Willebrand factor (VWF) is a multimeric protein that mediates ad hesion of platelets to sites of vascular injury. Only the very large VWF mu ltimers are effective in promoting plate let adhesion in flowing blood. A p rotein disulfide bond reductase in plasma reduces the average multimer size of vWF secreted by endothelial cells. This activity has been isolated from human endothelial cell conditioned medium and shown to be the trimeric gly coprotein, thrombospondin-1 (TSP-1). Incubation of purified TSP-1 with vWF resulted in formation of thiol-dependent complexes of TSP-1 and vWF, genera tion of new thiols in vWF, and reduction in the average multimer size of vW F. The ratio of the concentrations of TSP-1 and vWF in plasma reflected wit h average multimer size of vWF. The higher the plasma TSP-1/vWF molar ratio , the smaller the average vWF multimer size. In addition, administration of TSP-1 to mice resulted in reduction in the average multimer size of plasma vWF. Interaction of TSP-1 with vWF is mediated by TSP-1 type 1 properdin d omains and the vWF A3 domain. These results indicate that TSP-1 regulates t he multimeric size and therefore hemostatic activity of vWF.