Thrombospondin 1 requires von Willebrand factor to modulate arterial thrombosis in mice.

Abstract

Thrombospondin 1 (TSP1) has been suggested as a counter receptor to platelet glycoprotein Ib&#x3b1; that supports initial platelet adhesion in absence of von Willebrand factor (VWF). Conversely, several other studies have shown that TSP1 interacts with VWF and may play a mechanistic role in modulating thrombosis. However, the in vivo evidence to support this mechanism remains unclear. Using intravital microscopy, in a 10% FeCl3-induced thrombosis model, we report similar platelet adhesion in Tsp1(-/-)/Vwf(-/-) mice compared with littermate Vwf(-/-) mice, suggesting that TSP1 does not mediate initial platelet adhesion in the absence of VWF. Tsp1(-/-) mice exhibited prolonged occlusion time and a significant decrease in the rate of thrombus growth (P < .05 vs wild-type), but not in the initial platelet adhesion. Complete deficiency of VWF abrogated the rate of thrombus growth in Tsp1(-/-) mice; therefore, we generated Tsp1(-/-)/Vwf(+/-) mice to determine whether TSP1 modulates thrombus growth under conditions of partial VWF deficiency. Tsp1(-/-)/Vwf(+/-) mice exhibited delayed thrombus growth kinetics and prolonged occlusion time (P < .05 vs Vwf(+/-)). Finally, we demonstrate that platelet-derived TSP1 modulates arterial thrombosis in vivo. We conclude that TSP1 released from platelets plays a mechanistic role in modulating thrombosis in the presence of VWF.