Abstract 448: Platelets Contribute to Arterial and Venous Thrombosis in vivo
Background: Arterial (AT) and venous thromboses (VT) are the major causes of morbidity in industrialized countries. While the critical contribution of platelets to AT has been recognized, the molecular and cellular mechanisms that trigger the development of VT are not yet fully understood.
Methods: We established a novel model of VT, where thrombus formation occurs after venous stasis in the absence of mechanical endothelial injury. In contrast to published models, our approach closely resembles the triggers that lead to VT in humans. The molecular and cellular events in VT were assessed using intravital and electron microscopy. In particular, we evaluated the differential contribution of platelets (pts) and leukocytes (lcs) to AT and VT.
Results: We found that in AT pts adhere rapidly, whereas only few lcs are recruited. The loss of platelet P-Selectin reduced lc accumulation during AT, was associated with thrombus destabilization, but had no effect on pt adhesion/aggregation. The loss of GPIIb led to a complete lack of pt adhesion/aggregation in AT. While AT largely depends on pts, lc adhesion was the prominent initial phenomenon during VT and involved both P-selectin and Mac-1. P-Selectin−/− as well as Mac-1−/− mice showed a massive reduction in lc accumulation. The lack of P-Selectin was accompanied by a reduction of the thrombus size 48 hours after stasis and was only marginally reduced in Mac 1−/− mice, indicating that lc rolling is sufficient to promote VT. The expression of tissue factor by lcs played a pivotal role for VT. Accordingly, mice with reduced TF expression showed a dramatic reduction in venous thrombus size. In addition to TF-bearing lcs, pts were recruited to the vessel wall early in VT. Pt accumulation involved both the fibrinogen and the vWF receptor and was virtually abolished in mice lacking GPIIb or GPIbα. To our surprise, we observed that pts do not accumulate during VT but play a functional role. Reduced pt adhesion in mice lacking either GPIIb, GPIbα, or VWF was associated with a significant reduction in venous thrombus size.
Conclusion: Together, we show that VT, unlike AT depends on the concerted action of both lcs and pts. Hence, targeting pt activation and adhesion might provide a promising strategy in the prophylaxis and treatment of VT.