Relative Contributions of von Willebrand Factor and Platelets in High Shear Thrombosis

Abstract

Platelets and von Willebrand factor (VWF) are recognized as important mediators of thrombosis at high shear rates, but their relative contributions are unclear. We employ a stenotic microfluidic test system to induce thrombus formation to occlusion on collagen at pathologic shear rates of 3500-6000 s-1. To obtain blood analogs with reduced platelet and VWF concentrations, human whole blood was diluted with saline by 90% or 99% and hematocrit restored by adding washed red blood cells. Platelets and VWF were selectively restored to normal levels. Blood from patients with known von Willebrand disease (VWD) was also investigated with and without the addition of VWF to investigate the contribution of platelet VWF. Normal whole blood led to channel occlusion in all tests (occlusion time, tocc=6.1 ± 2.2 min). 90% dilution with restored VWF occluded in 6/7 subjects even without restored platelets (tocc=16.6 ± 1.4 min). 90% dilution with restored platelets occluded in 2/5 subjects (tocc=27.2 ± 1.8 min), showing that added VWF is more effective for restoring occlusion than platelets. Addition of plasma VWF to VWD blood restored occlusion in only 1/4 severe subjects (VWF:RCo<15) and did not reduce normal occlusion time in the occluding subject, suggesting that VWF release from platelets plays an important role in high shear thrombosis. Logistic regression shows that VWF concentration and platelet count are strong predictors of thrombotic occlusion. Efforts to control high shear thrombosis may focus on VWF in addition to platelet function.