Margination and stretching of von Willebrand factor in the blood stream enable adhesion

Kathrin Rack,Gerhard Gompper,Masoud Hoore,Stefan W Schneider,Volker Huck,Dmitry A Fedosov

doi:10.1038/s41598-017-14346-4

Abstract

The protein von Willebrand factor (VWF) is essential in primary hemostasis, as it mediates platelet adhesion to vessel walls. VWF retains its compact (globule-like) shape in equilibrium due to internal molecular associations, but is able to stretch when a high enough shear stress is applied. Even though the shear-flow sensitivity of VWF conformation is well accepted, the behavior of VWF under realistic blood flow conditions remains poorly understood. We perform mesoscopic numerical simulations together with microfluidic experiments in order to characterize VWF behavior in blood flow for a wide range of flow-rate and hematocrit conditions. In particular, our results demonstrate that the compact shape of VWF is important for its migration (or margination) toward vessel walls and that VWF stretches primarily in a near-wall region in blood flow making its adhesion possible. Our results show that VWF is a highly optimized protein in terms of its size and internal associations which are necessary to achieve its vital function. A better understanding of the relevant mechanisms for VWF behavior in microcirculation provides a further step toward the elucidation of the role of mutations in various VWF-related diseases.

Highlights

The blood glycoprotein von Willebrand factor (VWF) is involved in hemostasis, as it mediates platelet adhesion at vessel walls in case of an injury[1,2,3]
We find that large multimeric VWFs mainly retain their compact shape within the blood-flow core populated primarily by RBCs, and that this compact configuration facilitates their efficient margination into the RBC-free layer (RBC-FL)
Blood is modeled as a suspension of RBCs38 and a few macromolecules, which flow in a cylindrical microvessel in 3D with diameter

Summary

Introduction

The blood glycoprotein von Willebrand factor (VWF) is involved in hemostasis, as it mediates platelet adhesion at vessel walls in case of an injury[1,2,3]. Several experimental studies[17,18,19] have focused on adhesion of platelets to VWF, suggesting that the adhesion depends strongly on the shear rate and the length of VWF. These studies indicate that with increasing shear rate, a conformational change of VWF occurs both at a dimeric level (opening-up of the dimer structure)[1,20] and multimeric level (stretching of VWF from a compact globule-like form to an extended chain form)[21], and is accompanied by an increased platelet adhesion. We study margination and stretching of large multimeric VWFs for a wide range of flow rates and Ht values using mesoscopic hydrodynamic simulations, and consistently link the obtained picture of VWF behavior in blood flow to our microfluidic experiments on VWF margination and adhesion. Our findings are relevant for VWF-pertinent blood diseases resulting from various VWF mutations

Methods

Results

Conclusion