Platelet adhesion and aggregate formation controlled by immobilised and soluble VWF

Matthias F Schneider,Volker Huck,Mohammad A Fallah,Reinhard Schneppenheim,Alfredo Alexander-Katz,Christian Mess,Tobias Obser,Stefan W Schneider

doi:10.1186/s12860-020-00309-7

Abstract

BackgroundIt has been demonstrated that von Willebrand factor (VWF) mediated platelet-endothelium and platelet-platelet interactions are shear dependent. The VWF’s mobility under dynamic conditions (e.g. flow) is pivotal to platelet adhesion and VWF-mediated aggregate formation in the cascade of VWF-platelet interactions in haemostasis.ResultsCombining microfluidic tools with fluorescence and reflection interference contrast microscopy (RICM), here we show, that specific deletions in the A-domains of the biopolymer VWF affect both, adhesion and aggregation properties independently. Intuitively, the deletion of the A1-domain led to a significant decrease in both adhesion and aggregate formation of platelets. Nevertheless, the deletion of the A2-domain revealed a completely different picture, with a significant increase in formation of rolling aggregates (gain of function). We predict that the A2-domain effectively ‘masks’ the potential between the platelet glycoprotein (GP) Ib and the VWF A1-domain. Furthermore, the deletion of the A3-domain led to no significant variation in either of the two functional characteristics.ConclusionsThese data demonstrate that the macroscopic functional properties i.e. adhesion and aggregate formation cannot simply be assigned to the properties of one particular domain, but have to be explained by cooperative phenomena. The absence or presence of molecular entities likewise affects the properties (thermodynamic phenomenology) of its neighbours, therefore altering the macromolecular function.

Highlights

It has been demonstrated that von Willebrand factor (VWF) mediated platelet-endothelium and platelet-platelet interactions are shear dependent
The first step of haemostasis depends on the presence of an intact immobilised binding partner for platelets in the subendothelial vessel wall [16,17,18], bleeding episodes of patients suffering from acquired von Willebrand factor syndrome (AVWS) illustrate that the mobile VWF fraction is a prerequisite for an effective VWF triggered blood clotting
Whereas biofunctionalisation with wildtype von Willebrand factor (wt VWF) led to a time-dependent increase in platelet adhesion, coating with del-A1 VWF mutant failed to bind platelets, comparable to biofunctionalisation with bovine serum albumin (BSA) serving as negative control

Summary

Introduction

It has been demonstrated that von Willebrand factor (VWF) mediated platelet-endothelium and platelet-platelet interactions are shear dependent. Understanding the VWF function is consisted of the physical aspects of hydrodynamics and structural conformations, and physiological aspects Both qualitative (Type II) and quantitative (Type I and III) VWF variants are classified in the framework of von Willebrand disease (VWD) [11,12,13]. The acquired von Willebrand factor syndrome (AVWS), reviewed by Tiede and coworkers, subsumes diverse non-inherited qualitative, structural or functional VWF disorders resulting in an enhanced risk of bleeding [14, 15]. The first step of haemostasis depends on the presence of an intact immobilised binding partner for platelets in the subendothelial vessel wall [16,17,18], bleeding episodes of patients suffering from AVWS illustrate that the mobile VWF fraction is a prerequisite for an effective VWF triggered blood clotting. Independent of the different pathomechanisms and clinical manifestations, the similar symptomatic therapeutic regimens of these syndromes underline the central role of VWF’s functional characteristics

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Discussion

Conclusion