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The principal role of Von Willebrand Factor (VWF) is platelet capture at sites of vascular injury, via interaction of its A1 domain with platelet glycoprotein Ibα (GPIbα). The GPIbα binding site overlaps with a binding site for heparin, the functional significance, and physiological ligand, of which remains unknown. Previous studies have demonstrated heparin inhibition of VWF-dependent platelet binding, a secondary effect distinct from heparin’s anticoagulant role. Using a physiologically representative flow assay, this secondary effect has been demonstrated, with unfractionated heparin (UFH) exerting the greatest inhibition. This antithrombotic action of heparin is a potential mechanism for unpredictable bleeding complications during cardiopulmonary bypass surgery (CPB) when high concentrations of UFH are needed to maintain the extracorporeal circuit. A prospective cohort study to determine the changes in VWF antigen activity and function, occurring pre- and post-UFH in CPB demonstrates a significant rise in the VWF antigen (VWF:Ag) level by the end of surgery, with a relative fall in VWF collagen binding. The VWF Ristocetin Cofactor (VWF:RCo) fell but not significantly following UFH, with recovery seen in the absolute VWF:RCo after UFH reversal with protamine sulphate (PS) but not in the VWF:Ag/VWF:RCo. Both heparin and PS sulphate affect many components of haemostasis and these off-target effects, alongside the consumptive and dilutional coagulopathy during CPB make prediction of bleeding difficult. Recombinant VWF heparin binding site variants demonstrate impaired platelet capture on a collagen surface, suggesting a greater degree of overlap between the two binding sites or that the heparin-binding site of VWF has a role in the GPIbα interaction, identifying a potential physiological ligand. Heparan sulphate (HS) within the endothelial glycocalyx has been suggested as the physiological ligand for the VWF heparin-binding site. Removal of HS from the glycocalyx of human umbilical vein endothelial cells is a promising model to investigate this further. Open Access |
