Targeting von Willebrand Factor in Ischaemic Stroke: Focus on Clinical Evidence

Abstract

Despite great efforts in stroke research, disability and recurrence rates in ischaemic stroke remain unacceptably high. To address this issue, one potential target for novel therapeutics is the glycoprotein von Willebrand factor (vWF), which increases in thrombogenicity especially under high shear rates as it bridges between vascular sub-endothelial collagen and platelets. The rationale for vWF as a potential target in stroke comes from four bodies of evidence. (1) Animal models which recapitulate the pathogenesis of stroke and validate the concept of targeting vWF for stroke prevention and the use of the vWF cleavage enzyme ADAMTS13 in acute stroke treatment. (2) Extensive epidemiologic data establishing the prognostic role of vWF in the clinical setting showing that high vWF levels are associated with an increased risk of first stroke, stroke recurrence or stroke-associated mortality. As such, vWF levels may be a suitable marker for further risk stratification to potentially fine-tune current risk prediction models which are mainly based on clinical and imaging data. (3) Genetic studies showing an association between vWF levels and stroke risk on genomic levels. Finally, (4) studies of patients with primary disorders of excess or deficiency of function in the vWF axis (e.g. thrombotic thrombocytopenic purpura and von Willebrand disease, respectively) which demonstrate the crucial role of vWF in atherothrombosis. Therapeutic inhibition of VWF by novel agents appears particularly promising for secondary prevention of stroke recurrence in specific sub-groups of patients such as those suffering from large artery atherosclerosis, as designated according to the TOAST classification.

Covid-19: The Rollercoaster of Fibrin(Ogen), D-Dimer, Von Willebrand Factor, P-Selectin and Their Interactions with Endothelial Cells, Platelets and Erythrocytes

“…VWF is involved in platelet aggregation and thrombus formation and due to its important role in inflammation, VWF is identified as an acute phase reactant [113]. In addition, VWF is identified as a crucial player in the propagation of atherosclerosis by promoting plaque formation and inflammation [114]. This is important because atherosclerotic lesions cause obstruction, which further promotes thrombus formation (and embolization), resulting in reduced cerebral blood flow (cerebral ischemia) [115].…”

COVID-19: The Rollercoaster of Fibrin(ogen), D-dimer, von Willebrand Factor, P-selectin and Their Interactions with Endothelial Cells, Platelets and Erythrocytes

“…vWF is involved in platelet aggregation and thrombus formation and due to its important role in inflammation, vWF is identified as an acute phase reactant [107]. In addition, vWF is identified as a crucial player in the propagation of atherosclerosis by promoting plaque formation and inflammation [108]. This is important because atherosclerotic lesions cause obstruction, which further promotes thrombus formation (and embolization), resulting in reduced cerebral blood flow (cerebral ischemia) [108].…”

“…In addition, vWF is identified as a crucial player in the propagation of atherosclerosis by promoting plaque formation and inflammation [108]. This is important because atherosclerotic lesions cause obstruction, which further promotes thrombus formation (and embolization), resulting in reduced cerebral blood flow (cerebral ischemia) [108]. In addition, vWF tethers circulating platelets to the endothelium as part of the processes of coagulation, inflammation, and also tumor progression [109].…”

Platelet-rich emboli are associated with von Willebrand factor levels and have poorer revascularization outcomes

“…It has been suggested that targeting vWF with novel pharmacological agents could help to overcome some of the limitations of current thrombolytic drugs and also in secondary stroke prevention [6,26]. It is clear that vWF is a key mediator of thrombus formation and thus is a key component of thromboemboli.…”