OC 15.4 - A balance of von Willebrand factor multimer size and platelet activation in a high shear mouse model to modulate hemostasis

Background: Bleeding with nonphysiological shear occurs for severe aortic stenosis (incomplete opening of aortic valve), while bleeding and thrombosis remain risks in mechanical circulatory support (MCS) used to treat heart failure. It’s well-established that acquired von Willebrand syndrome (AVWS), i.e. loss in high molecular weight von Willebrand factor (VWF), occurs in both, but it’s less understood how/if AVWS impacts shear-induced platelet activation (SIPA), which may be a contributor to dichotomous thrombosis in MCS.

Aims: VWF and shear-induced platelet activation modulate hemostasis for nonphysiological shear.

Methods: We use a transthoracic aortic constriction (TAC) model of varying severity with wild type, VWF-/-, and ADAMTS13-/- mice to create nonphysiological shear. We characterize flow, VWF size and function, and quantified platelet activation. Samples were taken and tail bleeds were performed at 1 and 7 days.

Results: The amount of platelet activation increases with increasing stenosis severity at 24 hours, except for VWF-/- mice, suggesting VWF-dependent platelet activation in this model. There is a simultaneous reduction in HMWMs as a function of stenosis severity. Reduced bleeding times were seen with increasing stenosis severity, with very short bleeding times for ADAMTS13-/-. At 7 days, platelet activation is greatly reduced and almost eliminated, while HMWMs remain reduced. ADAMTS13-/- mice still had significant global platelet activation. Bleeding times were longer from tail bleeds with increasing stenosis. VWF-/- mice bled longest and ADAMTS13-/- mice bled for the shortest amount of time.

Conclusion(s): Shear and HMWMs work together in SIPA, not caused by injury-alone since it was absent in VWF -/-. Over time, reduced HMWMs for severe stenosis reduced platelet activation, whereas the lack of ADAMTS13 (and cleavage) continued to cause platelet activation. To our knowledge this is the first study to show the fine balance of VWF size distribution and SIPA from high shear stress as an important driver in hemostatic health.