Degradation Mechanism of Multimeric Structure of von Willebrand Factor

Acquired von Willebrand Syndrome (AVWS) characterized by the loss of high molecular weight multimers (HMWMs) of von Willebrand factor (vWF) is often associated with nonphysiologic blood flows. AVWS is found in patients with severe aortic stenosis (AS) or continuous flow left ventricular assist devices (cf-LVADs). Interestingly, this hemostatic abnormality associated with severe AS is fully corrected on the first day after surgery. For AVWS associated with cf-LVADs, it disappears quickly after removal of the device, strongly suggesting that the device itself is responsible for the syndrome. It is widely believed that the supraphysiologic shear stress and/or long exposure time in severe AS and cf-LVADs are responsible for the loss of HMWM. Although the destruction of HMWM is believed to be a combination of mechanical and enzymatic cleavage, the complete mechanism still remains unclear. Also notable is that AVWS is rarely observed in pulsatile flow devices. There is clearly a need to understand the degradation mechanism of vWF and exposure time especially when nonphysiologic blood flows are expected. The objective of this proposal is to characterize the degradation of HMWM under fully controlled laminar through turbulent blood flow conditions in terms of turbulent intensity and clinically relevant exposure times. The central hypothesis is that the degradation of HMWM of vWF is a time-sensitive mechano-enzymatic event that occurs primarily under turbulent flow conditions by exposing the ADAMTS13 to cleavage sites on vWF. We will use three different benchtop blood shearing systems to impart the entire range of shear stress and exposure times likely encountered in severe AS and continuous flow blood pumps and will determine the degradation of the HMWM, specifically focusing on turbulent flows encountered in severe AS and most cf-LVADs in terms of turbulent intensity and exposure time.