Predicting pathological von Willebrand factor unraveling in elongational flow.

The globular-to-unraveled conformation transition of von Willebrand factor (vWF), a large polymeric glycoprotein in human blood plasma, is a crucial step in the process of clotting at sites of vascular injury. However, unraveling of vWF multimers in uninjured vasculature can lead to pathology (i.e., thrombus formation or degradation of vWF proteins by enzyme ADAMTS13, making them nonfunctional). To identify blood flow conditions that might induce pathological unraveling of vWF multimers, here we have computed the globular-to-unraveled transition rate of vWF multimers subjected to varying strain rate elongational flow by employing an enhanced sampling technique, the weighted ensemble method. Weighted ensemble sampling was employed instead of standard brute-force simulations because pathological blood flow conditions can induce undesired vWF unraveling on timescales potentially inaccessible to standard simulation methods. Results here indicate that brief but periodic exposure of vWF to the elongational flow of strain rate greater than or equal to 2500 s represents a source of possible pathology caused by the undesired unraveling of vWF multimers.