Extensional flow-induced transitions from a compact to an unfolded conformation are explored for the human glycoprotein von Willebrand factor (vWF). Multimer unfolding is a crucial step in the process of blood clotting and protein size maintenance. Previous studies have shown that flow-induced conformational transitions are initiated by a thermally nucleated polymeric protrusion. Below a certain strain rate, such a transition is a rare event that cannot be studied using standard stochastic dynamic simulation. In the present study, we have employed Weighted Ensemble Brownian dynamic (WEBD) simulations to study rare events of conformation transition in extensional flow. Results are presented for the transition rate of VWF multimer unfolding, with concomitant analysis of the likelihood of pathological unfolding as a function of strain rate. Relative to the typical half-life of vWF proteins in the human body, results here indicate that pathological unfolding would not manifest for strain rate less than 2000 s−1.Statement of SignificancevWF multimers, as they transit through the circulation, are exposed to extensional flow multiple times, and the total exposure time to such intermittent extensional flow can be on the order of minutes to an hour. However, due to the time-scale limitation of Brownian dynamics simulation, all the present studies of vWF multimers are limited to a few seconds in total duration. Here, we have applied an enhanced sampling technique, i.e., Weighted Ensemble, in combination with Brownian dynamics to analyze the behavior of multimers in extensional flow at physiologically relevant time-scales of hours and longer. The findings presented here provide new physical insights into vWF behavior, including how it relates to hematological pathology, while also illustrating the time-scale bridging capability of the WEBD method.