Impact Of Diminished Pulsatility On Unravelling Of Von Willebrand Factor (VWF) In Patients With Continuous Flow Ventricular Assisted Devices (CF-VADs)

Introduction: Patients implanted with Continuous Flow Ventricular Assisted Devices (CF VADs) exhibit diminished pulsatility and are at a high risk for developing acquired von Willebrand Factor syndrome (AVWS) and non-surgical bleeding. This study aimed to understand how diminished pulsatility due to CF VAD impacts unravelling and patient plasma levels of von Willebrand Factor (vWF). A microfluidic approach was used to study unravelling of vWF under normal pulsatile flow and flow with diminished pulsatility. In addition, vWF levels in CF-VAD patients was measured to determine vWF levels in circulation. Hypothesis: We hypothesized that diminished pulsatility increases vWF unravelling, likely leading to increased vWF degradation and elevated levels of low MW vWF fragments in circulation, this in turn leads to decreased endothelial vWF production in CF-VAD patients. Methods: vWF molecules were immobilized in a microfluidic device and subjected to either normal pulsatile flow or flow with diminished pulsatility (same mean flow). vWF unravelling behavior was observed using total internal reflection fluorescence (TIRF) microscopy. Patient blood samples were collected 1-2 days pre CF-VAD implant and monthly post-implant. Patient plasma vWF levels were measured using an ELISA kit. Results: TIRF imaging showed that vWF molecules undergo unravelling and significantly greater elongation (p<0.05) under diminished pulsatility than with normal physiological pulsatility, despite higher levels of peak shear rates with normal pulsatility ( Fig.1A ). Evaluation of plasma vWF levels in patients (n=9) showed that vWF levels decreased progressively following CF-VAD placement ( Fig.1B ). These results suggest that diminished pulsatility increased unravelling of vWF and exposure of ADAMTS13 binding sites, potentially leading to enhanced cleavage of vWF into low molecular weight (MW) multimers. Review of literature suggests that both low MW multimers and diminished pulsatility cause endothelial dysfunction and decreased endothelial vWF production, which was evident in patient samples. Conclusion: Diminished pulsatility may independently promote vWF degradation and lead to decreased production of vWF, thus contributing to AVWS.