Effect of pulsatility on shear‐induced extensional behavior of Von Willebrand factor

Abstract

Background: Patients with continuous flow ventricular assist devices (CF-VADs) are at high risk for non-surgical bleeding, speculated to associate with the loss of pulsatility following CF-VAD placement. It has been hypothesized that continuous shear stress causes elongation and increased enzymatic degradation of von Willebrand Factor (vWF), a key player in thrombus formation at sites of vascular damage. However, the role of loss of pulsatility on the unravelling behavior of vWF has not been widely explored.Methods: vWF molecules were immobilized on the surface of microfluidic devices and subjected to various pulsatile flow profiles, including continuous flow and pulsatile flow of different magnitudes, dQ/dt (i.e., first derivative of flow rate) of pulsatility and pulse frequencies to mimic in vivo shear flow environments with and without CF-VAD support. VWF elongation was observed using total internal reflection fluorescence (TIRF) microscopy. Besides, the vWF level is measured from the patients' blood sample before and after CF-VAD implantation from a clinical perspective. To our knowledge, this work is the first in providing direct, visual observation of single vWF molecule extension under controlled-pulsatile shear flow. Results: Unravelling of vWF (total sample size n ~ 200 molecules) is significantly reduced under pulsatile flow (p < 0.01) compared to continuous flow. An increase in the magnitude of pulsatility further reduces unravelling lengths, while lower frequency of pulsatility (20 vs. 60 pulses per min) does not have a major effect on the maximum or minimum unravelling lengths. Evaluation of CF-VAD patient blood samples (n = 13) demonstrates that vWF levels decreased by ~40% following CF-VAD placement (p < 0.01), which correlates to single-molecule observations from a clinical point of view. Conclusions: Pulsatile flow reduces unfolding of vWF compared to continuous flow and a lower pulse frequency of 20 pulses/minute yielded comparable vWF unfolding to 60 pulses/minute. These findings could shed light on non-surgical bleeding associated with the loss of pulsatility following CF-VAD placement.

Gastrointestinal bleeding in patients with continuous‐flow left ventricular assist devices: A comprehensive review

“…The magnitude of VWF degradation has been shown modulated by the pulsatility of the CF‐LVAD, generating the hypothesis of pulsatility preservation as a new target to improve clinical outcomes of patients. The role of pulsatility has been an ongoing discussion as maintenance of a certain level of pulsatility contributes toward decreased GIB incidence 22–25,78–80 . Further longitudinal studies possibly using artificial intelligence algorithms are needed for better risk stratification.…”

“…The role of pulsatility has been an ongoing discussion as maintenance of a certain level of pulsatility contributes toward decreased GIB incidence. [22][23][24][25][78][79][80] Further longitudinal studies possibly using artificial intelligence algorithms are needed for better risk stratification. This review summarizes the most recent literature and differs from existing reviews and systematic reviews in that it is focused on the overall management with a suggested algorithm which includes pump speed adjustments.…”

“…High sheer stress and enzymatic breakdown from the enzyme ADAMTS‐13 cause pathological degradation of von Willebrand factor multimers creating dysfunctional low molecular weight fragments. The dysfunctional fragments lose their ability to bind platelets, leading to aVWS 21–25 . The aVWS may affect endothelial cell proliferation and cause abnormal angiogenesis via angiopoietin‐2 and vascular endothelial growth factor (VEGF) signaling, promoting angiodysplasia formation and an increased risk of bleeding.…”

“…The dysfunctional fragments lose their ability to bind platelets, leading to aVWS. [21][22][23][24][25] The aVWS may affect endothelial cell proliferation and cause abnormal angiogenesis via angiopoietin-2 and vascular endothelial growth factor (VEGF) signaling, promoting angiodysplasia formation and an increased risk of bleeding. Meyer et al 26 demonstrated that vWF multimer numbers were correct after the removal of the device suggesting a role for the presence of the device.…”

Vascular Function in Continuous Flow LVADs: Implications for Clinical Practice

“…VWF deficiency in the context of CF-LVAD occurs either through pump shear-induced VWF activation with subsequent exposure of the ADAMTS-13 cleavage site for enzymatic degradation or by shear stress-induced fragmentation of VWF into dysfunctional small fragments, independent of ADAMTS-13 [ 4 , 31 , 32 , 33 , 34 ]. The net effect of decreased production and increased degradation of VWF culminates in diminished VWF-dependent platelet aggregation.…”