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Patients on continuous flow ventricular assist devices (CF-VADs) are at high risk for the development of Acquired von-Willebrand Syndrome (AVWS) and non-surgical bleeding. von Willebrand Factor (vWF) plays an essential role in maintaining hemostasis via platelet binding to the damaged endothelium to facilitate coagulation. In CF-VAD patients, degradation of vWF into low MW multimers that are inefficient in facilitating coagulation occurs and has been primarily attributed to the supraphysiological shear stress associated with the CF-VAD impeller. Methods In this review, we evaluate information from the literature regarding the unraveling behavior of surface-immobilized vWF under pulsatile and continuous flow pertaining to: (A) the process of arterial endothelial vWF production and release into circulation, (B) the critical shear stress required to unravel surface bound versus soluble vWF which leads to degradation, and (C) the role of pulsatility in on the production and degradation of vWF. Results and Conclusion Taken together, these data suggests that the loss of pulsatility and its impact on arterial endothelial cells plays an important role in the production, release, unraveling, and proteolytic degradation of vWF into low MW multimers, contributing to the development of AVWS. Restoration of pulsatility can potentially mitigate this issue by preventing AVWS and minimizing the risk of non-surgical bleeding.
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Effect of pulsatility on shear‐induced extensional behavior of Von Willebrand factor
Abstract BackgroundPatients 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. MethodsvWF 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. ResultsUnravelling of vWF (total sample sizen ~ 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. ConclusionsPulsatile 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.
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- Award ID(s):
- 2004475
- PAR ID:
- 10446025
- Publisher / Repository:
- Wiley-Blackwell
- Date Published:
- Journal Name:
- Artificial Organs
- Volume:
- 46
- Issue:
- 5
- ISSN:
- 0160-564X
- Page Range / eLocation ID:
- p. 887-898
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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