Loss of pulsatility with continuous-flow left ventricular assist devices and the significance of the arterial endothelium in von-Willebrand factor production and degradation

Abstract

Background: 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.

Keywords: acquired von Willebrand syndrome; continuous flow; loss of pulsatility; von Willebrand Factor.

Figure 1:

Schematic representation of high MW vWF production and secretion. Transcription (1) and translation (2) of vWF monomers occurs in the nucleus. Dimerization (3) occurs in the endoplasmic reticulum (ER), followed by multimerization in the Golgi. vWF multimers are packaged into Weibel Palade bodies (4), from which vWF is secreted at the cell membrane (5). High MW VWF is cleaved from endothelial cells by ADAMTS-13 (6) leading to circulation (7).

Figure 2:

Shear mediated unravelling behavior of surface bound and free vWF under low, physiological and supraphysiological flow.

Figure 3:

Unravelling and recoiling of surface-bound vWF under pulsatile and continued unravelling of vWF under continuous flow.

Figure 4:. Proposed Mechanism of AVWS development:

Endothelial vWF requires cleavage by ADAMTS13 for vWF release into circulation. Under pulsatile flow, the unraveling is limited, resulting in release of high MW vWF whereas under continuous flow, sustained, unravelling results in exposure of the scissile bond in the A2 domain resulting in ADAMTS13 mediated proteolytic degradation into low MW multimers.