Pathologic von Willebrand factor degradation is a major contributor to left ventricular assist device-associated bleeding: pathophysiology and evolving clinical management

Bartoli, Carlo

doi:10.21037/acs-2020-cfmcs-29

Cited by 7 publications

(5 citation statements)

References 13 publications

(33 reference statements)

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“…10,11 However, none of these conventional treatment strategies target the molecular mechanism (i.e., excessive degradation of VWF by ADAMTS13) that could be responsible for the bleeding. 46 Our data show that targeting ADAMTS13 using an inhibitory anti-ADAMTS13 mAb is a successful strategy to prevent aVWS in in vitro MCS devices and reverse aVWS in a preclinical Impella-induced aVWS calf model. These data further underline the idea that the main cause of VWF degradation in LVADs is increased VWF proteolysis of VWF by ADAMTS13 rather than shear-induced mechanical destruction of VWF or clearance of VWFplatelet complexes, as previously suggested.…”

Section: Discussionmentioning

confidence: 71%

“…Nowadays, treatment of gastrointestinal bleedings in LVAD patients relies on endoscopic intervention or downshifting of antithrombotic therapy or a reduction in pump speed 10,11 . However, none of these conventional treatment strategies target the molecular mechanism (i.e., excessive degradation of VWF by ADAMTS13) that could be responsible for the bleeding 46 . Our data show that targeting ADAMTS13 using an inhibitory anti‐ADAMTS13 mAb is a successful strategy to prevent aVWS in in vitro MCS devices and reverse aVWS in a preclinical Impella‐induced aVWS calf model.…”

Section: Discussionmentioning

confidence: 99%

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ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation

Deconinck

Nix

Barth

et al. 2022

Journal of Thrombosis and Haemostasis

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Background Acquired von Willebrand syndrome (aVWS) is common in patients with mechanical circulatory support (MCS) devices. In these patients, the high shear stress in the device leads to increased shear‐induced proteolysis of von Willebrand factor (VWF) by A Disintegrin And Metalloprotease with Thrombospondin type 1 repeats, number 13 (ADAMTS13). As a result, the high molecular weight (HMW) VWF multimers are lost, leading to a decreased VWF function and impaired hemostasis that could explain the bleeding complications that are frequently observed in these patients. To counteract this abnormal VWF degradation by ADAMTS13, we developed a novel targeted therapy, using an anti‐ADAMTS13 monoclonal antibody (mAb) that inhibits the shear‐induced proteolysis of VWF by ADAMTS13. Methods Human or bovine blood was circulated through in vitro MCS device systems with either inhibitory anti‐ADAMTS13 mAb 3H9 or 17C7 (20 μg/ml) or control anti‐ADAMTS13 mAb 5C11 or phosphate buffered saline (PBS). VWF multimers and function (collagen binding activity) were determined at different time points. Next, Impella pumps were implanted in calves and the calves were injected with PBS and subsequently treated with mAb 17C7. VWF, ADAMTS13, and blood parameters were determined. Results We demonstrated that blocking ADAMTS13 could prevent the loss of HMW VWF multimers in in vitro MCS device systems. Importantly, our antibody could reverse aVWS in a preclinical Impella‐induced aVWS calf model. Conclusion Hence, inhibition of ADAMTS13 could become a novel therapeutic strategy to manage aVWS in MCS device patients.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation

Deconinck

Nix

Barth

et al. 2022

Journal of Thrombosis and Haemostasis

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“…4 Bartoli al. 4,44 distinguished the major- ( i.e ., mechanoenzymatic) and the minor destructive mechanism ( i.e ., nonenzymatic; high laminar-/turbulent viscous shear stress alone) by using polyacrylamide gel electrophoresis for degradation fragments to characterize not only the degradation quantities that are being generated but also the sizes; depending on the size of the fragment, it can be understood whether it is ADAMTS13-mediated degradation or mechanistic-mediated ripping of multimers apart that are awaiting for our future study.…”

Section: Discussionmentioning

confidence: 99%

Kinetic and Dynamic Effects on Degradation of von Willebrand Factor

Jhun

Siedlecki

et al. 2022

ASAIO Journal

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The loss of high molecular weight multimers (HMWM) of von Willebrand factor (vWF) in aortic stenosis (AS) and continuous-flow left ventricular assist devices (cf-LVADs) is believed to be associated with high turbulent blood shear. The objective of this study is to understand the degradation mechanism of HMWM in terms of exposure time (kinetic) and flow regime (dynamics) within clinically relevant pathophysiologic conditions. A custom high-shear rotary device capable of creating fully controlled exposure times and flows was used. The system was set so that human platelet-poor plasma flowed through at 1.75 ml/sec, 0.76 ml/sec, or 0.38 ml/sec resulting in the exposure time (texp) of 22, 50, or 100 ms, respectively. The flow was characterized by the Reynolds number (Re). The device was run under laminar (Re = 1,500), transitional (Re = 3,000; Re = 3,500), and turbulent (Re = 4,500) conditions at a given texp followed by multimer analysis. No degradation was observed at laminar flow at all given texp. Degradation of HMWM at a given texp increases with the Re. Re (p < 0.0001) and texp (p = 0.0034) are significant factors in the degradation of HMWM. Interaction between Re and texp, however, is not always significant (p = 0.73).

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“…11 Quantitative evaluation of vWF multimers shows that CF-VAD patients often display a significant reduction in plasma vWF levels, and increased vWF degradation. 12 While decreased circulating high MW vWF multimers does not always lead to GI bleeding, patients experiencing GI bleeds have significantly lower levels of vWF. 9 The requisite anticoagulation therapy CF-VAD patients undergo complicates this pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

“…In AVWS, the large globular plasma glycoprotein vWF, which plays a critical role in facilitating coagulation through platelet adhesion, undergoes cleavage into low molecular weight (MW) multimers, which bind poorly to platelets and sub‐endothelial collagen 11 . Quantitative evaluation of vWF multimers shows that CF‐VAD patients often display a significant reduction in plasma vWF levels, and increased vWF degradation 12 . While decreased circulating high MW vWF multimers does not always lead to GI bleeding, patients experiencing GI bleeds have significantly lower levels of vWF 9 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Pathologic von Willebrand factor degradation is a major contributor to left ventricular assist device-associated bleeding: pathophysiology and evolving clinical management

Cited by 7 publications

References 13 publications

ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation

ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation

Kinetic and Dynamic Effects on Degradation of von Willebrand Factor

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

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