Clinical and In Vitro Evidence That Left Ventricular Assist Device–Induced von Willebrand Factor Degradation Alters Angiogenesis

Abstract

Background Gastrointestinal bleeding from angiodysplasia is a major problem in continuous-flow left ventricular assist device (LVAD) patients. LVAD shear stress causes pathologic degradation of VWF (von Willebrand factor). A mechanistic relationship between VWF degradation and angiodysplasia has not been explored. We tested 2 novel hypotheses: (1) clinical hypothesis: VWF fragments are elevated in LVAD patients that develop angiodysplasia and (2) in vitro hypothesis: VWF fragments generated during LVAD support alter angiogenesis, which may contribute to angiodysplasia. Methods and Results Clinical study: Paired blood samples were collected from continuous-flow LVAD patients (n=35). VWF was quantified with immunoblotting. In vitro experiments: (1) To investigate whether LVAD support alters angiogenesis, human endothelial cells were cultured with LVAD patient plasma (n=11). To investigate mechanism, endothelial cells were cultured with VWF fragments produced by exposing human VWF and ADAMTS-13 (VWF protease) to LVAD-like shear stress (175 dyne/cm 2 , n=8). Clinical study results: in all patients (n=35, mean support 666±430 days), LVAD support degraded high-molecular-weight VWF multimers ( P <0.0001) into low-molecular-weight VWF multimers ( P <0.0001) and VWF fragments ( P <0.0001). In patients with gastrointestinal bleeding from angiodysplasia (n=7), VWF fragments were elevated ( P =0.02) versus nonbleeders. In contrast, in patients with gastrointestinal bleeding without angiodysplasia, VWF fragments were not elevated versus nonbleeders ( P =0.96). In vitro experiments results: LVAD patient plasma caused abnormal angiogenesis with reduced tubule length ( P =0.04) and migration ( P =0.05). Similarly, endothelial cells grown with VWF degradation fragments exhibited reduced tubule length ( P <0.001) and migration ( P =0.01). Conclusions LVAD patients who bled from angiodysplasia had higher levels of VWF fragments than nonbleeders and gastrointestinal bleeders without angiodysplasia. VWF fragments caused abnormal angiogenesis in vitro. These findings suggest that VWF fragments may be a mechanistic link between LVAD support, abnormal angiogenesis, angiodysplasia, and gastrointestinal bleeding.

Bionic women and men ‐ Part 1: Cardiovascular lessons from heart failure patients implanted with left ventricular assist devices

“…The necessary anti-coagulation regimen may contribute to gastrointestinal (GI) bleeding as well as the development of angiodysplasia, although the latter may originate already in heart failure and only manifest itself in GI bleeding during LVAD support (Patel et al, 2018). Additionally, degradation of the von Willebrand factor, which typically 'mediates platelet adhesion to both the subendothelial matrix and endothelial surfaces and acts as a carrier for coagulation factor VIII in the circulation' (Starke et al, 2011) has been widely reported in LVAD patients (Bartoli et al, 2014(Bartoli et al, , 2018Nascimbene, Neelamegham, Frazier, Moake, & Dong, 2016). This has been largely attributed to the altered conformation of the high molecular mass multimers caused during the passage of blood through the bearings of the mechanical pumps and may be an important contributor to the increased prevalence of GI bleeding as well as microcirculatory bleeds in the brain of continuous-flow, second generation LVAD patients (Yoshioka et al, 2017).…”

The “double whammy” of a continuous-flow left ventricular assist device on von Willebrand factor

“…In combination, these observations describe the multifactorial competing mechanisms that create the considerable challenge of managing the balance between nonsurgical bleeding and thrombotic events in CF-LVAD recipients. Improving our understanding of the nuances associated with the physiologic pathways and mechanisms of action that link vWF, pulsatility, and pump shear to clotting disorders, as well as likely contributors to angiodysplasia such as low-molecular-weight vWF multimers 17 and reduced omega-3 fatty acid intake, 18 will help advance the efforts to promote the clinical optimization of CF-LVAD therapies. To provide further information regarding the potential interaction between reduced arterial pulsatility and pump shear, studies looking specifically at vWF or GIB in patients with heart failure implanted with a mechanical circulatory support system were included: LVAD pumps: HeartMate II (Abbott, Chicago, Ill); HeartMate3, HeartWare HVAD (HeartWare Inc, Framingham, Mass), EVAHEART (EVAHEART Inc, Houston, Tex); and 2 total artificial heart devices: CardioWest (SynCardia Systems, Tucson, Ariz) and CARMAT (V elizy-Villacoublay, France).…”

Commentary: Alive without a pulse and bleeding

“…Although gastrointestinal bleeding in these patients is undoubtedly multifactorial, we would like to highlight a recently identified mechanism that further links vWF deficiency to gastrointestinal bleeding. 6 The imbalance between vWF multimers (low) and vWF degradation fragments (high) may stimulate angiogenesis through a direct proangiogenic effect. In a recent study, Bartoli and associates 6 demonstrated that patients with continuous-flow LVAD support who had angiodysplasias and gastrointestinal bleeding had lower levels of vWF multimers and higher levels of vWF degradation fragments.…”

“…This proangiogenic mechanism of vWF degradation fragments may be the factor linking shear stress, lack of pulsatility, angiodysplasias, and gastrointestinal bleeding. [6][7][8] Acquired vWF deficiency and gastrointestinal bleeding are not unique to patients receiving continuous-flow LVAD support. These conditions have also been described in patients with valvular heart disease (aortic and mitral stenosis, regurgitant valve lesions, and structural and nonstructural valve deterioration), congenital heart disease, and pulmonary hypertension.…”