Contributor: Darien Allen
GI bleeds in continuous-flow left ventricular assist device (CF-LVAD) patients are an increasing problem. Bartoli et al posit a two-hit hypothesis to explain the increased risk of mucosal bleeds in this population:
Hit 1: CF-LVAD-induced shear stress activates von Willebrand factor (VWF) multimers leading to enzymatic and mechanical degradation into variably sized fragments and acquired VWF deficiency. CF-LVAD induced VWF deficiency reduces VWF-collagen and VWF-platelet binding resulting in increased risk of mucosal bleeding.
Hit 2: Higher circulating concentrations of VWF fragments lead to altered angiogenesis and likely contribute to the development of angiodysplasia.
Blood samples collected from CF-LVAD patients were studied.
Clinical Evidence: All CF-LVAD patients demonstrated increases in circulating VWF fragments. 37.1% of the study population developed GI bleeds with endoscopically confirmed angiodysplasia as the most common cause (20%). Patients who developed angiodysplasia demonstrated significantly elevated circulating VWF fragments compared to GI bleeders without angiodysplasia and non-bleeders (p=0.02). There was no significant difference in the concentration of circulating VWF fragments between GI bleeders without angiodysplasia and non-bleeders.
In Vitro Evidence: Using human umbilical vein cultured endothelial cell model, total endothelial tubule length per unit area and endothelial cell migration was examined. Tubule formation was significantly reduced when endothelial cells were co-cultured with VWF fragments compared to intact VWF multimers (p<0.001; p=0.01) and when grown in CF-LVAD patient plasma compared with pre-LVAD patient plasma (p=0.04; p=0.05). These results suggest VWF multimers play a role in normal angiogenesis that is altered by VWF fragmentation.
GI bleeds following CF-LVAD intervention are a cause of significant morbidity and the underlying molecular mechanisms are poorly understood. This work by Bartoli et al suggests a relationship between shear stress induced VWF fragments, bleeding and abnormal angiogenesis that will allow future work to focus on potential therapies targeting the underlying pathology: minimizing LVAD-induced shear stress and preventing VWF multimer fragmentation.
No study is perfect. The study is limited by the small study population (n=35). Also, there was only indirect evidence of VWF fragmentation and GI bleeding — no direct causal analysis was performed.