Abstract
Mucosal bleeding is a common complication in patients on left ventricular assist device (LVAD) support and often originates at sites of angiodysplasia. LVAD-induced bleeding has been attributed to the loss of large von Willebrand factor (VWF) multimers due to excessive proteolysis; however, this tentative mechanism is not fully supported by clinical and research observations. We have previously shown that phosphatidylserine (PS)-expressing extracellular membrane vesicles (EMVs) are associated with adverse events in LVAD patients. In this study, we used an unbiased proteomic approach to identify EMV-derived molecules associated with LVAD-induced hemostatic complications and studied their role in systemic coagulation dysregulation in vitro and in mouse model. Levels of hemopexin on red blood cell (RBC)-derived EMVs in samples collected 3 months post-LVAD differentiated between patients with bleeding, thrombosis, or uncomplicated assessed 6 months post-LVAD. Furthermore, we detected a subset of deformed RBCs in these patients that were smaller, denser, and less granular than normal RBCs and were prone to hemolysis. The proportion of deformed RBCs increased from 15.3% at baseline to 46.8% after LVAD implantation. These deformed RBCs extensively expressed PS, making them highly procoagulant in vitro and in mice. We found that the mechanosensitive ion channel Piezo1 mediated this RBC deformation and microvesiculation under high shear stress. We further demonstrated that hemolysis and RBC-mediated procoagulant activity contribute to the systemic consumptive coagulopathy that develops after LVAD implantation.