Hyperadhesive von Willebrand Factor Promotes Extracellular Vesicle-Induced Angiogenesis: Implication for LVAD-Induced Bleeding

Mengchen Yang; Katie L Houck; Xinlong Dong; Maria Hernandez; Yi Wang; Sriram S Nathan; Xiaoping Wu; Vahid Afshar-Kharghan; Xiaoyun Fu; Miguel A Cruz; Jianning Zhang; Angelo Nascimbene; Jing-Fei Dong

doi:10.1016/j.jacbts.2021.12.005

Hyperadhesive von Willebrand Factor Promotes Extracellular Vesicle-Induced Angiogenesis: Implication for LVAD-Induced Bleeding

JACC Basic Transl Sci. 2022 Mar 28;7(3):247-261. doi: 10.1016/j.jacbts.2021.12.005. eCollection 2022 Mar.

Authors

Mengchen Yang^{1

2}, Katie L Houck¹, Xinlong Dong¹, Maria Hernandez³, Yi Wang¹, Sriram S Nathan³, Xiaoping Wu⁴, Vahid Afshar-Kharghan⁵, Xiaoyun Fu¹, Miguel A Cruz^{6

7}, Jianning Zhang⁸, Angelo Nascimbene³, Jing-Fei Dong^{1

9}

Affiliations

¹ Bloodworks Research Institute, Seattle, Washington, USA.
² Department of Urology, Tianjin Medical University General Hospital, Tianjin, China.
³ Center for Advanced Heart Failure, University of Texas at Houston, Houston, Texas, USA.
⁴ Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA.
⁵ Division of Internal Medicine, Department of Pulmonary Medicine, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.
⁶ Cardiovascular Research Section, Department of Medicine, Baylor College of Medicine.
⁷ Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey VA Medical Center, Houston, Texas, USA.
⁸ Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.
⁹ Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.

Abstract

Bleeding associated with left ventricular assist device (LVAD) implantation has been attributed to the loss of large von Willebrand factor (VWF) multimers to excessive cleavage by ADAMTS-13, but this mechanism is not fully supported by the current evidence. We analyzed VWF reactivity in longitudinal samples from LVAD patients and studied normal VWF and platelets exposed to high shear stress to show that VWF became hyperadhesive in LVAD patients to induce platelet microvesiculation. Platelet microvesicles activated endothelial cells, induced vascular permeability, and promoted angiogenesis in a VWF-dependent manner. Our findings suggest that LVAD-driven high shear stress primarily activates VWF, rather than inducing cleavage in the majority of patients.

Keywords: ADAMTS-13:Ag, ADAMTS-13 antigen; AVS, aortic vascular segment; EC, endothelial cell; EV, extracellular vesicle; EVFP, extracellular vesicle–free plasma; GI, gastrointestinal; GOF, gain of function; GP, glycoprotein; GPM, growth factor-poor medium; GRM, growth factor-rich medium; HSS, high shear stress; LVAD, left ventricular assist device; PS, phosphatidylserine; SIPA, shear-induced platelet aggregation; ULVWF, ultra-large von Willebrand factor; VEGF, vascular endothelial growth factor; VWF, von Willebrand factor; VWF:Ag, von Willebrand factor antigen; VWF:CB, von Willebrand factor binding to collagen; VWF:pp, von Willebrand factor propeptide; aVWS, acquired von Willebrand syndrome; angiogenesis; extracellular vesicles; left ventricular assist devices; pEV, extracellular vesicle from von Willebrand factor-activated platelets; platelets; shear stress; von Willebrand factor.