title: Mechanistic pathway(s) of acquired von willebrand syndrome with a continuous-flow ventricular assist device: in vitro findings.
abstract: In patients with a ventricular assist device (VAD), diminished high-molecular-weight von Willebrand factor (vWF) multimers may contribute to a bleeding diathesis. The mechanistic pathway(s) of vWF degradation and the role of ADAMTS-13, the vWF-cleaving metalloproteinase, are unknown. The objective of this study was to investigate the molecular mechanisms of VAD-induced vWF impairment in an in vitro system.Simple, mock circulatory loops (n = 4) were developed with a clinically approved, paracorporeal continuous-flow VAD. The loops were primed with anticoagulated, whole bovine blood (750 ml). The VAD was operated at constant blood flow and pressure. Blood samples were drawn at baseline and hourly for 6 hours. vWF multimers and ADAMTS-13 protein were quantified by agarose and polyacrylamide gel electrophoresis with immunoblotting. Plasma platelet factor 4 (PF4), a marker of platelet activation, was quantified via ELISA.Within 120 minutes, high-molecular-weight vWF multimers decreased, and low-molecular-weight multimers increased. Multiple low-molecular-weight vWF fragments emerged (~140, 176, 225, and 310 kDa). Total plasma ADAMTS-13 increased by 13 ± 3% (p < 0.05). Plasma PF4 increased by 21 ± 7% (p = 0.05).During VAD support, vWF degradation occurred quickly. Multiple mechanisms were responsible and included vWF cleavage by ADAMTS-13 (140 and 176 kDa fragments), and what may have been mechanical demolition of endogenous plasma vWF (225 kDa fragments) and nascent vWF (225 and 310 kDa fragments) from platelets. A modest increase in plasma ADAMTS-13 from activated platelets may have contributed to this process but was not the major mechanism. Mechanical demolition was likely the dominant process and warrants further evaluation.
authors: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors: Sujith
authors: S
authors: Dassanayaka
authors: Mark S
authors: MS
authors: Slaughter
authors: Carlo R
authors: CR
authors: Bartoli
mesh_terms: D051722:ADAM Proteins / Q000097:blood / Q000502:physiology; D000071120:ADAMTS13 Protein; D000818:Animals; D002417:Cattle; D006353:Heart-Assist Devices; D008970:Molecular Weight; D010978:Platelet Factor 4 / Q000097:blood; D033081:Shear Strength; D014842:von Willebrand Diseases / Q000097:blood* / Q000601:surgery; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D014841:von Willebrand Factor; D010978:Platelet Factor 4; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human