title: Insights into the mechanism(s) of von Willebrand factor degradation during mechanical circulatory support.
abstract: OBJECTIVE
  Left ventricular assist device support produces a bleeding diathesis. Evidence suggests a major role for von Willebrand factor (vWF). We examined vWF metabolism in a preclinical model of short-term mechanical circulatory support.
  
  
  METHODS
  In 25 calves (weight, 80-110 kg), the inflow/outflow graft of the Symphony Heart Assist System was sewn end-to-side to the carotid artery. Support was initiated (acute, n = 4; 1 week, n = 16; 2 weeks, n = 5). Acutely, carotid artery pressure and flow were measured to evaluate the hemodynamic changes near the anastomosis. At baseline and after ≤2 weeks of support, platelet aggregometry with adenosine 5'-diphosphate, collagen, and ristocetin was performed. Gel electrophoresis and wet immunoblotting qualitatively evaluated vWF multimers and quantified plasma ADAMTS-13, the vWF-cleaving protease. Carotid arterial rings near the anastomosis were studied with immunohistochemical staining for ADAMTS-13 and were cultured to quantify endothelial ADAMTS-13 production. Fluorescent resonance energy transfer was used to evaluate the enzymatic activity of ADAMTS-13 in the plasma and in supernatant from cultured carotid arterial rings. Plasma interleukin-6, which inhibits ADAMTS-13 activity, was measured using an enzyme-linked immunosorbent assay.
  
  
  RESULTS
  During support, statistically significant (P < .05) changes in the carotid endothelium arterial hemodynamics were observed. The highest molecular weight vWF multimers were absent, and the vWF-ristocetin platelet aggregation pathway was significantly impaired. A modest but significant increase in plasma ADAMTS-13 protein and activity was observed. ADAMTS-13 decreased significantly in the carotid near the anastomosis but increased significantly in supernatant from cultured carotid arterial rings. The plasma interleukin-6 levels did not change significantly.
  
  
  CONCLUSIONS
  Hemodynamic activation of vWF and increased plasma ADAMTS-13 activity may have reduced high-molecular-weight vWF multimers and thereby impaired the vWF-platelet aggregation pathway. Additional delineation of these pathways may improve management of left ventricular assist device-associated bleeding.
authors.affiliation: Division of Cardiovascular Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pa; MD/PhD Program, University of Louisville School of Medicine, Louisville, Ky.
authors.forename: Carlo R
authors.initials: CR
authors.lastname: Bartoli
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, Ky; Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, Ky.
authors.forename: Sujith
authors.initials: S
authors.lastname: Dassanayaka
authors.affiliation: Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, Ky.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Brittian
authors.affiliation: University of Louisville School of Medicine, Louisville, Ky.
authors.forename: Andrew
authors.initials: A
authors.lastname: Luckett
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Ky.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Sithu
authors.affiliation: Abiomed Inc, Danvers, Mass.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Siess
authors.affiliation: Abiomed Inc, Danvers, Mass.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Raess
authors.affiliation: SCR Inc, Louisville, Ky.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Spence
authors.affiliation: Cardiovascular Innovation Institute, University of Louisville School of Medicine, Louisville, Ky; Department of Bioengineering, University of Louisville, Louisville, Ky.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Koenig
authors.affiliation: Dowling Consulting, PSC, Louisville, Ky.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Dowling
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Ky. Electronic address: sedsou01@louisville.edu.
authors.forename: Stanley E
authors.initials: SE
authors.lastname: D'Souza
mesh_terms: D051722:ADAM Proteins / Q000097:blood; D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism / Q000601:surgery*; D002417:Cattle; D042783:Endothelial Cells / Q000378:metabolism; D006353:Heart-Assist Devices / Q000009:adverse effects; D006439:Hemodynamics; D006470:Hemorrhage / Q000097:blood / Q000209:etiology; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D023421:Models, Animal; D008970:Molecular Weight; D010974:Platelet Aggregation; D010979:Platelet Function Tests; D011474:Prosthesis Design; D013997:Time Factors; D046509:Tissue Culture Techniques; D016277:Ventricular Function, Left; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D014841:von Willebrand Factor; D051722:ADAM Proteins