Insights into the Mechanism(s) of von Willebrand Factor Degradation during Mechanical Circulatory Support

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.