EXPLORING THE SHEAR-AND-TIME DEPENDENT DEGRADATION OF VON WILLEBRAND FACTOR UNDER VENTRICULAR ASSIST DEVICE-RELATED FLOW CONDITIONS
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Abnormalities in VWF can cause impaired blood coagulation which results in higher bleeding tendency in patients with this disorder. Alteration in VWF is characteristic in ventricular assist devices (VADs) implanted subjects with failing hearts. The nature of the abnormalities produced and the conditions which produce such abnormalities are not fully understood. The studies in this thesis investigate quantitatively the effects of VADs and VAD-related flow conditions on VWF degradation. This thesis consists of three studies: 1) an in vitro VAD loop study in which was investigated the degradation effects of three VADs either under preclinical development (VAD I) or being commercially available (VAD II & III); 2) a viscometer shear study in which was investigated a variety of factors under the controlled condition of a modified Couette viscometer, namely, shear stress, exposure time, pulsatile frequency and protease function, with respect to VWF degradation 3) a tubular shear study in which was investigated the relative degradation effects of shear stress versus exposure time under more VAD-related shear stresses (10 - 100 times higher than physiological levels) and exposure times of miliseconds. In the VAD flow loop, significant VWF degradation induced by VADs wee observed with an approximately 95% loss of high molecular weight VWF by 60 minutes. In the viscometer and the tubular studies, the factors studied enhanced VWF degradation in the following manner: increased shear stress above physiological levels, prolonged exposure time and higher pulsatile shear frequency were associated with greater degradation; shear stress was a more dominant factor than exposure time with respect to the degradation; and a various shear stress regions demonstrated maximal degradation effects. In addition, calcium-dependent protease function was a necessity for VWF degradation at all shear stress levels investigated. The studies also revealed that the unfolding of VWF to expose the cleavage sites appeared to take more time under shear than the refolding to re-cover those sites under static conditions. Critical shear regions may be important for unfolding and degrading VWF multimers of various sizes.