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Acquired von Willebrand Syndrome

Von Willebrand Factor (vWF) plays a key role in both platelet plug and fibrin clot formation. When endothelial damage occurs, vWF multimers bind to exposed subendothelial collagen and to platelets, promoting platelet adhesion and aggregation at the site of injury. Activated platelets initiate the coagulation cascade resulting in the formation of a fibrin clot.

During the past 55 years, many publications have documented the association of aortic stenosis and bleeding from gastrointestinal angiodysplasia. Bleeding associated with aortic stenosis was found to be caused by excessive proteolysis of high molecular weight vWF multimers under conditions of increased shear stress. Aortic valve replacement usually cures GI bleeding due to replenishment of the largest vWF multimers within a few hours.

Bleeding due to defects in vWF structure or function that are not inherited, but are consequences of other medical disorders, has been classified as acquired von Willebrand syndrome (AVWS) to distinguish it from congenital von Willebrand disease (vWD). More recently, excessive bleeding associated with other cardiovascular disorders such as ventricular septal defect, hypertrophic obstructive cardiomyopathy, and placement of left ventricular assist device (LVAD) has also been attributed to development of AVWS.

Development of AvWS and mucosal bleeding may be an additional indication for consideration of surgical correction of the underlying cardiovascular disorder. Laboratory detection of AVWS may provide an additional tool to evaluate the efficacy of surgical management. Unfortunately, the panel of tests recommended to diagnose congenital vWD (vWF antigen, vWF activity and FVIIIc) are usually normal in AVWS. Laboratory confirmation of AVWS requires VWF multimer analysis to detect the loss of high molecular weight multimers. This analysis involves a labor-intensive assay involving separation of vWF multimers by protein electrophoresis and detection of all molecular weight forms by Western Blot. Multimer analysis is only available at a few reference laboratories and has a long turnaround time. Results may not be available in time for clinical decision making.

Another sensitive indicator of impaired vWF function in cardiovascular disorders with high shear stress is the whole blood platelet function screen performed on the PFA-100 analyzer. This assay is very sensitive for detection of vWD and AVWS. Prolonged closure times with both COL/EPI and COL/ADP are typical of either vWD or AVWS. One 5.0 mL sodium citrate (light blue top) tube is required. Sample must be received by the laboratory within 3 hours of collection.

Various transfusion therapies have been tried to treat excessive bleeding associated with these cardiovascular disorders including plasma, desmopressin (DDAVP), aprotinin,  tranexamic acid, aminocaproic acid and recombinant FVIIa (Novoseven). However, none of these products specifically addresses the specific underlying problem. Replacement of loss of high molecular weight vWF can best be achieved by transfusion of cryoprecipitate or a factor concentrate that contains Factor VIII and vWF, such as Humate P.

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