Acquired von Willebrand syndrome (AvWS) is bleeding disorder that develops de novo in an individual with a negative past personal and family history of bleeding in association with laboratory studies indicative of von Willebrand disease. This diagnosis can be difficult to distinguish from hereditary von Willebrand syndrome, especially in children. Potential mechanisms causing AvWS include decreased protein synthesis, increased proteolysis of mature von Willebrand factor or accelerated clearance of mature vWF(on an immunologic or adsorptive basis). VWF is synthesized in endothelial cells and megakaryocytes as a pre-propolypeptide that undergoes proteolytic cleavage forming the propolypeptide (vWAgII) and mature vWF. These two proteins are immunologically distinct. We hypothesized that since vWAgII has different functional and immunological characteristics from mature vWF, levels of vWAgII should be normal or increased in states of increased vWF clearance or proteolysis. In contrast, levels of vW AgII should parallel those of mature vWF in states of decreased protein synthesis. We studied 24 individuals, 3-79 years of age, referred for evaluation of AvWS. All 24 had reduced levels of vWF antigen, mean 17±3 u/dL. There was a striking difference in vWAgII levels for the 5 individuals with hypothyroidism when compared to all other individuals, mean 55±4 for hypothyroid subjects v. 120±13 u/dL for all other diagnoses (p=.0001). We had previously shown that the ratio of vWF antigen to vWAgII in normal plasma and in plasma from individuals with type 1 von Willebrand disease was unity. This ratio was markedly different between the groups with AvWS, mean vWF/vWAgII for hypothyroid subjects was 0.53±.11 v. 0.14±.04 for other diagnoses (p=.02). In support of the hypothesis that decreased vWF and vWAgII levels in hypothyroidism are secondary to decreased protein synthesis, 4 patients demonstrated normalization of both vWF and vWAgII following thyroid replacement. Although no subject studied had an inhibitor of vWF ristocetin cofactor activity, 3 euthyroid subjects who underwent DDAVP trials demonstrated accelerated clearance of vWF antigen. vWAgII successfully differentiates AvWS caused by decreased synthesis from AvWS due to increased clearance of vWF.