Upshaw-Schulman syndrome (USS) is a thrombo-hemorrhagic disease caused by congenital deficiency of ADAMTS13 due to ADAMTS13 gene mutations. USS is characterized by repeated episodes of
thrombocytopenia and
microangiopathic hemolytic anemia that respond dramatically to infusions of fresh frozen plasma. There are two phenotypic expressions of USS: one is the early-onset type and the other, the late-onset type, is asymptomatic during childhood with the first bout of
thrombotic thrombocytopenic purpura (
TTP) developing after adolescence or during adulthood. We found that gravida with the latter phenotype developed
thrombocytopenia and
hemolytic anemia during the second or third trimesters, often followed by
thrombotic microangiopathies (TMAs). These phenomena suggest that elevated plasma
von Willebrand Factor (VWF) might be crucial because plasma levels of VWF
antigen usually increase by 200-500% during this period of gestation. Here, we performed platelet function assays using a mixture of anti-coagulated blood from normal volunteers, human VWF, anti-ADAMTS13
monoclonal antibody A10, and purified plasma-derived ADAMTS13 to investigate the effect of plasma VWF levels on platelet
thrombus formation in the context of deficient ADAMTS13. In vitro studies showed that mural
thrombus formation and platelet aggregation under high shear stress were markedly augmented by increasing the amounts of exogenously added VWF when ADAMTS13 activity was deficient, as may be the case in the in vivo circulation of gravida with USS. These results suggest that highly elevated plasma VWF might accelerate platelet
thrombus formation not only in the circulation but also on the surface of vascular endothelial cells in the setting of ADAMTS13 deficiency in USS.