Search

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. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Autoantibodies to ADAMTS13 have a pivotal role in the pathogenesis of acquired thrombotic thrombocytopenic purpura (TTP). By decreasing the function of ADAMTS13, autoantibodies impair the cleavage of ultra-large von Willebrand factor (UL-VWF) multimers into smaller sizes, leading to lethal platelet-VWF thrombi in the microcirculation. We therefore aimed to determine the sites of autoantibody recognition on ADAMTS13. Materials and Methods: In this study, IgG purified from 13 acquired TTP patients were examined to determine their binding sites on ADAMTS13. Immobilized IgG on microtiter plate or proteinG beads was screened by phage library expressing various peptides of ADAMTS13. Results: In screening, diverse peptide sequences were obtained from almost all of the ADAMTS13 domains, including the spacer domain, which is considered a major binding site. In particular, we detected an identical amino-acid sequence in the C-terminus of the spacer domain from Gly662 to Val687 that was recognized by autoantibodies from 5 TTP patients. The specific autoantibody was expected to be associated with the plasma levels of the ADAMTS13 antigen or activity, and with the quantity of ADAMTS13 autoantibodies or the inhibitory autoantibody titer in TTP patient plasma. These measurements, however, did not seem to be related to the presence or absence of the specific autoantibody. Conclusions: These findings indicate that the specific autoantibody might be a feature of acquired TTP, although its clinical significance remains to be elucidated. [Copyright &y& Elsevier]

Abstract: Introduction: Thrombotic microangiopathy (TMA) is a complication occurring after liver transplantation (LT), and an unusually large multimer (ULM) of Von Willebrand factor (VWF) and ADAMTS13 may play an important role in the onset of TMA during LT. Material and Methods: Eight-one patients underwent living donor LT (LDLT). Seventeen of those patients had both severe thrombocytopenia and hemolytic anemia with fragmented red cells and were diagnosed as TMA- like syndrome (TMALS). Results and Conclusions: A significant reduction of ADAMTS13 and an increase of VWF were observed in the patients with TMALS. The ADAMTS13 activity in patients after LDLT was significantly reduced from day 1 to day 21, and it was significantly low in those with TMALS at day 14 and 28. The VWF levels in patients with LDLT were significantly high, and the VWF/ADAMTS13 ratio was significantly increased in patients at 7, 14 and 28 days after LDLT, especially in patients with TMALS at day 14 and 28 after LDLT. High molecular weight multimers of VWF were observed to have increased in patients with LDLT, and the high molecular weight multimers of VWF were further increased in those with mild TMALS but they decreased in those with severe TMA. These findings suggest that ULM- VWF and ADAMTS13 might be associated with the onset of TMA after LT. [Copyright &y& Elsevier]

Abstract: The ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I domain 13) activity was measured by a fluorescence resonance energy transfer (FRET) assay in the plasma of healthy volunteers and thrombotic thrombocytopenic purpura (TTP) patients to examine its usefulness in the diagnosis of TTP. The plasma levels of the ADAMTS13 activity did not show a normal distribution. Its median value was 107% (range: 55–170%) in healthy volunteers, but was significantly lower in patients with TTP (acquired or familial) and in patients with hematopoietic stem cell transplantation. However, it was not significantly lower in patients with antiphospholipid syndrome (APS). The ADAMTS13 activity by a FRET assay was closely correlated with that by the ADAMTS13 multimer method (r =0.816; p <0.001). In 18 patients with less than 10% of ADAMTS13 activity by FRET assay, less than 10% of that by multimer assay was 16, thus suggesting a good correlation for a low level of ADAMTS13. These findings suggest that the ADAMTS13 FRET assay correlates well with the ADAMTS13 multimer method and it is therefore useful for making a diagnosis of TTP. [Copyright &y& Elsevier]