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ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 repeats) is the specific von Willebrand factor (VWF)-cleaving protease. ADAMTS13 was partially purified from human plasma in 1996 and its gene was cloned in 2001. In case of vascular injury, multimeric VWF is the mediator of both platelet adhesion to the sub-endothelium and platelet aggregation within the microvessels at high shear rates of blood flow. ADAMTS13 regulates VWF adhesive capacity by reducing the size of VWF multimers. A severe functional deficiency of ADAMTS13 (activity lower than 10%) is associated with most cases of thrombotic thrombocytopenic purpura (TTP), a thrombotic microangiopathy characterized by the spontaneous formation, within the microcirculation, of VWF-rich platelet thrombi responsible for a mechanical hemolytic anemia, a consumption thrombocytopenia and a multivisceral ishemia. TTP is a rare disease (4 cases/10(6)/year) with a life-threatening prognosis in the absence of an appropriate treatment in emergency (plasmatherapy). In 90% of cases, TTP is acquired and related to the development of auto-antibodies to ADAMTS13. In the other cases, TTP is inherited via bi-allelic autosomic recessive mutations of ADAMTS13 gene (Upshaw-Schulman syndrome). A better characterization of ADAMTS13 structure/function combined to clinical trials led in TTP patients is crucial to evaluate the relevance of either a -plasma-purified or a -recombinant ADAMTS13 as a therapeutic agent., (© 2011 médecine/sciences – Inserm / SRMS.)

Thrombotic thrombocytopenic purpura (TTP) is a severe form of thrombotic microangiopathy (TMA) characterized by systemic platelet clumping, hemolytic anemia, and multiorgan failure. TTP results from a defect in ADAMTS13, a plasma enzyme specifically involved in the cleavage of highly hemostatic unusually large (UL) von Willebrand factor (vWF) multimers into smaller and less adhesive vWF forms. Failure to degrade these UL-vWF multimers leads to excessive platelet aggregation and capillary occlusion. ADAMTS13 deficiency is related to mutations of the encoding gene in hereditary TTP, whereas in acquired forms it results from autoantibodies that may alter the protein function. This latter finding strongly suggests that acquired idiopathic TTP corresponds to an autoimmune disease. Acquired idiopathic TTP appears to be associated with clinical features suggestive of autoimmunity in one third of cases. In two thirds, autoantibodies such as antinuclear antibodies may be observed. This review, based on an analysis of the literature and on French experience with TMA, focuses on the different autoimmune manifestations that may be observed in TTP, as well as the putative pathophysiological link between autoimmune manifestations and TTP.

During the last decade, major progresses have been performed in the understanding and classification of hereditary haemolytic uremic syndromes and thrombotic thrombocytopenic purpura. The identification of patients with congenital thrombotic thrombocytopenic purpura due to hereditary deficiency of von Willebrand factor protease (Adamts 13) is of primordial importance, as fresh frozen plasma infusions prevent relapses and the risk of visceral (mainly cerebral and renal) involvement. The identification of patients with haemolytic uremic syndromes due to mutations in the genes that encode complement alternative pathway regulatory proteins (factor H, factor I, MCP) opens the way to new physiopathologic and therapeutic advances.