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Thrombotic thrombocytopenic purpura related to an inherited ADAMTS13 deficiency (Upshaw-Schulman syndrome): update and perspectives Volume 11, issue 5, Octobre 2005

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Unité 143 Inserm, 80, rue du Général-Leclerc, Hôpital de Bicêtre, 94276 Le Kremlin-Bicêtre Cedex, Service d’hématologie biologique, hôpital Antoine-Béclère, AP-HP, Clamart, Service de néphrologie pédiatrique, hôpital Robert-Debré, AP-HP, Paris, Service d’hématologie clinique et de thérapie cellulaire, hôpital Saint-Antoine, AP-HP, Paris

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy defined by the spontaneous formation of platelet thrombi in the microvessels. These platelet microthrombi are responsible for a mechanical hemolytic anemia, a thrombocytopenia and a multivisceral ischemia involving mainly the kidneys and the brain. Pediatric TTP (Upshaw-Schulman syndrome) is a very rare (orphan disease) but life-threatening disease in the absence of appropriate treatment (plasmatherapy). This disease which onset occurs in half cases as soon as birth, is characterized by multiple acute relapses separated either by complete remission periods or a mild chronic background (thrombocytopenia and hemolysis). TTP pathophysiology has remained obscure until 2001 when the cloning for a new metalloprotease gene, ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats), has elucidated most of the disease pathogenesis. The substrate for ADAMTS13 is von Willebrand factor (VWF), a plasma multimeric glycoprotein crucial for both platelet adhesion and aggregation in the microcirculation. Physiologically, ADAMTS13 function consists in limiting the size of VWF multimers and consequently, their hemostatic capacity. Upshaw-Schulman syndrome is characterized by a severe functional deficiency of ADAMTS13 (plasma activity lower than 5 %) responsible for the accumulation of ultralarge VWF multimers inducing the spontaneous formation of platelet thrombi within the microvessels. ADAMTS13 deficiency is related to ADAMTS13 gene mutations (60 % of substitutions and 40 % of truncating mutations) recessively inherited and spread all over the gene. The clinical phenotype is however heterogeneous ranging from mild forms limited to a fluctuating thrombocytopenia to very severe forms consisting in concerning renal and neurological consequences. In addition to answers to questions focused on phenotype/genotype correlation, a better structural and functional characterization of ADAMTS13 is crucial to evaluate the relevance of either plasmatic or recombinant purified ADAMTS13 in the therapeutic management of Upshaw-Schulman syndrome.