ADAMTS13, la protéase spécifique du clivage du facteur von Willebrand

Abstract

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/106/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.