4A.3 Thrombotic thrombocytopenic purpura

Abstract

Historical background More than 80 years after the first description of thrombotic thrombocytopenic purpura (TTP) by Eli Moschcowitz [1,2], the pathogenesis of this syndrome is still a mystery and in spite of improved modalities of therapy mortality rate of around 15% presents a great challenge for the medical team. The originally described pentad, including fever, thrombocytopenia, microangiopathic hemolytic anemia, renal failure and neurological abnormalities, is no longer required for establishing the diagnosis of TTP. Thus, the association of thrombocytopenia and microangiopathic hemolytic anemia is sufficient for a TTP alert [3]. It was only in the early 1980s when ultra-large VWF (ULVWF) multimers were found in plasma of TTP patients, suggesting a defect in VWF multimers processing, yielding an increased platelet clumping as a basis for the various clinical manifestations of TTP [4]. In 1997 8 two different groups have described for the first time the lack of a cleaving protease activity among inherited as well as acquired TTP patients, and a serum IgG fraction was identified to induce this effect in the latter group, establishing the autoimmune nature of acquired TTP [5,6]. At that time it was established that a level of <5% of the cleaving protease is required for induction of increased platelet adhesion and TTP symptoms. In 2001 2 the VWF cleaving protease has been characterized as the 13th member of the ADAMTS (A Disintegrin and Metalloprotease with Thrombospondin type motifs) metalloprotease family; the gene was sequenced and mutations responsible for inherited TTP were identified [7 9]. Later studies have clarified in greater detail the mechanism of action of ADAMTS 13, its binding site on the A3 domain of the VWF molecule, and the cleavage site on the A2 domain (Tyr 842 843 Met) [10]. It was also discovered that optimal cleavage of ULVWF is executed under high shear flow conditions, when ULVWF is attached to the surface and stretched due to the flow effect, thus exposing the different sites of interaction with ADAMTS 13 [11 13]. These later discoveries opened the road to the development of new diagnostic as well as therapeutic approaches. Thus different new tests have been developed for diagnosis and monitoring of ADAMTS-13 activity, including the testing of the cleavage products of VWF by collagen binding assays, by electrophoretic as well as by ELISA methods. The latter method was based on the identification of the minimally 73 AA peptide required for cleavage by ADAMTS 13 [14]. In addition, physiological testing of ADAMTS 13 has been developed, based on platelet adhesion under flow as a function of ADAMTS-13 activity in the tested plasma [15]. Treatment of TTP is still a great challenge due to the stormy nature of the disease and the relatively high mortality rate of around 15%. Since 1991 it was established that plasma exchange (PE) is indeed the treatment of choice, yielding reduction in both the ULVWF multimers and the inhibitor of ADAMTS 13, and providing an active ADAMTS 13 and normal-size VWF multimers [16]. The role of other treatment modalities, including steroids, IVIG, aspirin and rituximab, is still a matter for future investigations. Treatment of inherited cases of TTP is based on replacement of the missing ADAMTS 13, routinely by plasma transfusion, and potentially by a recombinant product which is now available. In spite of these advancements there are still many open questions regarding the pathogenesis of TTP and its family of Thrombotic MicroAngiopathies (TMAs). Thus, although a <5% activity level of ADAMTS 13 was found to be necessary for the development of TTP, not all patients with such a low level will develop clinical symptoms. Pathogenesis of other TMAs, including HUS and those associated with bone marrow transplantation, with HIV and those which are drug induced is not yet established. The potential effect of PE in this group of disorders is also not established [17].