The role of ADAMTS 13 in the new pathogenesis of TTP FLORA PEYVANDI

Thrombotic Thrombocytopenic Purpura (TTP) is a severe microvascular occlusive microangiopathy characterized by thrombocytopenia, Coombs-negative hemolytic anemia and ischemic symptoms localized mainly but not exclusively in central nervous system and resulting from diffuse platelet thrombi in microcirculation [1]. To understand the broad clinical spectrum of TTP it is important to read the original case report prior to effective treatment, when the full natural history of this fatal illness was appreciated. In 1924 Dr. Moschowitz [2] described the first case in a previously healthy 16-year-old girl who died with multiple organ failure and post-mortem examination showed widespread thrombi in the terminal circulation of several organs, composed mainly by platelets. These thrombi remain the hallmark of pathologic diagnosis. The current era in our knowledge began with the observation by Moake and his colleagues in 1982 [3] of unusually large multimers of von Willebrand factor (ULVWF) in the plasma of patients with chronic relapsing TTP. They are similar to those normally contained in vascular endothelial cells and platelets but absent in plasma. These ULVWF multimers promote platelet-dependent microvascular thrombosis, suggesting that patients lacked a VWF protease able to reduce the size of VWF multimers by cleavage. The next key step was the discovery made 14 years later, when Furlan, Tsai et al. [4,5] isolated a VWFcleaving protease that had properties consistent with the activity that had been postulated to be absent in patients with TTP. These two groups subsequently published evidence that the consistently very low or undetectable plasma levels of this protease were indicative of TTP [6,7]. The VWF-cleaving protease is now known as ADAMTS13, a member of the ADAMTS metalloprotease family (A Disintegrin And Metalloprotease with Thrombospondin-1 repeats), thanks to the results obtained by Fujikawa [8], Gerritsen [9] and Zheng [10] in 2001. In the same year Levy identified the ADAMTS13 gene and described in seven unrelated families 12 distinct mutations, underlying the molecular mechanism responsible for congenital TTP [11]. At this point everything seemed to become clear: an enzyme deficiency allows ULVWF multimers to circulate; the unusually large multimers cause disseminated platelet clumping in the microcirculation; the deficient protease can be replaced by plasma infusion, which is sufficient in patients with congenital deficiency; the inhibitor of ADAMTS13 activity in patients with acquired disease can be removed by plasmapheresis, making plasma exchange a more effective treatment than plasma infusion. However, as clinical studies have extended beyond the initial translational research to community studies [12], the inevitable increase in complexity of these syndromes has been appreciated. The main finding of these subsequent studies is that only approximately 50% of patients with overt clinical disease have low plasma levels of the protease. Simultaneously an enormous number of in vitro studies have been initiated in order to comprehend the pathophysiology of TTP. Between 2002 and 2004 it has been demonstrated that ULVWF multimers are cleaved by ADAMTS13 between Tyr1605-Met1606 residues located within the A2 domain as they are secreted in long ‘‘strings’’ from stimulated endothelial cells [13,14]. The ULVWF strings are anchored to the endothelial cell membrane via P-selectin molecules that are secreted concurrently with the ULVWF multimers [15]. Specifically, ADAMTS13 enzyme binds under flow conditions to accessible A3 domains in the monomeric subunit of ULVWF multimers and then cleaves Tyr 1605-Met 1606 peptide bonds in adjacent A2 domain. Majerus et al. [16] have shown that the spacer and TSP1-1 like domains are required for ADAMTS13 binding to VWF, that may be modu-