Thrombotic thrombocytopenic purpura and its diagnosis

Thrombotic thrombocytopenic purpura (TTP) is a lifethreatening illness whose mortality rate exceeds 90% in the absence of rapid appropriate treatment. Empirical plasmatherapy instituted in the 1970s has reduced the death rate to approximately 25% and both plasma infusions and plasma exchanges remain the only efficient treatments so far. TTP prevalence is about four per one million with a preference for women of childbearing age [1]. To diagnose TTP implies to face a first challenge: to define it. The definition criteria for TTP have significantly evolved as a result of a 20-year retrospective accurate analysis of North American [2,3], European [4–8] and Japanese [9] patients registries and cohorts and a better understanding of TTP pathogenesis. Historically, TTP was originally described in 1924 by Eli Moschcovitz in a 16-year-old girl who presented with fever, anemia, central nervous system impairment, renal insufficiency and both respiratory and cardiac failure related to hyaline platelet thrombi in the terminal arterioles and capillaries of most organs [10]. Several case-reports and reviews of the literature have followed the initial description [11] leading to a definition concept focused on the following pentad: fever, microangiopathic hemolytic anemia, thrombocytopenia, central nervous system abnormalities and renal impairment. TTP, also called Moschcovitz syndrome , was described as a disease affecting primarily adults, but, interestingly, a rare pediatric form of the disease was also reported as early as 1960 [12] and named Upshaw-Schulman syndrome in 1978 [13]. However, further large retrospective analysis of patients clinical features showed that neither fever nor neurologic abnormalities and renal impairment were constant, especially during the early stage of the disease [14]. This observation led to the proposal that the association of microangiopathic hemolytic anemia and unexplained thrombocytopenia are sufficient and essential criteria to suspect TTP at an early stage in order to institute timely plasmatherapy [15,16]. In parallel to the evolution of the standard clinical and biological criteria required for a solid TTP suspicion, the pathophysiological mechanisms for TTP were further elucidated recently. Until the 1980s, the pathogenesis for TTP remained very unclear although numerous candidates like endothelium, platelets or plasma proteins were suggested to participate in the triggering of the disease [17]. The role of von Willebrand factor (VWF), a plasma multimeric protein essential for platelet adhesion and aggregation at the high shear rates of blood flow present in the microvessels, was first put forward in 1982 by Moake et al. [18] who found abnormally large VWF multimers in the plasma of TTP patients. These hyperadhesive ultralarge multimers of VWF were suspected to be directly responsible for spontaneous platelet clumping in the microcirculation leading to ischemic visceral dysfunction. This hypothesis was further supported in 1985 by Asada et al. [19] who demonstrated that platelet thrombi in TTP were enriched in VWF (and not in fibrin) using an immunohistochemistry study of vascular lesions. In 1996, Furlan et al. [20] and Tsai [21] independently isolated and partially characterized a new metalloprotease from human plasma that specifically cleaves VWF at Tyr842Met843, the peptide bond known to be cleaved in vivo. This enzyme was identified as the 13th member of the ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin type 1 repeats) family of metalloproteases and the corresponding gene was cloned in 2001 [22]. In 1998, Furlan et al. [23] and, Tsai and Chun-Yet Lian [24] revealed that most adult patients with acute TTP had a severe functional deficiency of ADAMTS-13 in plasma (< 5% of the activity of a normal pooled plasma), most often related to inhibitory IgG autoantibodies. Further studies of patients with miscellaneous diseases, including other thrombotic microangiopathies like hemolytic uremic syndrome (HUS), confirmed that ADAMTS-13 severe deficiency was about 90% sensitive and specific for TTP [8,25–27]. In addition, Levy et al. [22] found that patients with hereditary TTP associated with a severe ADAMTS-13 functional deficiency were doubly heterozygous or homozygous carriers of mutated ADAMTS-13 alleles. Thus, in 2005, ADAMTS-13 severe deficiency (< 5%), either acquired via circulating autoantibodies or more rarely inherited via recessive ADAMTS-13 mutations, appears as a major specific risk factor for TTP. However, this observation does not allow TTP to be redefined by an undetectable ADAMTS-13 activity in plasma because other Correspondence: Dominique Meyer, Inserm Unité 143, 80, rue du Général Leclerc, Hôpital de Bicêtre, 94276 Le Kremlin-Bicêtre Cedex, France. Tel.: +33 149 595 600; fax: +33 146 719 472; e-mail: dmeyer@ kb.inserm.fr Journal of Thrombosis and Haemostasis, 3: 2420–2427