Advances in the Pathogenesis, Diagnosis, and Treatment of Thrombotic Thrombocytopenic Purpura. Tsai H-M. Journal of the American Society of Nephrology 2003;14:1072-1081

ABSTRACT:

Thrombotic thrombocytopenic purpura (TTP) and the hemolytic uremic syndrome (HUS) are both characterized by thrombocytopenia, microangiopathic hemolysis, and organ dysfunction. HUS, originally described as a separate entity that characteristically develops in young children after a bout of hemorrhagic diarrhea, has a clinical course dominated by acute renal failure and occurs after infection by shiga toxin-producing microorganisms such as E. coli O157:H7 or S. dysenteriae serotype 1. The severity and mortality of E. coli O157:H7–associated HUS are age-dependent. With supportive management, the mortality of E. coli–associated HUS is less than 10% among young children but may be as high as 90% among the elderly. Because of its distinctive etiology and clinical features, E. coli O157:H7–associated HUS is believed to differ from TTP in pathogenesis. However, the spectrum of E. coli O157:H7–associated HUS is broader than originally recognized: it is not restricted to young children or the elderly; diarrhea may not be evident; the renal failure may be mild; and neurologic complications are not uncommon. These observations raised the suspicion that the HUS and TTP might have a common pathogenetic mechanism. Further confounding the distinction, the diagnosis of HUS is also applied to disorders that have the features of microangiopathic hemolysis, thrombocytopenia, and renal failure but no evidence of infection by shiga toxin-producing microorganisms. In a subset of these patients with "atypical" HUS, mutations in factor H, which is a component of the complement regulatory proteins, were detected. The course of patients with factor H mutation is notable for severe hypertension and a high rate of relapse and progression to end-stage renal failure. However, at its early stage or in its mild form, these characteristic features may not be prominent. Therefore a distinction between atypical HUS, with or without factor H mutations, and TTP may not be obvious. Other disorders occasionally present with similar manifestations. Recent studies have demonstrated that deficiency in the von Willebrand factor cleaving protease ADAMTS13, due to genetic mutations or autoimmune inhibitors, causes TTP. Molecular cloning of ADAMTS13 elucidates the structure of the protease, raising the prospect for advances in diagnosis and treatment of the disease. Assay of ADAMTS13 activity distinguishes TTP from HUS and other types of thrombotic microangiopathy (TMA); therefore, the term TTP/HUS should be avoided because it obscures the known or potential differences among the various types of TMA. Because of the presence of inhibitors, treatment of acquired TTP requires a large amount of plasma. Plasma exchange (PE) is more effective than plasma infusion, presumably because it allows the patients to receive large amount of plasma to overcome the inhibitors without imposing the risk of fluid overload. Removal of the inhibitors during PE may also contribute to its efficacy. Occasionally, the titer of inhibitors increases during the course of PE, resulting in treatment failure and a fatal outcome. In the future, measures that effectively remove the inhibitors or prevent the rise of inhibitor titers during therapy may decrease the risk of treatment failure and death. Further investigation is needed to delineate the efficacy of currently available therapies.