Pathogenesis and prognosis of thrombotic microangiopathy.
Thrombotic microangiopathy (TMA) is a clinicopathological syndrome characterized by thrombosis formation in the microvasculature of various organs. Included in the broad category of TMA are the hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Typical HUS is caused by Escherichia coli O157:H7, which produces the Shiga-like toxins; Stx-1 and Stx-2. In addition to damaging endothelial cells via the inhibition of protein synthesis, Shiga-like toxins also activate endothelial cells to produce inflammatory mediators, amplifying the prothrombogenic state. Although most patients with typical HUS recover renal functions, recent analysis has shown that typical HUS is not a benign disease in the long term. Genetic abnormalities of complement regulatory proteins predispose patients to atypical HUS. Mutations in factor H, membrane cofactor protein, and factor I are known to be associated with atypical HUS. Atypical HUS forms have a poor outcome and show recurrent and progressive courses. Autoimmune IgG inhibitors of a disintegrin and metalloprotease, with thrombospodin-1-like domains (ADAMTS) 13 and mutations of the ADAMTS13 gene lead to the development of TTP. Without treatment, TTP is associated with a very high mortality rate. As it is for atypical HUS, plasma exchange is currently the most feasible treatment for TTP. Etiological diagnosis at the bedside and the development of disease-specific therapeutic modalities will enable us to optimize the management of patients with TMA and improve their prognosis in the future.
Nangaku
Masaomi
M
Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. mnangaku-tky@umin.ac.jp.
Nishi
Hiroshi
H
Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Fujita
Toshiro
T
Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
D051722:ADAM Proteins / Q000235:genetics; D000071120:ADAMTS13 Protein; D003167:Complement Activation; D020022:Genetic Predisposition to Disease; D006463:Hemolytic-Uremic Syndrome / Q000175:diagnosis / Q000209:etiology*; D006801:Humans; D011379:Prognosis; D011697:Purpura, Thrombotic Thrombocytopenic / Q000175:diagnosis / Q000209:etiology*; D022603:Shiga Toxins / Q000009:adverse effects; D013927:Thrombosis / Q000175:diagnosis / Q000209:etiology*
D022603:Shiga Toxins; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human