Advances in the pathogenesis, diagnosis and treatment of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (original) (raw)
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Thrombotic Thrombocytopenic Purpura and Other Thrombotic Microangiopathic Hemolytic Anemias
Diagnostic Criteria in Autoimmune Diseases, 2008
TMAs) include several diseases, most prominently are thrombotic thrombocyto-23 penic purpura (TTP) and hemolytic-uremic syndrome (HUS). TMAs are characterized by profound thrombocyto-24 penia, microangiopathic hemolytic anemia and organ ischemia. In most cases TTP results from deficiency of 25 ADAMTS13, the von Willebrand factor-cleaving protease leading to increase of ultra-large von Willebrand factor 26 (ULVWF) multimers. Congenital TTP is due to mutations in the gene of ADAMTS13 whereas acquired TTP is due to 27 production of autoantibodies against ADAMTS13. In both cases severe deficiency of ADAMTS13 exists. However, 28 the presence of ADAMTS13 activity does not rule out TTP. Diagnostic criteria of TTP are based on clinical features 29 of neurologic and renal disfunction along with anemia and thrombocytopenia, low ADAMTS13 activity, and the 30 presence of ULVWF. The standard treatment of TTP includes plasma exchange, protein A immunoabsorption, 31 immunosuppressive drugs, CD20 antibodies against B cells, and splenectomy. HUS is commonly caused by infection 32 with Shiga-toxin produced by Escherichia coli. HUS is characterized by thrombocytopenia, anemia, renal impair-33 ment and diarrhea. Rarely, atypical HUS appears as a consequence of mutations related to the alternative pathway 34 for the compliment system. Plasmapheresis in HUS is not efficient. Alternatively, plasma therapy and in some cases 35 dialysis are used. TMA diseases may be associated with other infections, bone marrow transplantation, pregnancy, 36 systemic vasculitis, and certain drugs. 37
Advances in the Pathogenesis, Diagnosis, and Treatment of Thrombotic Thrombocytopenic Purpura
Journal of the American Society of Nephrology, 2003
ABSTRACT. Thrombotic thrombocytopenic purpura (TTP) and the hemolytic uremic syndrome (HUS) are both characterized by thrombocytopenia, microangiopathic hemolysis, and organ dysfunction. 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. E-mail: htsai@montefiore.org
Mechanisms of microvascular thrombosis in thrombotic thrombocytopenic purpura
Kidney International, 2009
Recent studies have demonstrated that thrombotic thrombocytopenic purpura (TTP), a serious thrombotic disorder affecting the arterioles and capillaries of multiple organs, is caused by a profound deficiency in the von Willebrand factor cleaving metalloprotease, ADAMTS13. ADAMTS13, a 190-kD plasma protease originating primarily in hepatic stellate cells, prevents microvascular thrombosis by cleaving von Willebrand factor when the substrate is conformationally unfolded by high levels of shear stress in the circulation. Deficiency of ADAMTS13, due to genetic mutations or inhibitory autoantibodies, leads to accumulation of superactive forms of vWF, resulting in vWF-platelet aggregation and microvascular thrombosis. Analysis of ADAMTS13 has led to the recognition of subclinical TTP and atypical TTP presenting with thrombocytopenia or acute focal neurological deficits without concurrent microangiopathic hemolysis. Infusion of plasma replenishes the missing ADAMTS13 and ameliorates the complications of hereditary TTP. The patients are at risk of both acute and chronic renal failure if they receive inadequate plasma therapy. The more frequent, autoimmune type of TTP requires plasma exchange therapy and perhaps immunomodulatory measures. Current studies focus on the factors affecting the phenotypic severity of TTP and newer approaches to improving the therapies for the patients.
2014
Thrombotic microangiopathies (TMAs) include several diseases, most prominently are thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS). TMAs are characterized by profound thrombocytopenia, microangiopathic hemolytic anemia and organ ischemia. In most cases TTP results from deficiency of ADAMTS13, the von Willebrand factor-cleaving protease leading to increase of ultra-large von Willebrand factor (ULVWF) multimers. Congenital TTP is due to mutations in the gene of ADAMTS13 whereas acquired TTP is due to production of autoantibodies against ADAMTS13. In both cases severe deficiency of ADAMTS13 exists. However, the presence of ADAMTS13 activity does not rule out TTP. Diagnostic criteria of TTP are based on clinical features of neurologic and renal disfunction along with anemia and thrombocytopenia, low ADAMTS13 activity, and the presence of ULVWF. The standard treatment of TTP includes plasma exchange, protein A immunoabsobtion, immunosuppressive drugs, CD20 antibodies against B cells, and splenectomy. HUS is commonly caused by infection with Shiga-toxin produced by Escherichia coli. HUS is characterized by thrombocytopenia, anemia, renal impairment and diarrhea. Rarely, atypical HUS appears as a consequence of mutations related to the alternative pathway for the compliment system. Plasmapheresis in HUS is not efficient. Alternatively, plasma therapy and in some cases dialysis are used. TMA diseases may be associated with other infections, bone marrow transplantation, pregnancy, systemic vasculitis, and certain drugs.
2016
Many diseases are first recognized as a syndrome or a collection of symptoms and signs that are presumed to be the consequence of a particular etiology or disease mechanism. This process works for many syndromes but can be confusing or misleading when the syndrome actually results from more than one disease with vastly different etiology or mechanism. This review discusses how the syndrome of Microangiopathic Hemolytic anemia (MAHA) and thrombocytopenia has evolved from vaguely defined ‘TTP’, ‘TTP/HUS’ or ‘TTP/TMA’ to a collection of diseases that include, among others, mechanistically defined thrombotic thrombocytopenic purpura (TTP) and Atypical Hemolytic Uremic Syndrome (AHUS). These two diseases account for the majority of patients presenting with the syndrome of MAHA and thrombocytopenia. Nevertheless, they may also present without either MAHA or thrombocytopenia. These advances highlight the need for a new scheme of disease classification and provide the basis for a more ratio...
Pathogenesis of thrombotic microangiopathies
2008
Profound thrombocytopenia and microangiopathic hemolytic anemia characterize thrombotic microangiopathy, which includes two major disorders: thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). TTP has at least three types: congenital or familial, idiopathic, and nonidiopathic. The congenital and idiopathic TTP syndromes are caused primarily by deficiency of ADAMTS13, owing to mutations in the ADAMTS13 gene or autoantibodies that inhibit ADAMTS13 activity. HUS is similar to TTP, but is associated with acute renal failure. Diarrhea-associated HUS accounts for more than 90% of cases and is usually caused by infection with Shiga-toxin-producing Escherichia coli (O157:H7). Diarrhea-negative HUS is associated with complement dysregulation in up to 50% of cases, caused by mutations in complement factor H, membrane cofactor protein, factor I or factor B, or by autoanti-bodies against factor H. The incomplete penetrance of mutations in either ADAMTS13 or complement regulatory genes suggests that precipitating events or triggers may be required to cause thrombotic microangiopathy in many patients. Keywords thrombotic thrombocytopenic purpura; hemolytic uremic syndrome; von Willebrand factor-cleaving metalloprotease; ADAMTS13; complement dysregulation DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.