Thrombotic Microangiopathies: Towards a Pathophysiology-Based Classification

Abstract

Thrombotic microangiopathies (TMA) encompass various diseases characterized by a microangiopathic hemolytic anemia, platelet clumping, and organ failure of variable severity. Thrombotic thrombocytopenic purpura (TTP) is a particularly severe form of TMA characterized by systemic organ failure which results from a severe defect in ADAMTS13, a plasma enzyme specifically involved in the cleavage of highly hemostatic unusually large (UL) von Willebrand factor (VWF) multimers into smaller and less adhesive VWF forms. Failure to degrade these UL-VWF multimers leads to excessive platelet aggregates and capillary occlusion. ADAMTS13 deficiency results from bi-allelic mutations in hereditary TTP, whereas in acquired forms it results from autoantibodies that alter the protein function. Patients with acquired idiopathic TTP have a trend to develop autoimmunity, since a clinical context of autoimmunity may be found in 30 p. cent of cases. Moreover, the remarkable efficiency of monoclonal antibodies directed against CD20 antigen of B lymphocytes in refractory or chronic relapsing forms provides an additional indirect argument to consider acquired TTP as an autoimmune disease. Hemolytic uremic syndrome (HUS) is characterized prominently by a renal failure. In most cases, HUS is caused by entero-hemorrhagic Escherichia coli (diarrhea-positive HUS). Diarrhea-negative HUS, termed atypical HUS, was associated with a dysfunction in complement pathway involving mutations in factor H, factor I, CD46/MCP, factor B and C3 components. The major improvement in our understanding of TMA pathophysiology allows now a more accurate molecular classification of TMA syndromes, which opens fascinating perspectives of targeted therapies in the forthcoming years.

The European Hematology Association Roadmap for European Hematology Research: a consensus document

“…231 In particular, complement dysfunction and immune-mediated ADAMTS13 deficiency are responsible for aHUS and TTP, respectively. The novel concepts and disease mechanisms identified in the laboratory were rapidly and successfully transferred into the clinic for the benefit of patients, and recent studies reporting on the use of monoclonal antibodies in the management of TTP and HUS provided convincing examples of translational medicine.…”

Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura

“…1 ADAMTS13 deficiency has been related to gene mutations in the hereditary form of the disease and to anti-ADAMTS13 autoantibodies in the autoimmune form. 2 Although immunomodulatory agents have been empirically used in TTP for many years, the direct pathogenic role of anti-ADAMTS13 antibodies was demonstrated only recently in a nonhuman primate model of acquired TTP, 3 thus providing a strong rationale for using B-cell-depleting drugs in this disease in association with daily therapeutic plasma exchange.…”

Microangiopatias trombóticas: púrpura trombocitopênica trombótica e síndrome hemolítico-urêmica

“…16 Recently, genetic studies have documented that the familial form is associated with genetic abnormalities of the complement regulatory protein, and there is evidence that similar genetic alterations can also predispose to sporadic cases of D-HUS. 21 Unlike TTP, HUS is rarely induced by genetic mutations of complement regulation factors (factors B, H, and I, and CD46) and by auto-antibodies against factor H. In the era preceding its effective treatment, TTP was defined by the following "pentad" of clinical manifestations: thrombocytopenia; microangiopathic hemolytic anemia; neurological abnormalities; kidney failure; and sudden fever. 19 Efficacy of the treatment with PE requires immediate diagnosis and a reduction in the number of clinical criteria necessary for diagnosing the disease.…”