Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies

Essentials An international collaboration provides a consensus for clinical definitions. This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP). The consensus defines diagnosis, disease monitoring and response to treatment. Requirements for ADAMTS-13 are given. Summary: Background Thrombotic thrombocytopenic purpura (TTP) and hemolytic\ue2\u80\u93uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small-vessel platelet aggregates. The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia, including cancer, infection, transplantation, drug use, autoimmune disease, and pre-eclampsia and hemolysis, elevated liver enzymes and low platelet count syndrome in pregnancy. Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiologies and treatment pathways. Objectives To present a consensus document from an International Working Group on TTP and associated thrombotic microangiopathies (TMAs). Methods The International Working Group has proposed definitions and terminology based on published information and consensus-based recommendations. Conclusion The consensus aims to aid clinical decisions, but also future studies and trials, utilizing standardized definitions. It presents a classification of the causes of TMA, and criteria for clinical response, remission and relapse of congenital and immune-mediated TTP

Caplacizumab reduces the frequency of major thromboembolic events, exacerbations, and death in patients with acquired thrombotic thrombocytopenic purpura.

BACKGROUND Acquired thrombotic thrombocytopenic purpura (aTTP) is a life-threatening autoimmune thrombotic microangiopathy. In spite of treatment with plasma exchange and immunosuppression, patients remain at risk for thrombotic complications, exacerbations and death. In the Phase II TITAN study, treatment with caplacizumab, an anti-vWF Nanobody(®) , was shown to reduce the time to confirmed platelet count normalization and exacerbations during treatment. OBJECTIVE The clinical benefit of caplacizumab was further investigated in a post-hoc analysis of the incidence of major thromboembolic events and exacerbations during the study drug treatment period and TTP-related death during the study. METHODS The Standardized MedDRA Query (SMQ) for 'embolic and thrombotic events' was run to investigate the occurrence of major thromboembolic events and exacerbations in the safety population of the TITAN study, which consisted of 72 patients of whom 35 received caplacizumab and 37 received placebo. RESULTS Four events (1 pulmonary embolism and 3 aTTP exacerbations) were reported in 4 patients in the caplacizumab group, while 20 such events were reported in 14 patients in the placebo group (2 acute myocardial infarctions, 1 ischemic and 1 hemorrhagic stroke, 1 pulmonary embolism, 1 deep vein thrombosis, 1 venous thrombosis and 13 aTTP exacerbations). Two of the placebo-treated patients died from aTTP during the study. CONCLUSION In total, 11.4% of caplacizumab-treated patients versus 43.2% of placebo-treated patients experienced one or more major thromboembolic event, an exacerbation or died. This analysis shows the potential for caplacizumab to reduce the risk of major thromboembolic morbidities and mortality associated with aTTP. This article is protected by copyright. All rights reserved

Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies.

BACKGROUND Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic Microangiopathy is a broad pathophysiological process that leads to microangiopathic hemolytic anemia, thrombocytopenia and involves capillary and small vessel platelet aggregates. The most common cause being disseminated intravascular coagulation (DIC), which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia (MAHAT), including cancer, infection, transplantation, drugs, autoimmune disease and pre-eclampsia and HELLP (Hemolysis, Elevated Liver enzymes, Low Platelet count) syndrome in pregnancy. Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiology and treatment pathways. OBJECTIVES Presented is a consensus document from an international working group on TTP and associated TMAs (thrombotic microangiopathies). METHODS The international working group has proposed definitions and terminology based on published information and consensus based recommendations. CONCLUSION The consensus aims to aid clinical decisions but also future studies and trials, utilizing standardized definitions. It presents classification of the causes of TMA, and criteria for clinical response, remission and relapse of congenital and immune mediated TTP. This article is protected by copyright. All rights reserved

Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature

Many drugs have been reported to cause thrombotic microangiopathy (TMA), yet evidence supporting a direct association is often weak. In particular, TMA has been reported in association with recombinant type I interferon (IFN) therapies, with recent concern regarding the use of IFN in multiple sclerosis patients. However, a causal association has yet to be demonstrated. Here, we adopt a combined clinical and experimental approach to provide evidence of such an association between type I IFN and TMA. We show that the clinical phenotype of cases referred to a national center is uniformly consistent with a direct dose-dependent drug-induced TMA. We then show that dose-dependent microvascular disease is seen in a transgenic mouse model of IFN toxicity. This includes specific microvascular pathological changes seen in patient biopsies and is dependent on transcriptional activation of the IFN response through the type I interferon α/β receptor (IFNAR). Together our clinical and experimental findings provide evidence of a causal link between type I IFN and TMA. As such, recombinant type I IFN therapies should be stopped at the earliest stage in patients who develop this complication, with implications for risk mitigation