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.Background Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic 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.© 2016 International Society on Thrombosis and Haemostasis.

Thrombotic microangiopathy (TMA) refers to a diverse group of diseases that share clinical and histopathologic features. TMA is clinically characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and organ injury that stems from endothelial damage and vascular occlusion. There are several disease states with distinct pathophysiological mechanisms that manifest as TMA. These conditions are associated with significant morbidity and mortality and require urgent recognition and treatment. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are traditionally considered to be primary forms of TMA, but TMA more commonly occurs in association with a coexisting condition such as infection, pregnancy, autoimmune disease, or malignant hypertension, among others. Determining the cause of TMA is a diagnostic challenge because of limited availability of disease‐specific testing. However, identifying the underlying etiology is imperative as treatment strategies differ. Our understanding of the conditions that cause TMA is evolving. Recent advances have led to improved comprehension of the varying pathogenic mechanisms that drive TMA. Development of targeted therapeutics has resulted in significant improvements in patient outcomes. In this article, we review the pathogenesis and clinical features of the different TMA‐causing conditions. We outline a practical approach to diagnosis and management and discuss empiric and disease‐specific treatment strategies.

Pregnancy and postpartum are high-risk periods for different forms of thrombotic microangiopathy (TMA). However, the management of pregnancy-associated TMA remains ill defined. This report, by an international multidisciplinary working group of obstetricians, nephrologists, hematologists, intensivists, neonatologists, and complement biologists, summarizes the current knowledge of these potentially severe disorders and proposes a practical clinical approach to diagnose and manage an episode of pregnancy-associated TMA. This approach takes into account the timing of TMA in pregnancy or postpartum, coexisting symptoms, first-line laboratory workup, and probability-based assessment of possible causes of pregnancy-associated TMA. Its aims are: to rule thrombotic thrombocytopenic purpura (TTP) in or out, with urgency, using ADAMTS13 activity testing; to consider alternative disorders with features of TMA (preeclampsia/eclampsia; hemolysis elevated liver enzymes low platelets syndrome; antiphospholipid syndrome); or, ultimately, to diagnose complement-mediated atypical hemolytic uremic syndrome (aHUS; a diagnosis of exclusion). Although they are rare, diagnosing TTP and aHUS associated with pregnancy, and postpartum, is paramount as both require urgent specific treatment.© 2020 by The American Society of Hematology.

The most common thrombotic microangiopathy (TMA) of pregnancy is the well-recognized syndrome of preeclampsia with hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. However, rare TMAs, including thrombotic thrombocytopenic purpura, complement-mediated hemolytic-uremic syndrome, and catastrophic antiphospholipid syndrome, may occur during pregnancy or postpartum and present with features similar to those of preeclampsia with severe features. Early recognition and treatment of these infrequently encountered conditions are key for avoiding serious maternal morbidities with long-term sequelae and possible maternal or fetal death. Differentiating between preeclampsia with severe features and these rare TMAs is diagnostically challenging as there is significant overlap in their clinical and laboratory presentation. Given the rarity of these TMAs, high-quality evidence-based recommendations on diagnosis and management during pregnancy are lacking. Using current objective information and recommendations from working groups, this report provides practical clinical approaches to diagnose and manage these rare TMAs. This report also discusses how to manage individuals with a history of these rare TMAs who are planning to conceive. To optimize favorable outcomes, a multidisciplinary approach including obstetricians, maternal-fetal medicine specialists, hematologists, and nephrologists alongside close clinical and laboratory monitoring is vital.

Studies of complement genetics have changed the landscape of thrombotic microangiopathies (TMAs), particularly atypical haemolytic uraemic syndrome (aHUS). Knowledge of complement genetics paved the way for the design of the first specific treatment for aHUS, eculizumab, and is increasingly being used to aid decisions regarding discontinuation of anti-complement treatment in this setting. Complement genetic studies have also been used to investigate the pathogenic mechanisms that underlie other forms of HUS and provided evidence that contributed to the reclassification of pregnancy- and postpartum-associated HUS within the spectrum of complement-mediated aHUS. By contrast, complement genetics has not provided definite evidence of a link between constitutional complement dysregulation and secondary forms of HUS. Therefore, the available data do not support systematic testing of complement genes in patients with typical HUS or secondary HUS. The potential relevance of complement genetics for distinguishing the underlying mechanisms of malignant hypertension-associated TMA should be assessed with caution owing to the overlap between aHUS and other causes of malignant hypertension. In all cases, the interpretation of complement genetics results remains complex, as even complement-mediated aHUS is not a classical monogenic disease. Such interpretation requires the input of trained geneticists and experts who have a comprehensive view of complement biology.

Thrombotic thrombocytopenic purpura (TTP) is a rare but serious complication in pregnancy that places the mother and fetus at high risk for morbidity and mortality. This case illustrates novel pregnancy complications associated with this rare medical condition.

Pregnancy is a high-risk period for various types of thrombotic microangiopathies (TMA). The improvement of our understanding of the pathophysiology of TMAs has translated into better management of pregnancy-related TMAs. The two main types of TMA, TTP (thrombotic thrombocytopenic purpura) and hemolytic uremic syndrome (HUS), can both occur during pregnancy and postpartum. TTP is related in most cases to acquired or congenital deficiency of ADAMTS13; it tends to develop mainly during the second and third trimesters of pregnancy. The treatment of pregnancy-TTP aims to restore a detectable ADAMTS13 activity through plasma therapy, and if needed, to induce or sustain remission, immunosuppressive agents. In contrast, HUS develops mainly in the postpartum period. Accumulating data indicate that pregnancy-HUS is an atypical, i.e., complement-mediated HUS, triggered by pregnancy. Its treatment therefore should include the use of the anti-C5 humanized monoclonal antibody eculizumab. In other TMA-like disorders associated with pregnancy, including HELLP (hemolysis, elevated liver enzymes, low platelets) and pre-eclampsia/eclampsia, complement involvement, and the need for specific anti-complement therapies, is an active area of investigation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Haemolytic uraemic syndrome is a form of thrombotic microangiopathy affecting predominantly the kidney and characterised by a triad of thrombocytopenia, mechanical haemolytic anaemia, and acute kidney injury. The term encompasses several disorders: shiga toxin-induced and pneumococcus-induced haemolytic uraemic syndrome, haemolytic uraemic syndrome associated with complement dysregulation or mutation of diacylglycerol kinase ɛ, haemolytic uraemic syndrome related to cobalamin C defect, and haemolytic uraemic syndrome secondary to a heterogeneous group of causes (infections, drugs, cancer, and systemic diseases). In the past two decades, experimental, genetic, and clinical studies have helped to decipher the pathophysiology of these various forms of haemolytic uraemic syndrome and undoubtedly improved diagnostic approaches. Moreover, a specific mechanism-based treatment has been made available for patients affected by atypical haemolytic uraemic syndrome due to complement dysregulation. Such treatment is, however, still absent for several other disease types, including shiga toxin-induced haemolytic uraemic syndrome.Copyright © 2017 Elsevier Ltd. All rights reserved.

Pregnancy is associated with various forms of thrombotic microangiopathy, including hemolytic uremic syndrome. A previous small French study suggested that pregnancy-associated hemolytic uremic syndrome was to be included in the spectrum of atypical hemolytic uremic syndrome linked to complement alternative pathway dysregulation.

Thrombotic microangiopathy (TMA) represents a heterogeneous group of disorders characterized by microvascular thrombosis and end-organ damage. Pregnancy-associated thrombotic microangiopathy (p-TMA) has emerged as a distinct clinical entity with unique diagnostic challenges. Identifying the specific form of p-TMA is critical for appropriate and timely management. This review offers a comprehensive overview of the various forms of thrombotic microangiopathies associated with pregnancy, highlighting our current understanding of their pathophysiology and the evolving landscape of diagnosis and treatment for each.© 2024 International Society of Nephrology. Published by Elsevier Inc.

Atypical hemolytic uremic syndrome (aHUS) is a rare disease in which uncontrolled terminal complement activation leads to systemic thrombotic microangiopathy (TMA). Pregnancy can trigger aHUS and, without complement inhibition, many women with pregnancy-triggered aHUS (p-aHUS) progress to end-stage renal disease (ESRD) with a high risk of morbidity. Owing to relatively small patient numbers, published characterizations of p-aHUS have been limited, thus the Global aHUS Registry (NCT01522183, April 2012) provides a unique opportunity to analyze data from a large single cohort of women with p-aHUS.The demographics and clinical characteristics of women with p-aHUS (n = 51) were compared with those of women of childbearing age with aHUS and no identified trigger (non-p-aHUS, n = 397). Outcome evaluations, including renal survival according to time to ESRD, were compared for patients with and without eculizumab treatment (a complement C5 inhibitor) in both aHUS groups.Baseline demographics and clinical characteristics were broadly similar in both groups. The proportion of women with p-aHUS and non-p-aHUS with pathogenic variant(s) in complement genes and/or anti-complement factor H antibodies was similar (45% and 43%, respectively), as was the proportion with a family history of aHUS (12% and 13%, respectively). Eculizumab treatment led to significantly improved renal outcomes in women with aHUS, regardless of whether aHUS was triggered by pregnancy or not: adjusted hazard ratio for time to ESRD was 0.06 (p = 0.006) in the p-aHUS group and 0.20 (p < 0.0001) in the non-p-aHUS group.Findings from this study support the characterization of p-aHUS as a complement-mediated TMA.

A review of pregnancy-associated thrombotic thrombocytopenic purpura (TTP) in 166 pregnancies was undertaken using 92 English-language publications from 1955 to 2006. Initial and recurrent TTP presents most often in the second trimester (55.5%) after 1-2 days of signs/symptoms; postpartum TTP usually occurs following term delivery. TTP with preeclampsia (n = 28) exhibits 2-4 times higher aspartate aminotransferase (AST) values and lower total lactate dehydrogenase (LDH) to AST ratios (LDH to AST ratio = 13:1), compared with TTP without preeclampsia (LDH to AST ratio = 29:1). Maternal mortality is higher with initial TTP (26% vs 10.7%), especially with concurrent preeclampsia (44.4% vs 21.8%, P <.02). Although maternal mortality with TTP has substantially declined when plasma therapy is utilized, delay of diagnosis and therapy for initial TTP confounded by preeclampsia/hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome remains a significant maternal-perinatal threat. Rapid and readily available laboratory testing to quickly diagnose TTP and HELLP syndrome/preeclampsia is desperately needed to improve care.