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ObjectivesSevere thrombotic antiphospholipid syndrome (APS) frequently affects the kidney, heart, and central nervous system. The precise frequency, clinical picture, differential diagnoses, and outcome of APS-related hematological involvement are lacking, especially in patients requiring ICU admission. This study aimed to describe the hematological manifestations associated with critically ill thrombotic APS patients and catastrophic antiphospholipid syndrome.MethodsThis French, national, multicenter, retrospective study, conducted, from January 2000 to September 2018, included all APS patients admitted to 24 participating centers’ ICUs with any new thrombotic manifestation. The prevalence of hematological manifestations and their associated outcomes were studied.ResultsOne hundred and thirty-four patients, female 72%, median [IQR] age 45 [34–56] years, with 152 episodes were included. Anemia was present in 95% of episodes and thrombocytopenia in 93%. The lowest values for hemoglobin and platelets were 7.1 [6.3–8.8] g/dL and 38 [21–60] g/L, respectively. The lowest platelet count below 20 g/L was significantly associated with a higher in-ICU mortality rate (50%, p < 0.0001). A thrombotic microangiopathy syndrome (TMA) syndrome was seen in 16 patients (12%) and was associated with higher in-hospital mortality (p = 0.05). Median ADAMTS-13 levels were 44% [27–74]. Anti-ADAMTS13 antibodies were tested in 11 patients and found negative in all. A suspicion of heparin-induced thrombocytopenia (HIT) was raised in 66 patients but only four patients were classified as definite HIT. Disseminated intravascular coagulation (DIC) was seen in 51% of patients.ConclusionThrombocytopenia is very frequent in severe APS patients and may be related to TMA, HIT, or DIC. Deciphering the mechanisms of thrombocytopenia is decisive in CAPS patients.Key Points• Thrombocytopenia is the hallmark laboratory finding in CAPS.• A complete thrombotic microangiopathy pattern is infrequent in CAPS patients.• Alternate diagnoses of CAPS, especially heparin-induced thrombocytopenia, need to be adequately investigated.

This review article covers the diverse pathophysiological pathways that can lead to microangiopathic hemolytic anemia and a procoagulant state with or without damage to the kidneys and other organs. The thrombotic microangiopathy (TMA) syndromes are extraordinarily diverse. They may be hereditary or acquired. They occur in children and adults. The onset can be sudden or gradual. Despite their diversity, TMA syndromes are united by common, defining clinical and pathological features. The clinical features include microangiopathic hemolytic anemia, thrombocytopenia, and organ injury. 1 The pathological features are vascular damage that is manifested by arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium and vessel wall. 2 We focus on nine disorders that we describe as primary TMA syndromes, for which there is evidence supporting a defined abnormality as the probable cause . . .

The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics.This Review summarizes the latest evidence indicating that platelet and endothelial dysfunction are essential components of COVID-19 pathology, describes the potential mechanisms underlying the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19, and highlights the roles of coagulopathy, thrombocytopathy and endotheliopathy in COVID-19 pathogenesis.

Thrombotic microangiopathies (TMAs) are a heterogeneous group of syndromes presenting with a distinct clinical triad: microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. We currently recognize two major entities with distinct pathophysiology: thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Beyond them, differential diagnosis also includes TMAs associated with underlying conditions, such as drugs, malignancy, infections, scleroderma-associated renal crisis, systemic lupus erythematosus (SLE), malignant hypertension, transplantation, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), and disseminated intravascular coagulation (DIC). Since clinical presentation alone is not sufficient to differentiate between these entities, robust pathophysiological features need to be used for early diagnosis and appropriate treatment. Over the last decades, our understanding of the complement system has evolved rapidly leading to the characterization of diseases which are fueled by complement dysregulation. Among TMAs, complement-mediated HUS (CM-HUS) has long served as a disease model, in which mutations of complement-related genes represent the first hit of the disease and complement inhibition is an effective and safe strategy. Based on this knowledge, clinical conditions resembling CM-HUS in terms of phenotype and genotype have been recognized. As a result, the role of complement in TMAs is rapidly expanding in recent years based on genetic and functional studies. Herein we provide an updated overview of key pathophysiological processes underpinning complement activation and dysregulation in TMAs. We also discuss emerging clinical challenges in streamlining diagnostic algorithms and stratifying TMA patients that could benefit more from complement modulation. With the advent of next-generation complement therapeutics and suitable disease models, these translational perspectives could guide a more comprehensive, disease- and target-tailored complement intervention in these disorders.

The novel coronavirus infection (COVID-19) is caused by the new coronavirus SARS-CoV-2 and is characterized by an exaggerated inflammatory response that can lead to severe manifestations such as adult respiratory syndrome, sepsis, coagulopathy, and death in a proportion of patients. Among other factors and direct viral effects, the increase in the vasoconstrictor angiotensin II, the decrease in the vasodilator angiotensin, and the sepsis-induced release of cytokines can trigger a coagulopathy in COVID-19. A coagulopathy has been reported in up to 50% of patients with severe COVID-19 manifestations. An increase in d-dimer is the most significant change in coagulation parameters in severe COVID-19 patients, and progressively increasing values can be used as a prognostic parameter indicating a worse outcome. Limited data suggest a high incidence of deep vein thrombosis and pulmonary embolism in up to 40% of patients, despite the use of a standard dose of low-molecular-weight heparin (LMWH) in most cases. In addition, pulmonary microvascular thrombosis has been reported and may play a role in progressive lung failure. Prophylactic LMWH has been recommended by the International Society on Thrombosis and Haemostasis (ISTH) and the American Society of Hematology (ASH), but the best effective dosage is uncertain. Adapted to the individual risk of thrombosis and the d-dimer value, higher doses can be considered, especially since bleeding events in COVID-19 are rare. Besides the anticoagulant effect of LMWH, nonanticoagulant properties such as the reduction in interleukin 6 release have been shown to improve the complex picture of coagulopathy in patients with COVID-19.

Thrombotic thrombocytopenic purpura is broadly defined as a thrombotic microangiopathy occurring in the context of severe ADAMTS13 deficiency (< 10%).7 ADAMTS13 is a normal enzyme in plasma that cleaves large forms of the coagulation protein von Willebrand factor into smaller functional subunits. The acquired form of TTP is thought to be due to an autoantibody against ADAMTS13, and the inherited form is due to a genetic deficiency of ADAMTS13. In 1996, Furlan and colleagues28 and Tsai29 independently found that patients with TTP had unusually large von Willebrand factor multimers in their plasma and that this was due to a reduction in the levels of the cleaving enzyme. Large von Willebrand factor multimers bind to platelets and form plateletrich fibrin strands, which leads to intravascular hemolysis and ischemic tissue injury. Tsai and [Lian EC]10 and Furlan and colleagues11 subsequently identified inhibitory antibodies as the cause for acquired disease. In 2001, the von Willebrand factor cleaving enzyme was identified as ADAMTS13 based on kindred studies involving patients with the congenital form of TTP called Upshaw-Schulman syndrome.8 Congenital TTP often presents in childhood but can manifest for the first time after a \"second hit\" later in life; for women, this can occur during or immediately after pregnancy.8,9 ADAMTS13 testing has no role in the initial management of thrombotic microangiopathy. Severely reduced levels of ADAMTS13 are consistent with the diagnosis of TTP and can distinguish TTP from atypical HUS; however, results of ADAMTS13 testing should not be used to guide initial treatment. If TTP is suspected, plasma exchange should be instituted regardless of the results of ADAMTS13 testing.

Thrombotic microangiopathies (TMAs) are a heterogeneous group of disorders characterized by endothelial damage, microvascular thrombosis, thrombocytopenia, and microangiopathic hemolytic anemia. While the initiating triggers may differ—ranging from infections and autoimmune diseases to genetic complement dysregulation—a unifying pathophysiological feature is injury to the vascular endothelium. Recent advances have highlighted the critical role of pro-inflammatory cytokines in mediating endothelial dysfunction, contributing to both the initiation and propagation of thrombotic events in TMAs. Cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) have been implicated in promoting endothelial activation, increased permeability, leukocyte adhesion, and procoagulant changes. These effects contribute to the loss of vascular integrity and the formation of microthrombi. Moreover, cytokine-mediated inflammation appears to be a common feature across various TMA subtypes, including Shiga toxin-associated hemolytic uremic syndrome (HUS), atypical HUS, thrombotic thrombocytopenic purpura (TTP), and secondary TMAs. The intensity and profile of cytokine involvement may vary, but their pathological influence on endothelial health remains a shared mechanism.

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.Knowledge of complement genetics has improved understanding of the pathogenesis of primary atypical haemolytic uraemic syndrome (aHUS). This Review summarizes current knowledge of complement genetics in aHUS and discusses how complement studies affect the management of patients with other thrombotic microangiopathies.

The syndrome of thrombotic microangiopathy (TMA) is a clinical-pathological entity characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end organ involvement. It comprises a spectrum of underlying etiologies that may differ in children and adults. In children, apart from ruling out shigatoxin-associated hemolytic uremic syndrome (HUS) and other infection-associated TMA like Streptococcus pneumoniae -HUS, rare inherited causes including complement-associated HUS, cobalamin defects, and mutations in diacylglycerol kinase epsilon gene must be investigated. TMA should also be considered in the setting of solid organ or hematopoietic stem cell transplantation. In this review, acquired and inherited causes of TMA are described with a focus on particularities of the main causes of TMA in children. A pragmatic approach that may help the clinician tailor evaluation and management is provided. The described approach will allow for early initiation of treatment while waiting for the definitive diagnosis of the underlying TMA.

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (TA-TMA) remains a difficult complication to address due to its high mortality rate, lack of standard diagnostic criteria and limited therapeutic options. Underscoring this challenge is the complex pathophysiology involved and multiple contributing factors that converge on a final pathway involving widespread endothelial injury and complement activation. In addressing our current understanding of TA-TMA, we highlight the risk factors leading to endothelial damage and a pathophysiological cascade that ensues. We have also compared the different definition criteria and biomarkers that can enable early intervention in TA-TMA patients. Current first-line management includes discontinuation or alteration of the immunosuppressive regimen, treatment of co-existing infectious and GVHD, aggressive hypertension control and supportive therapy. We discuss current pharmacological therapies, including newer agents that target the complement cascade and nitric oxide pathways.