Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy.
ABSTRACT Hematopoietic stem cell transplant (HSCT)-associated thrombotic microangiopathy (TMA) is a complication that occurs in 25-35 % of HSCT recipients and shares histomorphological similarities with hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). The hallmark of all thrombotic microangiopathies is vascular endothelial cell injury of various origins, resulting in microangiopathic hemolytic anemia, platelet consumption, fibrin deposition in the microcirculation and tissue damage. While significant advances have been made in the understanding of the pathogenesis of other thrombotic microangiopathies, post-HSCT TMA remains poorly understood. We report an analysis of the complement alternative pathway, which has recently been linked to the pathogenesis of both the Shiga toxin mediated and the atypical forms of HUS, with a focus on genetic variations in the complement Factor H (CFH) gene cluster and CFH autoantibodies in six children with post-HSCT TMA. We identified a high prevalence of deletions in CFH-related genes 3 and 1 (delCFHR3-CFHR1) and CFH autoantibodies in these patients with HSCT-TMA. Conversely, CFH autoantibodies were not detected in 18 children undergoing HSCT who did not develop TMA. Our observations suggest that complement alternative pathway dysregulation may be involved in the pathogenesis of post-HSCT TMA. These findings shed light on a novel mechanism of endothelial injury in transplant-associated thrombotic microangiopathy and may therefore guide the development of targeted treatment interventions.
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ABSTRACT: Thrombotic microangiopathies (TMA) are rare but severe disorders, characterized by endothelial cell activation and thrombus formation leading to hemolytic anemia, thrombocytopenia, and organ failure. Complement over activation in combination with defects in its regulation is described in an increasing number of TMA and if primary for the disease denominated as atypical hemolytic-uremic syndrome. Although TMA predominantly affects the renal microvasculature, extra-renal manifestations are observed in 20% of patients including involvement of the central nerve system, cardiovascular system, lungs, skin, skeletal muscle, and gastrointestinal tract. Prompt diagnosis and treatment initiation are therefore crucial for the prognosis of disease acute phase and the long-term outcome. This review summarizes the available evidence on extra-renal TMA manifestations and discusses the role of acute and chronic complement activation by highlighting its complex interaction with inflammation, coagulation, and endothelial homeostasis.Frontiers in Pediatrics 09/2014; 2:97.
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ABSTRACT: The haemolytic uraemic syndrome (HUS) is part of a spectrum of thrombotic microangiopathies. The most common etiologies of HUS are the ones seen in childhood caused by an infection of Shiga toxin-producing Escherichia coli, HUS caused by an infection with Streptococcus pneumoniae and HUS due to abnormalities in the alternative pathway of the complement system. In the past decade, enormous progress has been made in understanding the pathogenesis in the latter group of patients. The analysis of genes that encode for complement regulatory proteins and the development of assays for measuring the activity of ADAMTS13 and the detection of antibodies against factor H contributed significantly to the diagnostic tools in patients with HUS. These assays have made it possible to clearly differentiate between thrombotic thrombocytopenic purpura and various forms of HUS. With the introduction of eculizumab, a monoclonal anti-C5 inhibitor, in the clinical arena as effective treatment of most complement-mediated forms of HUS, a new era of treatment in HUS has begun. We review the recent advances in HUS, with the focus on treatment. We discuss unsolved questions, which should be addressed in future studies.Nephrology Dialysis Transplantation 09/2014; 29(suppl 4):iv131-iv141. · 3.49 Impact Factor
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ABSTRACT: Thrombotic microangiopathies (TMA) are disorders defined by the presence of a microangiopathic hemolytic anemia (with the characteristic hallmark of schistocytes in the peripheral blood smear), thrombocytopenia and organ malfunction of variable intensity. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are the most important forms of TMA and, without the adequate treatment, they are associated with high morbimortality. In recent years, significant advances in the knowledge of the pathophysiology of TMA have occurred. Those advances have allowed us to move from a syndromic diagnosis with a similar treatment to all entities to the search of etiologic diagnosis which would lead to a specific treatment, finally leading to a better outcome of the patient. This document pretends to summarize the current status of knowledge of the pathophysiology of TMA and the therapeutic options available, and to offer a diagnostic and therapeutic practical tool to the professionals caring for the patients. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.Medicina clinica. 11/2014;