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P Dhakal, V R Bhatt
Diagnosis and management of hematopoietic cell transplant-associated thrombotic microangiopathy (TA-TMA) are very complex and controversial, given multiple ongoing issues and comorbidities in sick transplant recipients. Complement activation via classic and alternative pathways is emerging as a potential pathogenetic mechanism in the development of TA-TMA. Complement-centric diagnostic strategy using functional and genetic tests may possibly support diagnosis, enhance molecular understanding and direct drug development...
October 24, 2016: Bone Marrow Transplantation
Valentina Talarico, Monica Aloe, Alice Monzani, Roberto Miniero, Gianni Bona
Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy defined by thrombocytopenia, non-immune microangiopathic hemolytic anemia and acute renal failure. HUS is typically classified into two primary types: 1) HUS due to infections, often associated with diarrhea (D+HUS, Shiga toxin-producing Escherichia Coli-HUS), with the rare exception of HUS due to a severe disseminated infection caused by Streptococcus; 2) HUS related to complement, such HUS is also known as "atypical HUS" and is not diarrhea associated (D-HUS, aHUS); but recent studies have shown other forms of HUS, that can occur in the course of systemic diseases or physiopathological conditions such as pregnancy, after transplantation or after drug assumption...
December 2016: Minerva Pediatrica
Yu-Min Shen
Atypical hemolytic uremic syndrome (aHUS) is a rare genetic disorder caused by defective complement regulation resulting in thrombotic microangiopathy (TMA). Patients can present as children or adults. The syndrome consists of hemolytic anemia with schistocytosis, thrombocytopenia, significant renal damage, and/or other organ system dysfunction(s). Patients with aHUS may succumb to the complications of the disease with the very first manifestation; surviving patients often suffer from progressive organ dysfunction with significant morbidity and mortality despite plasma infusion or plasma exchange...
2016: Thrombosis Journal
Silvia De-la-Iglesia, Hugo Luzardo, Angelina Lemes, Melissa Torres, Maria Teresa Gómez-Casares, Naylen Cruz, Teresa Molero
Paroxysmal nocturnal hemoglobinuria (PNH) is associated with severe end-organ damage and a high risk of thrombosis. Budd-Chiari syndrome, which develops after thrombotic occlusion of major hepatic blood vessels, is relatively common in PNH and has been associated with increased mortality. We report the case of a 46-year-old male with PNH who presented with Budd-Chiari syndrome associated with portal cavernoma, portal hypertension and hypersplenism. In September 2010, the patient suffered gastrointestinal bleeding, hematuria, and elevated plasma lactate dehydrogenase; he started eculizumab therapy with a good response...
September 28, 2016: Hematology Reports
Emmanuel Gonzales, Tim Ulinski, Dalila Habes, Georges Deschênes, Véronique Frémeaux-Bacchi, Albert Bensman
BACKGROUND: Rational options for the treatment of end-stage renal disease (ESRD) due to atypical hemolytic uremic syndrome (aHUS) in children are still open to discussion. In the case of human complement factor H (CFH) deficiency, the choice is either kidney transplantation in combination with eculizumab, a humanized anti-C5 monoclonal antibody, or a combined liver-kidney transplantation. CASE-DIAGNOSIS/TREATMENT: A child with a homozygous CFH deficiency underwent a successful liver-kidney transplantation...
October 15, 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Fusun Gediz, Bahriye Kadriye Payzin, Sertac Ecemis, Naile Güler, Asu Fergun Yilmaz, Fusun Topcugil, Afig Berdeli
INTRODUCTION: Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy, which develops as a result of defective activity of the alternative complement pathway and excessive complement activation due to genetic or acquired factors. No satisfactory responses were obtained by plasmapheresis, corticosteroids and fresh frozen plasma (FFP) transfusion. However, promising results are obtained in recent years by eculuzimab treatment, which inhibits C5 activation. OBJECTIVE: To evaluate the efficacy, safety and effect of eculizumab on quality of life of adult aHUS patients followed in our center...
September 30, 2016: Transfusion and Apheresis Science
Diana Karpman, Peter Höglund
Orphan drugs designed to treat rare diseases are often overpriced per patient. Novel treatments are sometimes even more expensive for patients with ultra-rare diseases, in part due to the limited number of patients. Pharmaceutical companies that develop a patented life-saving drug are in a position to charge a very high price, which, at best, may enable these companies to further develop drugs for use in rare disease. However, is there a limit to how much a life-saving drug should cost annually per patient? Government interventions and regulations may opt to withhold a life-saving drug solely due to its high price and cost-effectiveness...
October 13, 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
A Frazer-Abel, L Sepiashvili, M M Mbughuni, M A V Willrich
Historically, complement disorders have been attributed to immunodeficiency associated with severe or frequent infection. More recently, however, complement has been recognized for its role in inflammation, autoimmune disorders, and vision loss. This paradigm shift requires a fundamental change in how complement testing is performed and interpreted. Here, we provide an overview of the complement pathways and summarize recent literature related to hereditary and acquired angioedema, infectious diseases, autoimmunity, and age-related macular degeneration...
2016: Advances in Clinical Chemistry
Tanja Kersnik Levart, Dušan Ferluga, Alenka Vizjak, Jerica Mraz, Nika Kojc
BACKGROUND: Understanding the role of alternative complement pathway dysregulation in membranoproliferative glomerulonephritis (MPGN) has led to a dramatic shift in its classification into two subgroups: immune complex-mediated MPGN and complement-mediated MPGN, consisting of dense deposit disease and C3 glomerulonephritis (C3GN). A limited number of C3GN cases have been published to date with not yet conclusive results since the novel therapeutic approach with eculizumab was introduced...
October 7, 2016: Diagnostic Pathology
Hassib Chehade, Samuel Rotman, Véronique Frémeaux-Bacchi, Vincent Aubert, Salima Sadallah, Loukia Sifaki, Rémi Salomon, Manuel Pascual
Activation of the complement cascade plays an important role in the pathogenesis of postinfectious glomerulonephritis. We report successful terminal complement pathway blockade using an anti-C5 monoclonal antibody (eculizumab) in an 8-year-old child with severe acute postinfectious glomerulonephritis requiring hemodialysis. The child presented with clinical, serologic, and histopathologic criteria for diffuse crescentic postinfectious glomerulonephritis. Complement measurements showed low C3 and C4 levels, with increased SC5b-9 titers...
September 24, 2016: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
Jie Lin, Binbin Xue, Xiang Li, Junhui Xia
Monoclonal-antibody has been used for patients with autoimmune disorders for several years, and efficacy and safety were appreciated for these patients. Neuromyelitis optica specturm disorder (NMOSD) has been defined as an autoimmune demyelination disorder of the central nervous system (CNS) with a course of relapse-remission. Treatment of prevention is important for patients with NMOSD because of the increased disability after several attacks. Multiple factors were involved in the pathogenesis of NMOSD. Currently, targeting specific factor was favored in the research into the treatment for NMOSD...
October 14, 2016: International Journal of Neuroscience
Marie Scully
Thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS) are thrombotic microangiopathies (TMAs) that can present in pregnancy. The presentation can be with typical microangiopathic features and thrombocytopenia, but there is also a significant risk of in-utero fetal loss. TTP presents most commonly in the third trimester and aHUS in the postpartum period. On presumptive diagnosis, plasma exchange should be started and ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity measured...
September 20, 2016: Seminars in Thrombosis and Hemostasis
Selçuk Yüksel, Havva Evrengül, Z Birsin Özçakar, Tülay Becerir, Nagihan Yalçın, Emine Korkmaz, Fatih Ozaltin
INTRODUCTION: Studies relating to first-line, early, and long-term eculizumab treatment and outcomes in children with atypical hemolytic uremic syndrome (aHUS) are scarce and unclear. The aim of this case-series study was to evaluate the outcomes of first-line, early, and long-term eculizumab treatment in our aHUS patients. MATERIALS AND METHODS: We reviewed the data from four pediatric patients with aHUS who were treated with eculizumab. In three of them, eculizumab was used as a first-line therapy, and the follow-up period was ≥2 years in three patients...
September 19, 2016: Paediatric Drugs
Marta Subías Hidalgo, Hector Martin Merinero, Alicia López, Jaouad Anter, Sheila Pinto García, Fernando Ataúlfo Gonzalez-Fernández, Rafael Forés, Margarita Lopez-Trascasa, Ana Villegas, Emilio Ojeda, Santiago Rodríguez de Córdoba
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia characterized by complement-mediated intravascular hemolysis that is effectively treated with eculizumab. However, treatment responses are reported heterogeneous with some patients presenting residual hemolysis and requiring RBC transfusions. Recent reports have shown that both extravascular hemolysis and incomplete C5 blockade can explain these suboptimal hematological responses. Here we have tested our eculizumab-treated PNH patients (n=12) for signs of hemolysis and assessed complement biomarkers...
September 13, 2016: Immunobiology
Joseph Rosenthal
Transplant-associated thrombotic microangiopathy (TA-TMA) is a multifactorial disorder caused by systemic vascular endothelial injury that can be triggered by several mechanisms during the transplant process. Thrombotic microangiopathy may affect multiple systems and occurs in ~30% of patients undergoing hematopoietic stem cell transplantation. A subgroup of patients with thrombotic microangiopathy develop TA-TMA, and the other may develop other thrombotic microangiopathic disorders such as thrombotic thrombocytopenic purpura, a condition with similar finding but different pathophysiology involving ADAMTS-13...
2016: Journal of Blood Medicine
Nathalie Costedoat-Chalumeau, Laetitia Coutte, Véronique Le Guern, Nathalie Morel, Gaelle Leroux, Romain Paule, Luc Mouthon, Jean-Charles Piette
The catastrophic antiphospholipid syndrome (CAPS) develops in at least 1% of patients with antiphospholipid syndrome, either primary or associated with systemic lupus erythematosus. CAPS reveals the antiphospholipid syndrome in about 50% of cases. The CAPS is characterized by rapidly-progressive widespread thromboses mainly affecting the microvasculature in the presence of antiphospholipid antibodies. In a few days, the patients develop multiorgan failure with renal insufficiency with severe hypertension, pulmonary, cerebral, cardiac, digestive and/or cutaneous involvement...
September 9, 2016: La Presse Médicale
Kheir Eddine Kerboua, Fatma Haiba, Djamila Batouche
Treatment of atypical hemolytic uremic syndrome (aHUS) by the complement C5 inhibitor eculizumab (Soliris®) is highly effective but unfortunately, associated with an economic pressure on the health care systems even in high incomes countries. Despite spacing infusions has been proposed as the unique solution to minimize this economic impact, no reliable laboratory assays are available to tailor such therapy optimization. We aimed to propose and evaluate a complement composite marker for eculizumab efficacy monitoring in aHUS...
September 12, 2016: Journal of Immunoassay & Immunochemistry
Amy Riddell, Tim Goodship, Coralie Bingham
Eculizumab, a terminal complement inhibitor, has recently been used successfully to both prevent and treat the recurrence of atypical hemolytic uremic syndrome (aHUS) post renal transplantation. We describe a case that highlights the need to monitor the effects of eculizumab on the complement system and in this case alter the dosage. Despite taking the standard recommended dose of eculizumab for an adult, this aHUS patient developed a low-grade thrombotic microangiopathy on biopsy within months of renal transplantation...
October 2016: Clinical Nephrology
Saif A Khan, Dawood Al-Riyami, Yasser W Al-Mula Abed, Saja Mohammed, Marwa Al-Riyami, Nabil M Al-Lawati
Antibody-mediated rejection (ABMR) jeopardises short- and long-term transplant survival and remains a challenge in the field of organ transplantation. We report the first use of the anticomplement agent eculizumab in Oman in the treatment of a 61-year-old female patient with ABMR following a living unrelated kidney transplant. The patient was admitted to the Sultan Qaboos University Hospital in Muscat, Oman, in 2013 on the eighth day post-transplantation with serum creatinine (Cr) levels of 400 µmol/L which continued to rise, necessitating haemodialysis...
August 2016: Sultan Qaboos University Medical Journal
Laura J Wozniak, Bita V Naini, Michelle J Hickey, Sarathi Bhattacharyya, Elaine F Reed, Ronald W Busuttil, Douglas G Farmer, Jorge H Vargas, Robert S Venick, Sue V McDiarmid
Acute AMR is well reported following ABO-incompatible LTx. However, it remains uncommon in ABO-compatible LTx. It typically presents with graft dysfunction ≤2 weeks post-LTx and is often associated with graft loss. We report the clinical presentation, treatment regimen, and outcome of six pediatric LTx recipients diagnosed with early acute AMR based on (i) clinical signs of graft dysfunction, (ii) histopathology indicative of acute injury ± C4d staining, and (iii) presence of HLA DSA. All patients developed elevated ALT and GGT ≤ 45 days post-LTx...
September 5, 2016: Pediatric Transplantation
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