Thrombotic Microangiopathy in Solid Organ Transplantation

A Pilot Trial of Pre-Transplant Risk Stratification and Prophylactic Defibrotide to Prevent Serious Thrombotic Microangiopathy in High-Risk Pediatric Hematopoietic Stem Cell Transplant Patients

Background and Aims IgAN is characterized by the presence of intense deposits of C3 accompanying IgA. As documented in several studies this is due to the activation of the complement system by pathological IgA; the mechanism of IgA–mediated complement activation remains poorly understood but is thought to act with different mechanisms such as the stabilization of the C3 convertase, the activation of the lectin pathway through polymeric IgA and eventually inherited partial deficiencies of complement regulatory genes [Maillard N, Wyatt RJ, Julian BA, Kiryluk K, Gharavi A, Fremeaux-Bacchi V, Novak J.J Current Understanding of the Role of Complement in IgA Nephropathy.Am Soc Nephrol 26:, 2015] . Dysregulation of the C3 convertase is a recognized cause of thrombotic microangiopathy (TMA) in atypical hemolytic uremic syndrome (aHUS). The association between aHUS and IgAN has been sporadically described . In this study we report a series of 6 patients, observed in our department, with biopsy proven IgAN, who developed aHUS during the follow-up. We report a series of aHUS associated IgA nephropathy. Method This report describes 6 patients with aHUS IgAN who were identified among all patients with biopsy proven IgAN observed at the Department of Nephrology, University of Parma, from March 2010 to March 2015. The diagnosis of aHUS was suspected in the presence of renal biopsy with documented typical signs of TMA (glomerular or arteriolar thrombi, onion skin lesions) associated with non-immune microangiopathic haemolytic anemia, increased reticulocyte count, negative Coomb test, thrombocytopenia (platelets <150000/mm3). Results Data collected on the 6 patients with IgA nephropathy associated with aHUS are described in Figure 1. All the cases of aHUS-IgAN were characterized by worsening of nephrotic proteinuria and reduced serum C3. Pathogenetic variant of CFH, predisposing for aHUS were identified in 2/6 cases; in the remaining patients a predisposing risk aplotype for aHUS was documented. All patients were treatment resistant for IgA nephropathy, had persistent proteinuria and progressed to ESRD. Conclusion It is known that most cases of aHUS are associated with the presence of genetic or acquired alterations of the regulation of the complement AP. However overlapping of other triggering conditions was documented in 70% of aHUS cases [Noris M, Caprioli J, Bresin E, et al. Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype. Clin J Am Soc Nephrol. 2010;5: 1844–1859]. Our case series shows that the presence of genetic factors predisposing to uncontrolled activation of the C3 convertase associated to continuous activation of the same enzyme from pathological IgA, could lead to sC3 consumption, development of aHUS and consequent rapid progression towards ESRD. In conclusion during the natural history of IgAN, appearance of hemolysis, thrombocytopenia, serum C3 reduction and increasing proteinuria would suggest to search for aHUS, allowing to early treatment with plasmapheresis and/or new available complement targeted inhibitors to prevent renal failure.

Ex vivo C5b-9 Deposition Test to Monitor Complement Activity in Clinical and Subclinical Atypical Hemolytic Uremic Syndrome and in Transplantation-Associated Thrombotic Microangiopathy

Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare complication of hematopoietic stem cell transplantation (HSCT) with variable presentations. TA-TMA has often been described as a diagnosis of exclusion but a renal biopsy is rarely pursued to confirm the diagnosis, an essential step for our patient with renally limited TMA. We report a case report from the onconephrology clinic and review the literature associated with TA-TMA as it relates to diagnosis and treatment. A 45-year-old woman with acute myeloid leukemia and stage 3 chronic kidney disease underwent a matched unrelated donor allogenic HSCT. Postoperatively, she developed gastrointestinal graft versus host disease (GvHD) and was treated with tacrolimus, sirolimus, budesonide, and beclomethasone. Following discharge, she developed uncontrolled hypertension and required losartan, amlodipine, carvedilol, clonidine patch, and hydralazine as needed. On day 180 post-transplant, she developed lower extremity edema and acute kidney injury (AKI) with creatinine increasing to 2 mg/dL. On day 480 post-transplant, she developed worsening thrombocytopenia, anemia, new hematuria, left flank pain, and worsening renal function with creatinine peaking to 6 mg/dL. Peripheral smear revealed no schistocytes, lactate dehydrogenase of 265 mg/dL, and urinalysis with 100 mg/dL protein. ADAMTS 13 activity was normal (92%) and no inhibitor was detected. She became anuric and was started on hemodialysis. Renal biopsy revealed glomerular changes consistent with TA-TMA. During HSCT, systemic vascular endothelial injury triggers microangiopathic hemolytic anemia, platelet consumption, injury of glomerular endothelial cells and fibrin occluded renal capillaries. Thus, TA-TMA should be considered in HSCT patients with elevated LDH, proteinuria, hypertension, and AKI. However, a diagnosis is difficult to confirm without a renal biopsy. Treatment involves discontinuing potentially toxic agents such as calcineurin inhibitors and sirolimus, prescribing adequate antimicrobial treatment, and using renal replacement therapy if needed. A renal biopsy early in the course of disease not only confirms the diagnosis, but may limit the extent of disease.

Thrombotic microangiopathy (TMA) is a medical emergency characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury (AKI). Its subtypes, including thrombotic thrombocytopenic purpura (TTP), atypical hemolytic uremic syndrome (aHUS), and secondary TMA, require rapid differentiation due to divergent treatments. Acute pancreatitis, in some cases, can trigger TMA through systemic inflammation and complement activation. A middle-aged male with chronic kidney disease and diabetes was admitted for acute pancreatitis, likely in the setting of glucagon-like peptide-1 (GLP-1) use. On day 3, he developed progressive thrombocytopenia, anemia, and worsening renal function. Peripheral smear showed schistocytes; laboratory valueswere remarkable for hemolysis. Given the high suspicion for TMA and a PLASMIC score of 5, empiric plasma exchange and corticosteroids were initiated, which showed clinical improvement. ADAMTS13 activity returned at 99%, effectively excluding TTP. Complement studies for aHUS were inconclusive and were obtained post-plasma exchange, which can alter results. The patient completed five sessions of plasma exchange and was discharged in stable condition. A follow-up was arranged for hematology.This case highlights the diagnostic complexity of TMA triggered by acute pancreatitis and the necessity of early empiric treatment. It also calls attention to the limitations of delayed ADAMTS13 and complement testing and advocates for broader implementation of rapid in-house assays to guide timely, precise therapy.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a multifactorial disorder, which occurs as a result of treatment-related endothelial injury and underlying disease process after hematopoietic stem cell transplantation (HSCT). The reported incidence of TA-TMA after HSCT is 0% to 74% and has shown to be associated with mortality rate of up to 100%. TA-TMA is often diagnosed late in the disease progression, and therapeutic plasma exchange (TPE) has not been shown to produce a high response rate. All English-language articles describing pharmacologic treatments for TA-TMA were identified using Ovid in the Medline database (1966-May 2014). Search was limited to the HSCT population. Approximately 50% to 63% of patients with TA-TMA respond to withdrawal of the offending agent (calcineurin inhibitors) and TPE, and many will require additional treatment to better control the disease. Unfortunately, there is no established treatment strategy for TA-TMA. A number of pharmacologic agents that have been explored for the treatment of TA-TMA include rituximab, vincristine, defibrotide, pravastatin, and eculizumab. The overall response rates of these agents were similar (69%-80%); however, the differences in the treatment costs vary significantly between these agents. Defibrotide is an investigational agent in the United States; therefore, it is not readily available for use. Larger studies are warranted to validate the role of these pharmacologic agents in TA-TMA as upfront therapy and in TPE-refractory patients. Recently suggested predictive biomarkers for TA-TMA, such as neutrophil extracellular traps and circulating endothelial cells, deserve more attention in future studies.

Improved Outcomes of Transplant Associated Thrombotic Microangiopathy with Early Initiation of Eculizumab

Interferon-complement loop in transplant-associated thrombotic microangiopathy

Transplant-associated thrombotic microangiopathy (TA-TMA) is considered one of the most severe complications after hematopoietic stem cell transplantation (HSCT). Transplant-associated thrombotic microangiopathy (TA-TMA) constitutes a form of microangiopathic haemolytic anemia and thrombocytopenia derived from a generalized endothelial dysfunction with intravascular platelet activation and formation of platelet-rich thrombi within the microcirculation. Since clinical features are common in several post hematopoietic stem cell transplantation (HSCT) complications such as capillary leak syndrome, engraftment syndrome, graft versus host disease (GVHD), diffuse alveolar hemorrhage and veno occlusive disease (VOD), an initial diagnosis of TA-TMA is not always certain, which is a principal reason for the failure of proposed treatments. Keywords: Thrombotic Microangiopathies; Hematopoietic Stem Cell Transplantation; Child; Hemolytic-Uremic Syndrome; Eculizumab. Normal 0 false false false EN-US X-NONE AR-SA

Information about a real patient is presented in stages (boldface type) to an expert clinician (Dr Scirica), who responds to the information, sharing his reasoning with the reader (regular type).

Transplantation-associated thrombotic microangiopathy (TMA) is one of the main complications after hematopoietic stem cell transplantation (HSCT). At the time of onset of gut TMA, a patient developed a high titer of an inhibitor of the non-immunoglobulin G type to ADAMTS13, which physiologically hydrolyzes von Willebrand factor to control spontaneous intravascular thrombus formation. The patient developed symptoms of myositis, a disorder that has occasionally been reported to manifest after HSCT and to resemble some idiopathic autoimmune diseases. However, a muscle biopsy specimen presented pathologic findings of TMA, including microvascular platelet thrombus formation, without inflammatory lymphocyte infiltration. ADAMTS13 activities returned to normal after steroid treatment, and the improvement of TMA symptoms followed. This patient appears to represent a rare case of post-HSCT TMA associated with the development of an ADAMTS13 inhibitor.

Combined Effects of Hematopoietic Cell Transplantation Associated Thrombotic Microangiopathy and Acute Graft-Versus-Host Disease on Requiring Renal Replacement Therapy in US Patient Population - a Secondary CIBMTR Analysis

Pegcetacoplan for patients with transplant-associated thrombotic microangiopathy treatment: A real-world report of six cases

Hematopoietic stem cell transplantation (HSCT) offers a potential cure for various hematologic malignancies and non-malignant disorders but is often accompanied by severe complications, one of the most challenging being transplant-associated thrombotic microangiopathy (TA-TMA). Eculizumab, a complement inhibitor, has emerged as an effective therapeutic option for TA-TMA. This single-center retrospective study was conducted at Pavlov University, St. Petersburg, to evaluate the efficacy of eculizumab in 14 adult and pediatric patients who developed high-risk TA-TMA following HSCT between 2015 and 2023. Treatment response was assessed by monitoring organ functions, blood counts, transfusion requirements, the presence of schistocytes in peripheral blood, and increased serum lactate dehydrogenase (LDH). The primary endpoint was overall survival at 100 days from eculizumab administration. Secondary endpoints included the cumulative incidence of a 25% decrease in serum lactate dehydrogenase levels and to the limit of the normal range for age from the date of the initiation of eculizumab, the cumulative incidence of a 50% increase in platelet count or stable platelet levels ≥ 20×109/l was 74% (95% CI, 32-92) with median time 21 days (range: 1-104), cumulative incidence of platelet level ≥ 50×109/l, and 1 year from the date of the initiation of eculizumab. Overall survival at 100 days was 57% (95%CI, 36-90). The cumulative incidence of LDH decreased by 25% was 89% (95% CI, 26-99) with a median time of 11 days (range: 2-27). Cumulative incidence of LDH ≤ 1.5 upper reference limits (URLs) after eculizumab therapy was 73% (95% CI, 34-91) with a median time of 22 days (range: 2-170). The cumulative incidence of a 50% increase in platelet level or stable platelet level ≥ 20×109/l was 74% (95% CI, 32-92) with a median time of 21 days (range: 1-104). The cumulative incidence of platelet level ≥ 50×109/l was 56% (95% CI, 22-80) with a median time of platelet increase of 75 days (range: 5-384). Complete response was documented in 57% of the group. In summary, eculizumab is a well-tolerated promising therapeutic intervention for TA-TMA, but more studies are needed to establish its timing and dosage regimen in TA-TMA.

Report of Rare Urachal Carcinoma Presenting with Thrombocytopenia and Microangiopathic Hemolytic Anemia