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Management of thrombotic microangiopathy after hematopoietic cell transplantation: A position statement of ThREG (Turkish Hematology Research and Education Group)
Abstract
Hematopoietic stem cell transplantation associated-thrombotic microangiopathy (TA-HCT) is one of the early complications of endothelial origin in the course of HCT. Endothelial damage to the microvascular structure and the platelet-rich microthrombi, which are formed as a result of accompanying complement activation, constitute the main pathological conditions resulting TA-TMA. Early diagnosis and management are of utmost importance to prevent multi-organ failure and death. This review summarizes the current understanding of TA-TMA regarding pathogenesis, definition, differential diagnosis, risk factors, surveillance for early diagnosis and management.
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Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic stem cell transplant (HSCT) with high morbidity and mortality. The triad of endothelial cell activation, complement dysregulation, and microvascular hemolytic anemia has the potential to cause end organ dysfunction, multiple organ dysfunction syndrome and death, but clinical features mimic other disorders following HSCT, delaying diagnosis. Recent advances have implicated complement as a major contributor and the therapeutic potential of complement inhibition has been explored. Eculizumab has emerged as an effective therapy and narsoplimab (OMS721) has been granted priority review by the FDA. Large studies performed mostly in pediatric patients suggest that earlier recognition and treatment may lead to improved outcomes. Here we present a clinically focused summary of recently published literature and propose a diagnostic and treatment algorithm.
Background
Transplant-associated thrombotic microangiopathy (TA-TMA) is a dangerous and life-threatening complication in patients undergoing hematopoietic stem cell transplantation (HSCT). Eculizumab has been used in the treatment of TA-TMA, and several studies have confirmed the benefit of Eculizumab in patients with TA-TMA. However, the results remain controversial. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Eculizumab for TA-TMA.
Materials and Methods
We searched PubMed and Embase for studies on the efficacy and safety of Eculizumab in TA-TMA patients. Efficacy outcomes consisted of overall response rate (ORR), complete response rate (CRR), and survival rate at the last follow-up (SR). Safety outcomes were adverse events (AEs), including infection, sepsis, impaired liver function, infusion reactions, and death.
Results
A total of 116 patients from six studies were subjected to meta-analysis. The pooled estimates of ORR, CRR, and SR for TA-TMA patients were 71% (95% CI: 58–82%), 32% (95% CI: 11–56%), and 52% (95% CI: 40–65%), respectively. Only one patient presented with a severe rash, and infection was the most common AEs. The main causes of death were infection and GvHD.
Conclusion
Current evidence suggests that Eculizumab improves SR and ORR in patients with TA-TMA and that Eculizumab is well tolerated. However, the number of studies is limited, and the findings are based mainly on data from observational studies. Higher quality randomized controlled trials and more extensive prospective cohort studies are needed.
Transplant‐associated thrombotic microangiopathy (TA‐TMA) is a complication of allogeneic transplantation (allo‐HCT). The incidence and risk factors associated with TA‐TMA are not well known. A retrospective analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR) was conducted including patients receiving allo‐HCT between 2008 and 2016, with the primary objective of evaluating the incidence of TA‐TMA. Secondary objectives included identification of risk factors associated with TA‐TMA, and the impact of TA‐TMA on overall survival and the need for renal replacement therapy (RRT). Among 23,665 allo‐HCT recipients, the 3‐year cumulative incidence of TA‐TMA was 3%. Variables independently‐associated with increased incidence of TA‐TMA included female sex, prior autologous transplant, primary disease (acute lymphoblastic leukaemia and severe aplastic anaemia), donor type (mismatched or unrelated donor), conditioning intensity (myeloablative), GVHD prophylaxis (sirolimus + calcineurin inhibitor), pre‐transplant kidney dysfunction and acute GVHD (time‐varying effect). TA‐TMA was associated with higher mortality (HR = 3·1, 95% Confidence Interval [CI] = 2·8–16·3) and RRT requirement (HR = 7·1, 95% CI = 5·7–311·6). This study provides epidemiologic data on TA‐TMA and its impact on transplant outcomes. Increased awareness of the risk factors will enable providers to be vigilant of this uncommon but serious transplant complication. The results will also provide benchmarking for future study designs and comparisons.
Introduction
Overactivated complement is a high-risk feature in HSCT recipients with transplant associated thrombotic microangiopathy (TA-TMA) and untreated patients have dismal outcomes. We present our experience in 64 pediatric HSCT recipients with high risk TA-TMA and multi-organ injury treated with the complement blocker eculizumab.
Objectives
• To evaluate the impact of high risk TA-TMA on clinical outcomes.
• To determine high risk TA-TMA response to complement blocking therapy with eculizumab.
• To gain clinical knowledge in this high-risk population for future study planning.
Methods
We performed retrospective chart review of all patients receiving eculizumab therapy for high risk TA-TMA at our institution (2012-2018). All patients were prospectively screened for TA-TMA and received PK/PD guided eculizumab dosing.
Results
We demonstrate a significant improvement in 1 year post-HSCT survival to 66% in treated patients from our previously reported untreated cohort with the same high-risk TA-TMA features that had 1 year post-HSCT survival of 16.7%. Responding patients benefited from a brief but intensive eculizumab therapy course using PK/PD guided drug dosing, requiring a median of 11 doses of eculizumab (IQR 7-20), and were off therapy in median of 66 days (IQR 41-110). Subjects with higher complement activation measured by elevated blood sC5b-9 at the start of therapy were less likely to respond to treatment (OR =0.15, p-value 0.0014) and required more doses of eculizumab [r = 0.43, p-value = 0.0004]. Patients with intestinal bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs 9, p=0.0015) and had lower 1y survival (44% vs 78%, p=0.01). Over 70% of survivors had mild proteinuria on long term follow up. The best CystC GFR recovery in survivors was a median 20% lower (IQR 7.3-40.3%) than their pre-HSCT CystC GFR.
Conclusion
Complement blockade with eculizumab is an effective therapeutic strategy for high risk TA-TMA, but some patients with severe disease lack a complete response, prompting us to propose early intervention strategies and search for additional targetable endothelial injury pathways.
Transplantation-associated thrombotic microangiopathy (TA-TMA) is an important complication of hematopoietic stem cell transplantation. To date, information regarding the organs that are affected by TA-TMA as confirmed histologically remains limited; the clinicopathologic differences between renal TA-TMA and intestinal TA-TMA have not been examined despite being the well-known and commonly affected sites of TA-TMA. We therefore examined 165 autopsied patients after hematopoietic stem cell transplantation and compared the clinicopathologic factors of renal and intestinal TA-TMA. It was clear that 38 (23%) of our patients had TA-TMA. In the TA-TMA cases, the kidney (61%) and intestine (53%) were commonly affected, and the ileum and right colon were vulnerable. Other organs that we found to be affected by TA-TMA included the stomach (8%), gallbladder (5%), and oral cavity, pharynx, esophagus, liver, heart, urinary bladder, and ureter (all at 3%), and symptoms thought to be caused by TA-TMA of these organs were not observed in any patient. Histologically, TA-TMA only affected the arteriole, or small arteries, regardless of the organ, and the veins or larger arteries were not affected at all. In the kidney, the glomerular capillary was also affected, and mesangiolysis and double contours of the basement membranes were often in evidence. The histologic overlap of renal and intestinal TA-TMA was rare (13%), and the patients in the intestinal TA-TMA group exhibited more frequency of a history of intestinal acute graft-versus-host disease (GVHD) during the clinical course compared with that of the renal TA-TMA group (80% versus 22%, P = .0016). Although TA-TMA can affect many other organs, the frequency of these ancillary events was low, and the clinical effect may have been small. Our results suggest that in comparison to renal TA-TMA, intestinal GVHD could be more closely associated with intestinal TA-TMA as a risk factor.
Veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT) conditioning or high-dose nontransplant chemotherapy. VOD/SOS with multi-organ dysfunction (MOD) is associated with a mortality rate of > 80%. Defibrotide (25 mg/kg/day) is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post HSCT in the United States and to treat severe hepatic VOD/SOS in patients > 1 month of age in the European Union. A random effects model was used for pooling data from 17 systematically chosen defibrotide studies. For patients in these reports (n = 2598), and those in the subset of 10 reports of patients treated with ~ 25 mg/kg/day (n = 1691), estimated Day + 100 survival rates were 54% and 56%, respectively. Among those patients treated with ~ 25 mg/kg/day, estimated Day + 100 survival was 44% among patients with MOD and 71% in patients without MOD; survival was 41% and 70%, respectively, for the population of patients receiving any dose of defibrotide. Safety results were not pooled owing to differences in reporting methodology but were generally consistent with the known tolerability profile of defibrotide. This analysis provides the largest assessment of survival in patients treated with defibrotide for VOD/SOS with or without MOD.
Transplant-associated thrombotic microangiopathy (TA-TMA), a complication of hematopoietic cell transplant (HCT), is associated with significant morbidity and mortality. The pathophysiology and overlap of TA-TMA with other posttransplant complications such as graft-versus-host disease (GVHD) is poorly understood. We retrospectively identified cases of TA-TMA among patients with grade 3/4 gastrointestinal (GI) GVHD, reviewed intestinal biopsy specimens, and performed correlative testing of biomarkers associated with TA-TMA. TA-TMA was more common in patients with steroid-refractory GVHD compared with steroid-responsive GVHD (79.3% vs 42.1%; P = .001). Among patients surviving 100 days post-HCT, 1-year survival from day 100 was significantly better for patients who had not developed TA-TMA in the first 100 days (69.5% vs 36.7%; P < .001). Only 1 of 7 proposed TA-TMA histology criteria (mucosal hemorrhage) differed significantly based on GVHD steroid response. In multivariable modeling, steroid-refractory GVHD was a risk factor for development of TA-TMA (hazard ratio, 3.09; 95% confidence interval, 1.68-5.67; P < .001). There were no differences in complement activation at GVHD onset; however, 2 to 6 weeks later, patients with TA-TMA had higher levels of BBPlus and C5b-9, markers of alternative and terminal pathway activation (BBPlus: median, 600 vs 209.3 ng/mL; P = .0045) (C5b-9: median, 425.9 vs 258.4 ng/mL; P = .029). TA-TMA is associated with poor overall survival (OS) following HCT and may be detected early by histologic findings and may be differentiated from GVHD by measurement of alternative and terminal complement pathway activation. It is unknown whether treatment of TA-TMA will improve survival in steroid-refractory GVHD.
Thrombotic microangiopathy is a potentially lethal complication of haematopoietic stem cell (bone marrow) transplantation. The pathophysiology is incompletely understood, although endothelial damage appears to be central. Platelet activation, neutrophil extracellular traps and complement activation appear to play key roles. Diagnosis may be difficult and universally accepted diagnostic criteria are not available. Treatment remains controversial. In some cases, withdrawal of calcineurin inhibitors is adequate. Rituximab and defibrotide also appear to have been used successfully. In severe cases, complement inhibitors such as eculizumab may play a valuable role. Further research is required to define the pathophysiology and determine both robust diagnostic criteria and the optimal treatment.
We report the results of a single center analysis of a cohort of 39 patients treated between 1997 and 2016 for transplantion-associated thrombotic microangiopathy. We evaluated two subgroups of patients: 24 patients treated between 1997 and 2014 who received conventional therapy and 15 patients who were treated with the complement-inhibiting monoclonal antibody eculizumab between 2014 and 2016. The conventional therapy group was predominantly treated with defibrotide alone or in combination with plasmapheresis or rituximab. Despite an initial response rate of 61 %, only four patients (16%) were long-term survivors two of whom had a low-risk thrombotic microangiopathy without multi-organ damage. Progression of thrombotic micorangiopathy as well as bacterial/fungal infections equally contributed to treatment failure. The overall response rate in the eculizumab group was significantly higher at 93%. Additionally, we were able to stop eculizumab treatment in five patients (33%), all with high-risk thrombotic microangiopathy, due to sustained recovery. Despite the very high response within the eculizumab-treated group, we did not observe a significant improved overall survival which was primarily due to a high rate of infection related mortality (70%). Therefore further studies are needed to identify the best therapeutic management for transplant-associated thrombotic microangiopathy to improve its dismal outcome.
Transplantation-associated thrombotic microangiopathy (TA-TMA) is a significant complication of haematopoietic stem cell transplantation. However, it remains controversial which clinical or laboratory markers are of evident risk and prognostic value. From 2006 to 2013, a nested case control study was carried out in our centre to study the risk and prognostic factors of TA-TMA. A total of 654 consecutive patients who underwent allogeneic haematopoietic stem cell transplantation were studied. Twenty-six (4.0%) patients matched the established diagnostic criteria. Subjects with TA-TMA had significantly higher 3-year none relapse mortality compared with those without (65.4% vs 15.4%, P < 0.0001). Grades 2 to 4 aGVHD and cytomegalovirus viremia were independent risk factors, and serum LDH level >500U/L as well as hypertension were early signs of TA-TMA occurrence. Liver dysfunction and significant gastric bleeding were independent risk factors for TA-TMA related mortality. Subjects with either liver dysfunction or significant gastric bleeding had significantly higher 3 year TA-TMA related mortality cumulative incidence than subjects without. These observations lead to the conclusion that allo-HSCT recipients with grades 2 to 4 aGVHD or cytomegalovirus viremia should be monitored for TA-TMA. Liver dysfunction and significant gastric bleeding are prognostic factors for TA-TMA. Copyright © 2016 John Wiley & Sons, Ltd.
Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life threatening complication that can develop after hematopoietic cell transplantation. Although SOS/VOD progressively resolves within a few weeks in most patients, the most severe forms result in multi-organ dysfunction and are associated with a high mortality rate (>80%). Therefore, careful attention must be paid to allow an early detection of SOS/VOD, particularly as drugs have now proven to be effective and licensed for its treatment. Unfortunately, current criteria lack sensitivity and specificity, making early identification and severity assessment of SOS/VOD difficult. The aim of this work is to propose a new definition for diagnosis, and a severity-grading system for SOS/VOD in adult patients, on behalf of the European Society for Blood and Marrow Transplantation.Bone Marrow Transplantation advance online publication, 16 May 2016; doi:10.1038/bmt.2016.130.
Transplant-associated thrombotic microangiopathy (TMA) leads to generalized endothelial dysfunction that can progress to multiorgan injury, and severe cases are associated with poor outcomes after hematopoietic stem cell transplantation (HSCT). Identifying patients at highest risk for severe disease is challenging. We prospectively evaluated 100 consecutive HSCT recipients to determine the incidence of moderate and severe TMA and factors associated with poor overall outcomes. Thirty-nine subjects (39%) met previously published criteria for TMA. Subjects with TMA had a significantly higher nonrelapse mortality (43.6% vs 7.8%, P < .0001) at 1 year post-HSCT compared with those without TMA. Elevated lactate dehydrogenase, proteinuria on routine urinalysis, and hypertension were the earliest markers of TMA. Proteinuria (>30 mg/dL) and evidence of terminal complement activation (elevated sC5b-9) in the blood at the time of TMA diagnosis were associated with very poor survival (<20% at 1 year), whereas all TMA subjects without proteinuria and a normal sC5b-9 serum concentration survived (P < .01). Based on these prospective observations, we conclude that severe TMA occurred in 18% of HSCT recipients in our cohort and propose an algorithm to identify the highest-risk patients who might benefit from prompt clinical interventions.
Posttransplantation thrombotic microangiopathy (TMA) is a multifactorial complication of allogeneic hematopoietic cell transplantation (allo-HCT) whose incidence is increased with the use of a sirolimus plus tacrolimus (SIR/TAC) regimen for acute graft-versus-host disease (aGVHD) prophylaxis. We evaluated the incidence and possible risk factors for TMA in a case series of 177 patients who received allo-HCT using SIR/TAC-based GVHD prophylaxis. The patients received either a sibling donor graft (n = 82) or a matched unrelated donor graft (n = 95). Within the first 100 days post-HCT, 30 patients (17%) were diagnosed with TMA, and an additional 9 patients (5%) were classified as probable TMA cases. The median time to onset of TMA was 4.6 weeks (range, 1.6-10.6 weeks). Thirty-four patients developed both TMA and aGVHD, with the majority (81%) developing aGVHD first. Multivariate analysis identified the following factors as associated with increased risk of TMA: day 14 serum sirolimus level ≥9.9 ng/mL (hazard ratio [HR], 2.19; 95% confidence interval [CI], 1.13-4.27; P = .02), presence of previous aGVHD grade II-IV (HR, 3.04; 95% CI, 1.38-6.71; P < .01), and fully myeloablative conditioning (HR, 3.47; 95% CI, 1.60-7.53; P < .01). These risk factors for TMA suggest that when using a SIR/TAC regimen for GVHD prophylaxis, careful monitoring and adjustment of the sirolimus dosage is critical, particularly in patients with active aGVHD.
Transplantation-associated thrombotic microangiopathy (TA-TMA) is a challenging diagnosis after hematopoietic stem cell transplantation. Although endothelial injury represents the final common pathway of disease, the exact pathophysiology of TA-TMA remains unclear. Potential causes include infections, chemotherapy, radiation, and calcineurin inhibitors. Recent literature addresses the roles of cytokines, graft-versus-host disease, the coagulation cascade, and complement in the pathogenesis of TA-TMA. Current diagnostic criteria are unsatisfactory, because patients who have received a transplant can have multiple other reasons for the laboratory abnormalities currently used to diagnose TA-TMA. Moreover, our lack of understanding of the exact mechanism of disease limits the development and evaluation of potential treatments. Short- and long-term renal complications contribute to TA-TMA's overall poor prognosis. In light of these challenges, future research must validate novel markers of disease to aid in early diagnosis, guide current and future treatments, prevent long-term morbidity, and improve outcomes. We focus on TA-TMA as a distinct complication of hematopoietic stem cell transplantation, emphasizing the central role of the kidney in this disease.
Thrombotic microangiopathy (TMA) is a known complication of hematopoietic cell transplantation (HCT). The etiology and diagnosis of TMA in this patient population is often difficult because thrombocytopenia, microangiopathic hemolytic anemia, and kidney injury occur frequently in HCT recipients, and are the result of a variety of insults.
The authors reviewed renal pathology and clinical data from HCT patients to determine the prevalence of TMA and to identify correlative factors for developing TMA in the kidney. Kidney tissue was evaluated from 314 consecutive autopsies on patients who died after their first HCT (received between 1992 and 1999). Renal pathology was classified into three groups: (1) no renal thrombus (65%), (2) TMA (20%), and (3) isolated thrombosis (15%). Logistic regression models estimated the associations between each histologic category and clinical parameters: donor and recipient gender, patient age, human leukocyte antigen (HLA) matching of the donor and recipient, total body irradiation (TBI), acute graft versus host disease (GVHD), acute kidney injury, medications, and viral infections.
In a multivariate analysis, TMA correlated with acute GVHD grades II to IV, followed by female recipient/male donor, TBI > 1200 cGy, and adenovirus infection. Grades II to IV acute GVHD and female gender were associated with isolated renal thrombus.
TMA in HCT recipients is associated with acute GVHD grades II to IV, recipient/donor mismatch, TBI > 1200 cGy, and adenovirus infection.
Bone Marrow Transplantation (2002) 29, 542–543. doi:10.1038/sj.bmt.1703414
The syndrome of microangiopathic hemolysis associated with renal failure, neurologic impairment, or both is a recognized complication of hematopoietic stem cell transplantation. This entity is often called hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP), yet it is clear that the pathophysiology of transplant-associated HUS/TTP is different from that of classic HUS or TTP. Furthermore, the incidence of this syndrome varies from 0.5% to 76% in different transplant series, primarily because of the lack of a uniform definition. The toxicity committee of the Blood and Marrow Transplant Clinical Trials Network has reviewed the current literature on transplant-related HUS/TTP and recommends that it be henceforth renamed posttransplantation thrombotic microangiopathy (TMA). An operational definition for TMA based on the presence of microangiopathic hemolysis and renal and/or neurologic dysfunction is proposed. The primary intervention after diagnosis of TMA should be withdrawal of calcineurin inhibitors. Plasma exchange, although frequently used in this condition, has not been proven to be effective. In the absence of definitive trials, plasma exchange cannot be considered a standard of care for TMA. It is hoped that these positions will improve the identification and reporting of this devastating complication after hematopoietic stem cell transplantation and facilitate future clinical studies for its prevention and treatment.
There are no widely accepted criteria for the definition of hematopoietic stem cell transplant -associated microangiopathy (TAM). An International Working Group was formed to develop a consensus formulation of criteria for diagnosing clinically significant TAM.
The participants proposed a list of candidate criteria, selected those considered necessary, and ranked those considered optional to identify a core set of criteria. Three obligatory criteria and four optional criteria that ranked highest formed a core set. In an appropriateness panel process, the participants scored the diagnosis of 16 patient profiles as appropriate or not appropriate for TAM. Using the experts' ratings on the patient profiles as a gold standard, the sensitivity and specificity of 24 candidate definitions of the disorder developed from the core set of criteria were evaluated. A nominal group technique was used to facilitate consensus formation. The definition of TAM with the highest score formed the final PROPOSAL:
The Working Group proposes that the diagnosis of TAM requires fulfilment of all of the following criteria: (i) >4% schistocytes in blood; (ii) de novo, prolonged or progressive thrombocytopenia (platelet count <50 x 109/L or 50% or greater reduction from previous counts); (iii) sudden and persistent increase in lactate dehydrogenase concentration; (iv) decrease in hemoglobin concentration or increased transfusion requirement; and (v) decrease in serum haptoglobin. The sensitivity and specificity of this definition exceed 80%.
The Working Group recommends that the presented criteria of TAM be adopted in clinical use, especially in scientific trials.
Thrombotic microangiopathy (TMA) is a grave complication after haematopoietic stem cell transplantation (HSCT) and effective treatment is undefined. Five patients with postHSCT TMA, which was refractory to at least 1 week of plasma exchange and prednisolone, were treated with rituximab (375 mg/m(2)/week x 4). Remission was achieved in four patients, of whom three remained in remission and one had died of sepsis at a median follow-up of 10 months. ADAMTS13 levels were low in all evaluable patients, and only one patient showed significant anti-ADAMTS13 antibody. The levels of ADAMTS13 and anti-ADAMTS13 antibody did not change significantly with rituximab-induced remission.
Description:
The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 clinical practice guideline for the management of blood pressure (BP) in patients with chronic kidney disease (CKD) not receiving dialysis is an update of the KDIGO 2012 guideline on the same topic and reflects new evidence on the risks and benefits of BP-lowering therapy among patients with CKD. It is intended to support shared decision making by health care professionals working with patients with CKD worldwide. This article is a synopsis of the full guideline.
Methods:
The KDIGO leadership commissioned 2 co-chairs to convene an international Work Group of researchers and clinicians. After a Controversies Conference in September 2017, the Work Group defined the scope of the evidence review, which was undertaken by an evidence review team between October 2017 and April 2020. Evidence reviews were done according to the Cochrane Handbook. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to guide the development of the recommendations and rate the strength and quality of the evidence. Practice points were included to provide guidance when evidence was insufficient to make a graded recommendation. The guideline was revised after public consultation between January and March 2020.
Recommendations:
The updated guideline comprises 11 recommendations and 20 practice points. This synopsis summarizes key recommendations pertinent to the diagnosis and management of high BP in adults with CKD, excluding those receiving kidney replacement therapy. In particular, the synopsis focuses on recommendations for standardized BP measurement and a target systolic BP of less than 120 mm Hg, because these recommendations differ from some other guidelines.
Overactivated complement is a high-risk feature in HSCT recipients with transplant associated thrombotic microangiopathy (TA-TMA), and untreated patients have dismal outcomes. We present our experience of 64 pediatric HSCT recipients with high risk TA-TMA and multi-organ injury treated with the complement blocker eculizumab. We demonstrate significant improvement in 1y post-HSCT survival to 66% in treated patients from our previously reported untreated cohort with same high-risk TA-TMA features that had 1y post-HSCT survival of 16.7%. Responding patients benefited from a brief but intensive eculizumab therapy course using PK/PD guided dosing, requiring a median of 11 doses of eculizumab (IQR 7-20). Therapy was discontinued due to resolution of TA-TMA at a median of 66 days (IQR 41-110). Subjects with higher complement activation measured by elevated blood sC5b-9 at the start of therapy were less likely to respond to treatment (OR =0.15, p-value 0.0014), and required more doses of eculizumab [r = 0.43, p-value = 0.0004]. Patients with intestinal bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs 9, p=0.0015), and had lower 1y survival (44% vs 78%, p=0.01). Over 70% of survivors had proteinuria on long term follow up. The best GFR recovery in survivors was a median 20% lower (IQR 7.3-40.3%) than their pre-HSCT GFR. In summary, complement blockade with eculizumab is an effective therapeutic strategy for high risk TA-TMA, but some patients with severe disease lack a complete response, prompting us to propose early intervention strategies and search for additional targetable endothelial injury pathways.
Introduction: ADAMTS13 (A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats) activity remains a key tool in differential diagnosis of thrombotic microangiopathies (TMAs). However, ADAMTS13 testing is not readily available in many hospitals. Recently, PLASMIC and PLASIC scores have been developed to facilitate rapid recognition of TTP. We aimed to evaluate their usefulness compared to ADAMTS13 testing in a real-world cohort of TMA patients.
Methods: We enrolled consecutive patients with samples referred to our Center for ADAMTS13 measurement due to TMA over the last 2 years. Samples were collected either at first diagnosis or relapse before initiation of treatment. ADAMTS13 activity was measured with a commercially available and validated ELISA kit (Technozym, Diapharma). Clinical data were retrospectively collected from referring centers. Management was based on treating physicians' decisions.
TTP was defined as severe ADAMTS13 deficiency (activity≤10%); while secondary TMAs were diagnosed in patients with cancer, connective tissue disorders or hematopoietic cell transplantation recipients (transplant-associated TMA). Atypical hemolytic uremic syndrome (aHUS) remained a diagnosis of exclusion in patients with ADAMTS13>10%. PLASMIC was calculated based on seven variables: platelets, hemolysis, cancer, transplant, MCV, INR, creatinine; while MCV was not included in PLASIC, as previously described. ROC curve analysis was performed to determine the sensitivity and specificity of scores. Multivariate binary or logistic regression models were performed when appropriate.
Results: We studied 50 TMA patients. Combined clinical and laboratory data conferred the following TMA classification: TTP in 36 patients (72%), transplant-associated TMA in 7 (14%), other secondary TMA in 5 and aHUS in 2. PLASMIC score was intermediate in 2 and high in another 4 patients without TTP. The PLASIC score was high in 5 patients without TTP, leading to less false positive results compared to PLASMIC (p<0.001). These patients suffered from secondary TMAs. In the ROC curve analysis, both PLASMIC and PLASIC significantly predicted TTP diagnosis (p<0.001 and area under the curve/AUC 0.891 and 0.892, Figure 1). In patients without secondary TMAs, PLASMIC and PLASIC had an excellent performance (p<0.001 and AUC 1).
Plasma exchange was commenced in the majority of patients (42/50, 84%). Among TTP patients, the majority (77%) received rituximab as salvage or prophylactic treatment. Rituximab administration was associated with platelet (p=0.003) and ADAMTS13 (p=0.015) levels at diagnosis. The complement inhibitor eculizumab was administered in 3 patients with TA-TMA, who achieved TMA resolution. With a median follow-up of 2.9 years (range 0.3-26.3), overall survival was significantly lower in patients with secondary TMAs (p<0.001). PLASMIC or PLASIC score were not associated with clinical outcomes in our cohort.
Conclusion: PLASMIC and PLASIC scores are excellent tools in TMA patients without secondary causes. While PLASMIC and PLASIC scores conferred similar outcomes, the PLASIC score requires six instead of seven variables, is classified as low/high omitting the intermediate category and leads to less false positive results. Further validation of the PLASIC score might confirm its clinical value. In addition, the role of ADAMTS13 levels in guiding rituximab administration needs to be further investigated. When an underlying etiology is detected, ADAMTS13 testing is necessary to exclude TTP and facilitate further therapeutic decisions.
Figure 1
Disclosures
Panayiotidis: Bayer: Other: Support of clinical trial.
The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating and categorizing indications for the evidence‐based use of therapeutic apheresis (TA) in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the committee has incorporated systematic review and evidence‐based approaches in the grading and categorization of apheresis indications. This Eighth Edition of the JCA Special Issue continues to maintain this methodology and rigor in order to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Eighth Edition, like its predecessor, continues to apply the category and grading system definitions in fact sheets. The general layout and concept of a fact sheet that was introduced in the Fourth Edition, has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease entity or medical condition. The Eighth Edition comprises 84 fact sheets for relevant diseases and medical conditions, with 157 graded and categorized indications and/or TA modalities. The Eighth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease.
Renewed interest has emerged in transplant‐associated thrombotic microangiopathy (TA‐TMA) with novel prognostic, diagnostic and treatment algorithms. We aimed to investigate the incidence, prognostic factors, morbidity and mortality of TA‐TMA in allogeneic hematopoietic cell transplantation (HCT) recipients. We enrolled consecutive HCT recipients (1990‐2017). Among 758 patients, 116 (15.5%) were diagnosed with TA‐TMA. In the multivariate analysis, TBI‐based conditioning, viral infections, acute and chronic GVHD remained independent predictors of TA‐TMA. With a median follow‐up of 23 (range 0.1‐329) months, TA‐TMA resulted in significantly lower overall survival (OS). In the multivariate analysis, TA‐TMA remained an independent predictor of OS, along with relapse, acute and chronic GVHD. Among 116 TA‐TMA patients, 70 developed renal (56) and/or neurologic (26) dysfunction that would be necessary for TA‐TMA diagnosis according to the Bone Marrow Transplant Clinical Trials Network criteria. TA‐TMA patients with renal dysfunction showed increased rates of acute GVHD, but no difference in OS compared to patients without renal dysfunction. However, neurologic dysfunction resulted in significantly lower OS. In conclusion, TA‐TMA is associated with increased morbidity and mortality in allogeneic transplant recipients. Successful prevention and treatment strategies of infections and GVHD need to be timely employed to improve survival in this complex setting.
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Objective
To evaluate response rates and survival in adults with transplant‐associated thrombotic microangiopathy (TA‐TMA) after allogeneic hematopoietic stem cell transplantation (HSCT) who were treated with eculizumab (ECU).
Methods
Patients were identified retrospectively and data collected through HSCT and pharmacy databases.
Results
Ten patients with TA‐TMA after allogeneic HSCT were treated with ECU between 2013 and 2016. TA‐TMA was diagnosed at a median of 93 days post‐HSCT. Organ‐specific injury was documented in all ten patients at time of TA‐TMA diagnosis, the most common being renal dysfunction (90%). Acute GVHD (70%) and active infection (80%) were common at time of diagnosis. The median time to ECU initiation from TA‐TMA diagnosis was 4 days. Seven patients received ECU as first‐line therapy in combination with other treatment modalities, while three patients were treated with ECU as second‐line therapy. ECU was well tolerated with the exception of one case of severe skin rash leading to discontinuation. ECU achieved an overall hematologic response rate of 70% and an overall survival rate of 60%. One patient achieved a complete response with corresponding organ recovery.
Conclusion
Early initiation of ECU may not alter the disease process enough to restore organ function, but it may prolong survival.
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Transplant-associated thrombotic microangiopathy (TA-TMA) is a form of microangiopathy specifically occurring in the context of hematopoietic stem cell transplantation. Similarly, to other microangiopathies, TA-TMA is characterized by hemolytic anemia, thrombocytopenia, and organ failure due to endothelial injury. Although its clinical association with medications (eg, calcineurin inhibitors), immune reactions (eg, graft vs host disease) or infectious complications is well established, the pathophysiology remains largely unknown. Recent data have highlighted the role of complement in the pathophysiology of TA-TMA, which are frequently associated with a functional impairment (either inherited or acquired) of the endogenous regulation of the complement classic and alternative pathway. This manuscript will review the data supporting the involvement of complement in the pathophysiology of TA-TMA, as well as the clinical data supporting the use of anticomplement agents in this rare condition.
Background:
Drug-induced transplant-associated thrombotic microangiopathy (DTA-TMA) is a rare but serious complication that can occur after hematopoietic cell transplantation (HCT) or solid organ transplantation (SOT) without guidelines for optimal management of this condition.
Study design and methods:
Given the ambiguity surrounding the treatment for DTA-TMA, we conducted a retrospective review to evaluate the impact of different treatment strategies in DTA-TMA patients. Our primary endpoint was to determine the overall response rate (ORR) for DTA-TMA based on the type of treatment modality chosen while secondary endpoints included the time to response, relapse rates, and overall survival for DTA-TMA cases.
Results:
There were a total of 14 DTA-TMA patients of whom nine were post-HCT and five were post-SOT. Most of the DTA-TMA cases were due to tacrolimus (n = 11) with a minority related to sirolimus (n = 3). A total of nine of 14 patients demonstrated response and five had no response to therapy. The ORR among the DTA-TMA patients after HCT and SOT who received plasma exchange (PLEX) were 25 and 100%, respectively. The ORRs among the patients (includes HCT and SOT) who received rituximab (n = 3) and eculizumab (n = 5) were 67 and 60%, respectively. There were two relapses noted in our study and both were in the HCT group.
Conclusion:
While discontinuation of the offending agent may be sufficient for treatment of DTA-TMA after HCT, PLEX may be a reasonable option for DTA-TMA after SOT. Although the results are encouraging with rituximab and eculizumab in the treatment of DTA-TMA, larger prospective studies are needed to validate our findings.
Thrombotic thrombocytopenic purpura (TTP; also known as Moschcowitz disease) is characterized by the concomitant occurrence of often severe thrombocytopenia, microangiopathic haemolytic anaemia and a variable degree of ischaemic organ damage, particularly affecting the brain, heart and kidneys. Acute TTP was almost universally fatal until the introduction of plasma therapy, which improved survival from <10% to 80–90%. However, patients who survive an acute episode are at high risk of relapse and of long-term morbidity. A timely diagnosis is vital but challenging, as TTP shares symptoms and clinical presentation with numerous conditions, including, for example, haemolytic uraemic syndrome and other thrombotic microangiopathies. The underlying pathophysiology is a severe deficiency of the activity of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13), the protease that cleaves von Willebrand factor (vWF) multimeric strings. Ultra-large vWF strings remain uncleaved after endothelial cell secretion and anchorage, bind to platelets and form microthrombi, leading to the clinical manifestations of TTP. Congenital TTP (Upshaw–Schulman syndrome) is the result of homozygous or compound heterozygous mutations in ADAMTS13, whereas acquired TTP is an autoimmune disorder caused by circulating anti-ADAMTS13 autoantibodies, which inhibit the enzyme or increase its clearance. Consequently, immunosuppressive drugs, such as corticosteroids and often rituximab, supplement plasma exchange therapy in patients with acquired TTP.
Thrombotic microangiopathy (TMA) occurring after allogeneic hematopoietic stem cell transplantation (HSCT) has a devastating prognosis. Response rates to current therapies (mainly plasma exchange) are unsatisfactory. Thrombotic microangiopathy after allogeneic HSCT shares similarities with atypical hemolytic uremic syndrome (aHUS) in the underlying pathomechanisms. Eculizumab has been associated with impressive results in aHUS.
We retrospectively analyzed 12 patients who received Eculizumab in France between 2010 and 2013 for severe post-HSCT TMA.
All 12 patients had severe TMA with neurological and/or renal involvement. Fifty-eight percent were refractory to first-line plasma exchange. At the time of TMA diagnosis, infections were present in 50% of the patients and acute graft-versus-host disease in 33%. Patients were treated with Eculizumab according to the aHUS therapeutic scheme. With a median follow-up of 14 months, hematological response and overall survival were 50% and 33%, respectively. Active acute graft-versus-host disease at TMA diagnosis was the only factor associated with worse overall survival (P = 0.009).
Response rate and overall survival after Eculizumab in our cohort compare favorably with previously published data in TMA after allogeneic HSCT. Prospective trials are warranted to confirm these results. Early initiation of Eculizumab may have a favorable effect on long-term renal function and further contribute to the prolongation of survival.
Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare clinical syndrome associated with significant mortality. Although the use of plasma exchange (PE) in TA-TMA continues to be explored, evidence for its efficacy is debated. We performed a single institution, retrospective study to evaluate the efficacy of PE in treating TA-TMA patients. Special attention was given to efficacy in relation to the timing of presentation with TA-TMA since transplant. Thirty-three patients diagnosed with TA-TMA and treated with PE between January 1999 and December 2010 were included in the study. Clinical improvement was seen in eight patients (24%); four patients achieved complete resolution while the remaining four achieved partial resolution. All-cause day-30 and day-100 mortality was 33 and 55%, respectively. There was a trend toward a better outcome (complete/partial) for those presenting ≥ 100 days after transplantation (42%) vs. < 100 days after transplantation (14%; P-value = 0.15). Similarly, those presenting at ≥ 100 days had better, but not significantly, 30-day and 100-day all-cause mortality rates (17 and 33%, respectively) than those presenting at < 100 days (43 and 67%, respectively) (P-value = 0.25 and 0.08, for 30- and 100-day all-cause mortality, respectively). This is the first study looking at the efficacy of PE while considering the time of presentation since transplantation and is one of the largest single institution series of TA-TMA. The overall efficacy of PE is poor; however, patients who present with TA-TMA ≥100 days after transplant may have better outcome and lower mortality. J. Clin. Apheresis, 2014. © 2014 Wiley Periodicals, Inc.
Background
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.Study Design and Methods
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.ResultsApproximately 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.Conclusion
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.
Background:
The mechanism of kidney injury in hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is not completely understood. Renal C4d staining is a marker of classic complement activation and endothelial injury and has been described in preliminary reports of HSCT recipients with TA-TMA. Our objective was to evaluate complement in the pathogenesis of small vessel injury in children receiving HSCT. We hypothesized that kidney tissue from children with TA-TMA would more frequently show C4d deposition compared with HSCT recipients without histologic TA-TMA.
Methods:
We reviewed kidney specimens (biopsy or autopsy) from children who had undergone HSCT at a single center. Using histologic criteria alone, subjects were divided into TA-TMA (n = 8) and non-TA-TMA (control) groups (n = 12). C4d staining was performed by immunohistochemistry and evaluated on arterioles, peritubular capillaries, glomeruli, and tubular basement membranes.
Results:
Diffuse or focal renal arteriolar C4d staining was more common in subjects with histologic TA-TMA (75%) compared with controls (8%). Rare peritubular capillary C4d staining was present in 50% of TA-TMA samples and was absent in controls. Glomerular C4d staining was seen at a similar frequency in cases and controls, whereas tubular basement membrane staining was less frequently observed and only in subjects with TA-TMA.
Conclusions:
Arteriolar C4d deposition may be a pathologic marker of TA-TMA, implicating localized complement fixation in HSCT recipients with kidney disease secondary to small vessel injury. Further studies to better characterize the preferential arteriolar C4d staining may identify a renal compartment of injury, possibly explaining the dramatic hypertension seen in TA-TMA.
In response to the recently released 2012 KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for acute kidney injury (AKI), the National Kidney Foundation organized a group of US experts in adult and pediatric AKI and critical care nephrology to review the recommendations and comment on their relevancy in the context of current US clinical practice and concerns. The first portion of the KDIGO guideline attempts to harmonize earlier consensus definitions and staging criteria for AKI. While the expert panel thought that the KDIGO definition and staging criteria are appropriate for defining the epidemiology of AKI and in the design of clinical trials, the panel concluded that there is insufficient evidence to support their widespread application to clinical care in the United States. The panel generally concurred with the remainder of the KDIGO guidelines that are focused on the prevention and pharmacologic and dialytic management of AKI, although noting the dearth of clinical trial evidence to provide strong evidence-based recommendations and the continued absence of effective therapies beyond hemodynamic optimization and avoidance of nephrotoxins for the prevention and treatment of AKI.
Thrombotic microangiopathy (TMA) refers to a clinical and pathologic syndrome in which endothelial injury results in the manifestations of thrombocytopenia, microangiopathic hemolytic anemia, and kidney injury. A host of causes may induce endothelial injury and TMA, including enteric bacterial toxins, deficiency or dysfunction of complement regulatory proteins, deficiency or inhibition of von Willebrand factor-cleaving proteases, and factors that inhibit endothelial cell proliferation and turnover. This has led specialists to concentrate on these specific inciting factors in terms of designing treatment and management. However, a key and less recognized factor is the underlying level of endothelial health. Many persons with hereditary causes may remain disease free for years or may never develop disease. Others with acute inciting events, such as Escherichia coli O157 enteritis, never manifest TMA. Experimental studies document the importance of specific factors, such as endothelial nitric oxide levels, in helping protect animals from TMA. This suggests that one might approach the management of TMA not simply with specific treatments aimed at the underlying hereditary cause or inciting event, but rather at general measures that may improve overall endothelial health. We propose studies to determine whether interventions that improve endothelial health, such as the administration of angiotensin-converting enzyme inhibitors, statins, vitamin C, allopurinol, or nitric oxide-producing drugs, may be able to prevent TMA, even in persons with underlying hereditary conditions that otherwise would predispose them to these diseases.
The lack of an accepted definition of transplantation-associated thrombotic microangiopathy (TMA) has led the Blood and Marrow Transplants Clinical Trials Network (CTN) and International Working Group (IWG) to propose a definition for TMA with some differences. However, there have been few studies validating and comparing both newly proposed criteria for TMA.
To validate recently proposed criteria for TMA by CTN and IWG, we analyzed 672 patients who underwent allogeneic stem-cell transplantation between January 2002 and December 2006.
The cumulative incidences of TMA by CTN and IWG were 6.1% and 2.5%, respectively. The cumulative incidence of overall TMA (O-TMA) including probable-TMA defined as meeting CTN criteria without renal or neurologic dysfunction, as well as TMA by CTN (definite-TMA), was 12.7%. Sixty-six percent of TMA by CTN did not have any degree of schistocytosis by IWG criteria (≥4%), and 18% of TMA by IWG criteria did not have renal or neurologic dysfunction. On multivariate analyses, probable-TMA as well as definite-TMA adversely affected the survival of a cohort including all patients. In patients with O-TMA, the degree of schistocytosis (≥4% or not) failed to show prognostic significance, whereas renal involvement was a significant prognostic factor associated with poor survival.
Both proposed consensus criteria have major pitfalls in their use as uniformly accepted diagnostic criteria for TMA. The use of O-TMA as a broad definition for TMA and the grading system by the presence of renal involvement may be a counterproposal for future trials.
The microangiopathic anaemia with thrombocytopenia--which can occur after haematopoietic stem cell transplant--resembles thrombotic thrombocytopenic purpura but has different pathophysiology and does not respond to plasma exchange. We describe a patient with severe manifestations of this disorder who recovered promptly following treatment with rituximab, an anti-CD20 antibody.
Bone Marrow Transplantation is a high quality, peer-reviewed journal covering all aspects of clinical and basic haemopoietic stem cell transplantation.
A survey was carried out among the European Group for Blood and Marrow Transplantation (EBMT) centres to determine the incidence, risk factors, treatment and outcome of thrombotic thrombocytopenic purpura (TTP) following allogeneic haematopoietic stem cell transplantation. TTP was defined as the simultaneous occurrence of red cell fragmentation, laboratory findings of haemolysis, red cell transfusion requirement and de novo or persistent thrombocytopenia caused by consumption, in the absence of disseminated intravascular coagulation. Forty-five centres reported all patients (n = 406) transplanted between July and December 1996. Twenty-three patients developed TTP; the risk of developing TTP was 6.7% at 2 years (95% CI: 4.1% to 9.3%). The median time of onset was 44 d (range 13-319) post transplantation. Significant risk factors for the development of TTP were female gender (P = 0.005) and an unrelated donor (P = 0.046). To treat TTP, cyclosporin administration was discontinued in 10 cases, plasma exchanges were performed in five cases and 12 patients received plasma infusions without plasma exchange. TTP resolved in 13 of the 23 patients (57%). The only factor predictive of resolution of TTP was the absence of nephropathy. Seven patients (30%) were alive at follow-up of 38-45 months from the onset of TTP. Sixteen patients died; the causes were multiple, only three patients had TTP as a central factor. The median time to death was 41 d (range 1-762 d) from the onset of TTP. TTP is a relatively frequent complication of allogeneic stem cell transplantation and it is associated with high mortality, though death is usually caused by multiple factors.
Transplantation-associated thrombotic microangiopathy (TA-TMA) has been associated with significantly reduced survival following allogeneic bone marrow transplantation. In this study we describe the course and response to plasma exchange therapy of TA-TMA as well as risk factors for its' development. Twenty-five patients who underwent plasma exchange therapy were matched to fifty control patients selected for transplant indication and stage of disease at the time of transplant. Transplant indications were acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, aplastic anemia, myelodysplastic syndrome and multiple myeloma. Groups were well balanced with respect to disease status, age at time of transplant and use of radiation-based conditioning. TA-TMA was diagnosed a median of 27 days after transplantation and neurological abnormalities were present in ten cases. Patients received a median of 10 (range 2-43) plasma exchange treatments. Hematological responses were recorded in eight cases. Risk factors for the development of TA-TMA included transplantation from unrelated donors (p = 0.002), hepatic venoocclusive disease (VOD) (p = 0.034), grade 2-4 acute graft-versus-host disease (GVHD) (p = 0.042) and bacteremia with diphtheroid organisms (p = 0.009). Only hepatic VOD (p = 0.0026) and grade 2-4 acute GVHD (p = 0.0436) remained significant risk factors for later development of TA-TMA in a multivariate logistic regression model. The median survival of patients with TA-TMA was 66 (range 32-733) days while that of unaffected patients was 742 (range 15-2392) days after transplantation. Only one patient with TA-TMA remains alive 733 days after transplantation.
Thrombotic microangiopathy (TMA) has been described as severe complication after hematopoietic stem cell transplantation (HSCT). The principal aim of this study was to focus the incidence and the outcome of TMA in the era of more complex HSCTs.
We analyzed the role of some predicting factors for the incidence and the outcome of TMA after HSCT. We enrolled 539 consecutive patients (307 males, median age 31 years) undergoing HSCT from match or mismatch human leukocyte antigen family donor (314) or match/mismatch unrelated (195) and haploidentical donor (30) for malignant or nonmalignant diseases. TMA diagnosis was performed by homogeneous clinical and laboratory criteria.
Sixty-four of 539 patients presented TMA (11,87%) and the five-year cumulative incidence of TMA was 14% (HR=0.13). Fifty nine of 64 patients were affected by malignant and 5/64 by non-malignant diseases. On multivariate analysis, TMA occurrence was influenced by graft versus host disease >grade II (P=0.0001), donor type (P=0.029), gender (P=0.0233), total body irradiation based conditioning regimen (P=0.0041). Three factors for TMA outcome proved to be statistically significant by multivariate analysis: age (P=0.009), donor type (P=0.0187) and TMA index (P=0.029). The TMA mortality rate was 50%. The outcome was influenced by defibrotide (P=0.02 in univariate analysis).
The study underlines the possibility of finding out which patients are more prone to developing post-HSCT TMA, and identifies which risk factors are more frequently associated with a dismal outcome after TMA.
The aim of this article is to assess the current understanding and uncertainties about the evaluation and management of thrombotic microangiopathy that occurs following allogeneic hematopoietic stem cell transplantation.
Current data may not be sufficient to establish posttransplantation thrombotic microangiopathy as a discrete clinical or pathologic entity, distinct from other well recognized transplant-related complications. Analysis of case series of posttransplantation thrombotic microangiopathy illustrates uncertainties regarding incidence, risk factors, diagnosis, treatment, and survival. These studies have suggested the lack of efficacy of plasma exchange treatment and have identified other transplant-related complications, such as acute graft-versus-host disease and opportunistic infections, as the predominant causes of death in patients who had been diagnosed with posttransplantation thrombotic microangiopathy. Recently consensus diagnostic criteria were proposed by two independent groups to provide more uniform identification of patients with posttransplantation thrombotic microangiopathy; these criteria may result in a clearer definition of this syndrome.
Posttransplantation thrombotic microangiopathy remains a diagnostic and therapeutic challenge. Further studies are required to determine if it is a specific entity and to define its relation to other transplant-related complications.
Transplant-associated microangiopathy (TAM) is a severe complication following allogeneic hematopoietic stem cell transplantation (HSCT) even after reduced-intensity conditioning (RIC). Data on 112 patients following RIC were analyzed with respect to TAM according to the ASBMT and risk factors, response to well-defined therapy and outcome were determined. TAM occurred in 11 of 112 patients. Univariate analysis determined acute graft-versus-host disease and ABO-incompatibility as risk factors for TAM. Treatment consisted of withdrawal of calcineurin inhibitors and plasma exchange (PE). Response to PE was 64%. PE seems to be an effective therapeutic option that should be assessed in larger patient cohorts.
Transplantation-associated thrombotic microangiopathy (TA-TMA) is an infrequent but devastating syndrome that occurs in allogeneic hematopoietic stem cell transplant recipients, and is associated with a variety of transplantation-related factors, including conditioning regimens, immunosuppressive agents, GVHD and opportunistic infections. Progress in managing this condition has been hampered by lack of a consensus definition and poor understanding of the pathophysiology of the disorder. Two different groups recently have proposed consensus definitions, yet they fail to distinguish the primary syndrome from the secondary causes, such as a variety of infections, medication exposure or other conditions. Increasing evidence suggests that TA-TMA is a multifactorial disorder that is distinct from thrombotic thrombocytopenic purpura (TTP), and likely represents the final common pathway of a number of endothelial cell insults. TA-TMA responds poorly to conventional treatment for TTP, including plasma exchange, but newer agents, including daclizumab and defibrotide show promise. In addition, other agents known to modify endothelial responses to injury, including statins, prostacyclin analogues, endothelin-receptor antagonists and free radical scavengers, may lead to improved outcomes for patients affected by this disorder.
The impact of thrombotic microangiopathy (TMA) on outcome was studied in 148 patients with acute graft-versus-host disease (GVHD) (> or =grade II). The Blood and Marrow Transplant Clinical Trials Network's definition for TMA was used to diagnose definite TMA. Probable TMA was diagnosed when none of the features of nephropathy and neurologic abnormalities associated with definite TMA were present. Overall, TMA developed in 43 (29%) patients; 16 definite and 27 probable. The occurrence of TMA, the maximum grade of acute GVHD and initial treatment failure were associated with shorter overall and GVHD-specific survival. The development of probable as well as definite TMA affected the survival of patients with acute GVHD adversely. These results show the clinical impact of TMA on patients with acute GVHD, and suggest that the proposed definitions and grading of TMA may need to be modified.
Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) has been described as a specific sequela of allogeneic HPC transplantation (HPCT). Nevertheless, because multiple transplant-related sequela can cause the characteristic clinical features of TTP-HUS, the diagnosis is difficult.
All English-language articles describing patients with TTP-HUS following HPCT were identified. Articles reporting five or more total patients, including at least one patient diagnosed with TTP-HUS following allogeneic HPCT, were reviewed. All articles describing autopsies of patients diagnosed with TTP-HUS following allogeneic HPCT were also reviewed.
Thirty-five articles reporting 5 or more total patients described 447 patients diagnosed with TTP-HUS following allogeneic HPCT. The frequency of diagnosis of TTP-HUS following allogeneic HPCT varied by 125-fold (0.5%-63.6%). Twenty-eight different sets of diagnostic criteria were described in the 35 articles; 25 articles included both RBC fragmentation and increased serum LDH. Many risk factors described as correlating with the diagnosis of TTP-HUS also predict greater risk for multiple transplant-related complications. Benefit of plasma exchange treatment could not be documented. Survival information was reported for 379 patients, 232 (61%) died, and reported mortality rates varied from 0 to 100 percent. Autopsies have been reported for 35 patients who were diagnosed with TTP-HUS following allogeneic HPCT; none had systemic thrombotic microangiopathy, the diagnostic abnormality of TTP-HUS; and infection (19 patients) was the most commonly reported cause of death.
The clinical features of TTP-HUS following allogeneic HPCT may be caused by common transplant-related complications; the benefit from plasma exchange treatment is uncertain.
Transplant-associated thrombotic microangiopathy (TA-TMA) and consensus based diagnostic and therapeutic recommendations: which TA-TMA patients to treat and when?
- Uderzo