Diagnosis Of Thrombotic Microangiopathy Research Articles

Transplant-Associated Thrombotic Microangiopathy (TA-TMA): Not a Singular Entity

▪Introduction: Thrombotic microangiopathy (TMA) is a clinical syndrome that can develop after hematopoietic cell transplantation (HCT). Previous studies have been limited to small case series with conflicting results. In this large, single-center longitudinal TA-TMA database, we describe the incidence, etiology, treatment, and outcome of this rare but challenging clinical presentation.Methods: We performed a retrospective cohort analysis of consecutive allogeneic HCT recipient during 2006-2015 at Fred Hutchinson Cancer Research Center. TA-TMA was defined as persistent microangiopathic hemolytic anemia (MAHA) composed of red cell fragmentation, elevated lactate dehydrogenase (LDH), thrombocytopenia, anemia, and lack of coagulopathy (Table 1). We performed a primary search algorithm using “consecutive MAHA” followed by a secondary search algorithm using “suspected hemolysis” to identify all cases from date of transplant until date of death or last follow-up (Table 1). For each suspected case, we further reviewed available patient records to confirm the diagnosis, determine the etiology, treatment, and complication. The most likely etiology was determined by reviewing the clinical events in the 2-week window before the TMA onset. Since 96% of patients were receiving calcineurin inhibitor (CNI), we chose idiopathic/drug as a diagnosis of exclusion if all other causes were excluded. TMA resolution was defined as LDH <1.5x ULN, platelet transfusion independence, and rare or no schistocytes. Continuous and categorical variables were shown as median (interquartile range) and percentage, respectively. Overall survival was depicted with Kaplan-Meier curves, after accounting for delayed entry with left truncation at TMA diagnosis. Cox regression model was built to test the association between TMA resolution as a time-varying covariate and overall survival.Results: Among 2241 consecutive adult allogeneic HCT recipients, 209 patients (9%) met the laboratory criteria of TA-TMA (Table 2) with a median onset time of 62d (35d-93d). One hundred and nine patients (52%) had end-organ damage with either acute kidney injury (AKI) or neurologic deficit. The median follow-up was 181d (92d-478d) and 53 patients (25%) achieved hematologic resolution. Diagnostically, acute GVHD (n=96) represented the largest category and those with GVHD refractory to high dose steroid (n=61) had poor prognosis. Diffuse alveolar hemorrhage (DAH) and idiopathic pneumonia syndrome (IPS) (n=30) also frequently preceded the TMA onset. Finally, despite excluding patients with coagulopathy, non-specific causes of TMA such as disease recurrence (n=20) and systemic infection (n=33) were frequently evident.Overall survival, separated by TMA etiology is shown in Figure 1. Whereas the idiopathic/drug and non-refractory acute GVHD categories approached the survival of non-TMA post-HCT recipients, the other groups had worse prognosis. Regardless of cause, the most common treatment (32%) was CNI cessation or CNI switch (in no particular pattern). We did not observe an association between changes to CNI therapy and TMA resolution (24% vs. 26%, Fisher P 0.80) or overall survival at 6 months (37% vs. 34%, Wald P 0.75). This remained true when each diagnostic category and each CNI drug was separately analyzed. Plasma exchange was rarely performed at our center. Finally, TMA resolution often correlated with improvement of the underlying disorder. The achievement of TMA resolution was associated with significantly improved survival (HR 0.35, P <0.01).Conclusion: Despite meeting the same laboratory definition for persistent MAHA, clinical review revealed heterogeneous disease groups with dissimilar prognostic implications. Our data suggest that TA-TMA is not one disease entity but rather a “final common pathway” for several disorders that likely have different pathophysiologic mechanisms. Instead of empiric treatment with CNI adjustment, we need to identify and understand the underlying causal pathway towards TA-TMA, and to determine if earlier recognition and successful treatment improves patient outcomes. [Display omitted] DisclosuresLee:Kadmon: Other: One-time advisory board member; Amgen: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Mallinckrodt: Honoraria. Gopal:Seattle Genetics: Consultancy, Research Funding.

Differential diagnosis of thrombotic microangiopathy in nephrology

BackgroundThe differential diagnosis of thrombotic microangiopathy (TMA) is complex however the rapid diagnosis of the underlying condition is vital to inform urgent treatment decisions. A survey was devised with the objective of understanding current practices across Europe and the Middle East, and of challenges when diagnosing the cause of TMA.MethodsOver 450 clinicians, from 16 countries were invited to complete an online survey.ResultsOf 254 respondents, the majority were nephrologists, had >10 years’ experience in their specialty, and had diagnosed a patient with TMA. The triad of thrombocytopenia, haemolytic anaemia and acute kidney injury are the main diagnostic criteria used. Responses indicate that a differential diagnosis of TMA is usually made within 1–2 (53%) or 3–4 days (26%) of presentation. Similarly, therapy is usually initiated within the first 4 days (74%), however 13% report treatment initiation >1-week post-presentation. Extrarenal symptoms and a panoply of other conditions are considered when assessing the differential diagnosis of TMA. While 70 and 78% of respondents stated they always request complement protein levels and ADAMTS13 activity, respectively. Diagnostic considerations of paediatric and adult nephrologists varied. A greater proportion of paediatric than adult nephrologists consider extrarenal manifestations clinically related to a diagnosis of TMA; pulmonary (45% vs. 18%), gastrointestinal (67% vs. 50%), CNS (96% vs. 84%) and cardiovascular (54% vs. 42%), respectively. Variability in the availability of guidelines and extent of family history taken was also evident.ConclusionsThis survey reveals the variability of current practices and the need for increased urgency among physicians in the differential diagnosis of TMA, despite their experience. Above all, the survey highlights the need for international clinical guidelines to provide systematically developed recommendations for understanding the relevance of complement protein levels, complement abnormalities and ADAMTS13 testing, in making a differential diagnosis of TMA. Such clinical guidelines would enable physicians to make a more rapid and informed diagnosis of TMA, therefore initiate effective treatment earlier, with a consequent improvement in patient outcomes.

Quinine-Induced Thrombotic Microangiopathy: A Report of 19 Patients

Quinine can cause diverse and severe immune-mediated adverse reactions, including thrombotic microangiopathy (TMA). Our objective was to describe the presenting features and long-term outcomes of patients with quinine-induced TMA. A case series of 19 patients with quinine-induced TMA treated with plasma exchange. Patients with quinine-induced TMA initially suspected of having thrombotic thrombocytopenic purpura (TTP) were identified among patients enrolled in the Oklahoma TTP-Hemolytic Uremic Syndrome Registry. The clinical course of the initial episode and morbidity and mortality following recovery. The diagnosis of quinine-induced TMA was confirmed by documentation of quinine-dependent antibodies reactive with platelets or neutrophils and/or by previous quinine-associated systemic symptoms. Clinical data from the initial episode and long-term follow-up were described, focusing on kidney function. 19 of the 509 patients enrolled in the registry in 1989 to 2015 had quinine-induced TMA. 18 patients had quinine-dependent antibodies reactive with platelets and/or neutrophils (1 patient died before testing); 8 patients had a history of quinine-associated systemic symptoms. All patients were white; 18 were women. Quinine exposure was in pill form for 18 patients and as tonic water for 1. All patients had microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. All were initially misdiagnosed as having TTP or hemolytic uremic syndrome, and adverse reactions to quinine were not initially suspected. 1 patient died before treatment began; 17 of the 18 surviving patients required dialysis. 14 patients developed chronic kidney disease, 3 of whom developed end-stage renal disease. 8 patients died. Patients for whom plasma exchange was not requested were not identified. Quinine-induced TMA causes severe acute kidney injury that commonly results in chronic kidney disease.

Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next‐generation sequencing

Unlabelled Box BackgroundThe 2 main forms of thrombotic microangiopathy (TMA) are thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS). Deficiency of ADAMTS13 and dysregulation of the complement pathway result in TTP and aHUS, respectively; however, overlap of their clinical characteristics makes differential diagnosis challenging. Objectives and MethodsWe aimed to develop a TMA diagnosis workflow based on ADAMTS13 activity and screening of ADAMTS13 and complement genes using a custom next‐generation sequencing (NGS) gene panel. PatientsFor this, from a cohort of 154 Portuguese patients with acute TMA, the genotype‐phenotype correlations were analyzed in 7 hereditary TTP (ADAMTS13 activity <10%, no inhibitor), 36 acquired TTP (ADAMTS13 activity <10%, presence of an inhibitor), and in 34 presumable aHUS. ResultsIn total, 37 different rare variants, 8 of which novel (in ADAMTS13, CFH, and CD46), were identified across 7 genes. Thirteen TTP patients were homozygous (n=6), compound heterozygous (n=2), and heterozygous (n=5) for 11 ADAMTS13 variants (6 pathogenic mutations). Among the 34 aHUS patients, 17 were heterozygous for 23 variants in the different complement genes with distinct consequences, ranging from single pathogenic mutations associated with complete disease penetrance to benign variants that cause aHUS only when combined with other variants and/or CFH and CD46 risk haplotypes or CFHR1‐3 deletion. ConclusionsOur study provides evidence of the usefulness of the NGS panel as an excellent technology that enables more rapid diagnosis of TMA, and is a valuable asset in clinical practice to discriminate between TTP and aHUS.

A rare case of thrombotic microangiopathy triggered by acute pancreatitis

Thrombotic microangiopathy (TMA) occurring after acute pancreatitis is rarely described. Without prompt intervention, TMA can be, and often is, lethal, so prompt recognition is important. Here, we present a case...

Gemcitabine-associated thrombotic microangiopathy in a patient with lung cancer: A case report.

Gemcitabine is frequently used for the treatment of a number of different cancer types. Gemcitabine-related thrombotic microangiopathy (TMA) has rarely been described, but it is a life-threatening complication. The incidence of the complication varies between 0.015 and 1.4%. The present study reports the case of a 63-year-old Caucasian male who was treated with 3 cycles of carboplatin plus gemcitabine, followed by 7 cycles of gemcitabine only, and developed clinical symptoms that, together with laboratory findings, were compatible with a diagnosis of hemolytic uremic syndrome TMA. The patient was admitted to Jean Godinot Cancer Center Institute with hemolysis, thrombocytopenia, macroscopic hematuria, renal dysfunction and worsening high blood pressure. Medical treatment for the high blood pressure, plasma infusion and hemodialysis were implemented without any improvement in creatine levels. The patient recovered from hematological disorders, left hospital and was followed-up. He required hemodialysis until he succumbed ~3 months subsequent to diagnosis of TMA. Even if thrombocytopenia, anemia and renal failure are common observations in patients treated by chemotherapy, clinicians should be aware of this potentially lethal complication. We recommend screening for TMA in such cases of anemia, thrombocytopenia and renal failure.

Diagnosis and treatment of TMA based on Japanese clinical guides.

Patients with thrombotic microangiopathies (TMAs), which include thrombotic thrombocytopenic purpura (TTP), atypical hemolytic uremic syndrome (aHUS), and Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS), exhibit multiple symptoms. These include thrombocytopenia (platelet count <15×104/µl), microangiopathic hemolytic anemia (hemoglobin <10 g/dl), and organ damage, such as renal dysfunction or neurological abnormalities. Guidelines for the management of TTP, aHUS, and STEC-HUS have been published. Diagnosis of TTP, STEC-HUS, or aHUS requires ADAMTS13 activity <10%, the detection of STEC or Shiga toxins, or a genetic analysis to investigate the complement regulatory system, respectively. In the established management of TMAs, fresh frozen plasma is used for congenital TTP to supplement ADAMTS13. Plasma exchange (PE) is used in acquired TTP (ATTP) to remove inhibitors and replace ADAMTS13. Steroid therapy is administered in ATTP to suppress inhibitor production, and rituximab is administered in ATTP without response to PE or with high titers of ADAMTS13 inhibitors. Eculizumab, a monoclonal antibody for complement protein 5, is used for the treatment of aHUS. Supportive therapy is required for some TMAs, particularly STEC-HUS, but platelet transfusion is generally contraindicated for other TMAs, such as TTP. Treatments should be administered in accordance with these guidelines to improve the outcome of TMAs.

Thrombotic complications after hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) involves some serious transplant-associated complications (TACs) or vascular disorders, such as veno-occlusive disease (VOD), thrombotic microangiopathy (TMA), and graft-versus-host disease (GVHD). VOD is related to a clinical syndrome characterized by tender hepatomegaly, jaundice, fluid retention, and unexplained weight gain. When TMA is described in patients who have undergone HSCT, it is often implied that the clinical diagnosis of TMA is similar to that of thrombotic thrombocytopenic purpura. Therefore, levels of cytokines, chemokines, and soluble molecules are useful biomarkers for VOD and TMA after HSCT. Acute GVHD (aGVHD) occurs in the early period after transplantation and is initiated by alloreactive donor T cells. The mechanisms whereby immune responses trigger this post-transplantation condition remain unclear, but endothelial cell function might play a role in this. The authors investigated the expression of endothelial cell activation markers such as sE-selectin, sVCAM-1, PAI-1, and microparticle in patients undergoing allogeneic HSCT. Levels of endothelial cell activation markers were significantly higher in 143 patients who developed aGVHD than in those who did not develop aGVHD. Moreover, patients who received rTM exhibited a significantly lower frequency of aGVHD and reduced levels of endothelial cell activation markers. These findings suggest that endothelial cell activation might be linked to TAC and that rTM may, at least in part, act to prevent TAC through its effect on endothelial cells.

Thrombotic microangiopathy associated with monoclonal gammopathy

Thrombotic microangiopathy (TMA) is a rare disease comprising of a diverse set of disorders linked by a common histologic finding of endothelial injury. Monoclonal immunoglobulins may act as a potential trigger in the pathogenesis of TMA. To determine the prevalence of monoclonal gammopathy and clinicopathological features of TMA associated with monoclonal immunoglobulin, we performed a retrospective study in adults (18 and older) with a clinical diagnosis of TMA. Of 146 patients with TMA, we detected monoclonal immunoglobulin in 20 patients (13.7%). Among patients 50 and older, the prevalence of monoclonal gammopathy was 21%, which is approximately five-fold higher than the 4.2% expected rate in this population. Fifteen patients had monoclonal gammopathy of undetermined significance, one had multiple myeloma, one with smoldering myeloma, two had POEMS syndrome, and one had T-cell lymphocytic leukemia. Renal biopsy was performed in 15 cases, of which six showed thrombi, 11 showed mesangiolysis, and all showed double contours along glomerular capillary walls. Acute tubular injury was present in 12 cases. Treatment options were varied and included therapeutic plasma exchange in 11 patients. Ten patients progressed to end-stage renal disease, of which two received kidney transplant. Thus, our study shows an unexpectedly high prevalence of monoclonal gammopathy in patients with TMA, suggesting a potential pathogenetic mechanism. This study underscores the importance of evaluating for a monoclonal gammopathy in patients with TMA as well as the potential for targeting the underlying hematologic disorder as an approach to treating TMA.

Increased Incidence of Thrombotic Microangiopathy After ABO-Incompatible Living Donor Liver Transplantation.

BACKGROUND Thrombotic microangiopathy (TMA) is a severe life-threatening complication associated with solid organ transplantation. We retrospectively investigated the incidence, risk factors, and appropriate treatment of TMA following adult living donor liver transplantation (LDLT). MATERIAL AND METHODS The subjects were 129 adult patients who underwent LDLT in our department from 1997 to 2014. Patients with TMA were identified retrospectively based on diagnostic criteria. We calculated the incidence of TMA and performed a risk factor analysis for TMA occurrence. We also assessed our past treatments for TMA and sought to identify the most appropriate form of treatment. RESULTS Thirteen patients were identified as having TMA. The incidence of TMA in the study cohort was 10.1% but was especially high (37.9%) among ABO-incompatible cases. A univariate analysis revealed that ABO incompatibility, usage of tacrolimus, usage of rituximab, and cold ischemic time ≥50 minutes are risk factors for occurrence of TMA (p<0.10). Multivariate analysis demonstrated that ABO incompatibility was the only independent risk factor for TMA (p=0.009). Initiation of treatment on the day of TMA diagnosis was associated with better survival. CONCLUSIONS ABO incompatibility is an independent risk factor for TMA following adult LDLT. Our results suggest that early initiation of treatment is crucial for improving the outcomes.

Efficacy of Eculizumab in Gemcitabine-Induced Thrombotic Microangiopathy: Experience of the French Thrombotic Microangiopathies Reference Centre

Background: Gemcitabine is a broadly prescribed chemotherapy, the use of which can be limited by renal adverse events, including hypertension, proteinuria, oedema, acute renal failure and thrombotic microangiopathy (TMA). As opposed to thrombotic thrombocytopenic purpura, gemcitabine-induced TMA generally responds poorly to therapeutic plasma exchange and prognosis is dismal. The usual severe renal involvement and the normal activity of the von Willebrand factor-cleaving protease ADAMTS13 relate gemcitabine-induced TMA to atypical haemolytic syndrome, in which complement blockage is remarkably efficient. In this regard, this study evaluated the efficacy of eculizumab, a monoclonal antibody targeting the terminal complement pathway, in patients with gemcitabine-induced TMA.Methods: We conducted an observational, retrospective, multicentric study including all patients with gemcitabine-induced TMA treated by eculizumab in 4 French centres, between 2011 and 2014. Patients with a TMA considered to be directly attributed to an uncontrolled cancer were excluded.Results: 8 patients with a gemcitabine-induced TMA treated by eculizumab were included (6 women, 2 men). Gemcitabine was prescribed for pancreatic (n=3, 37.5%), ovarian (n=3, 37.5%) and pulmonary (n=2, 25%) cancer. TMA occurred after a median of 5.5 months (range 1.7-13) and a median cumulative dose of 22.8g (range 9.0-48.0). The main characteristics were microangiopathic hemolytic anemia (100%), thrombocytopenia (87.5%), normal ADAMTS13 activity (100%), acute renal failure (100%, including 62% stage 3 acute kidney injury (AKI) and 25% renal replacement therapy), hypertension (75%) and diffuse oedema (62.5%). Eculizumab was started after a median of 19.5 days (range 6-44) following TMA diagnosis. A median of 4.5 injections of eculizumab was performed (range 3-22). Complete haematological remission was achieved in 6 patients (75%) and blood transfusion significantly decreased after only one injection of eculizumab (median of 2 packed red blood cells (range 0-10) before treatment vs 0 (range 0-1) after one injection, p=.015). Two patients recovered completely renal function (25%), and 4 achieved a partial remission (50%), with a median estimated glomerular filtration rate (GFR) improvement of 15 ml/min/1.73m2 (range 7-16). Five patients (62.5%) died during follow-up, from a septic and hemorrhagic shock on early stage (1 case), and from cancer evolution after a median of 6 months (range 2-13) following eculizumab initiation (4 cases).Conclusion: These encouraging results suggest that eculizumab is efficient on hemolysis and reduces transfusion requirement in gemcitabine-induced TMA. Moreover, eculizumab may improve renal function. Prospective trials are now required to further investigate this issue. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Systemic Involvement at Entry into the Global Atypical Hemolytic Uremic Syndrome (aHUS) Registry

Background: Atypical hemolytic uremic syndrome (aHUS) is a rare disease predominantly caused by chronic, uncontrolled complement activation, leading to systemic thrombotic microangiopathy (TMA). The aHUS Registry is a noninterventional global initiative established in April 2012 (NCT01522183). Overall objectives of the Registry are to collect information on patient outcomes, regardless of treatment approach, as well as safety and effectiveness data specific to the use of eculizumab, a terminal complement inhibitor approved for treatment of aHUS. The objective of the current analysis was to characterize organ involvement in patients with aHUS, who were enrolled in the global aHUS Registry, prior to eculizumab treatment.Methods: Eligible patients have clinical diagnoses of aHUS, regardless of whether a complement abnormality had been identified or how the disease was managed. Demographic and medical/disease history data are collected retrospectively prior to enrollment and prospectively following enrollment. All treatment modalities are captured, including eculizumab.Results: This analysis included 851 patients; 387 (46%) pediatric and 464 (55%) adult onset patients. Study entry within 6 months of aHUS onset was reported by 39% of pediatric and 52% of adult patients. In the 6 months prior to study entry, renal manifestations were reported in 34%, gastrointestinal in 18%, cardiovascular in 15%, central nervous system in 11%, and pulmonary in 9%. Overall, extrarenal manifestations occurred more frequently in adult patients compared with pediatric patients. Due to the mainly retrospective data collection and to avoid recollection bias, a subgroup of recently diagnosed (ie, during 2011 or later) patients were specifically analyzed (n=549). While systemic manifestations were reported among patients after initial presentation (time from aHUS onset to study entry ≥6 months) in 12% to 47% of patients (Table), they were more frequent among patients with study entry within the first 6 months of disease onset (19% to 75% of patients). Overall, the most frequent organ manifestations occurring among patients with study entry within 6 months of disease onset were renal (75%), gastrointestinal (38%), cardiovascular (32%), central nervous system (25%), and pulmonary (19%). Pediatric patients experienced more gastrointestinal and fewer pulmonary manifestations than adult patients.Conclusions: In this large cohort of patients with aHUS, extrarenal manifestations were frequently reported at the time of disease onset. In light of the differential diagnosis of TMA, this highlights the importance to consider non-renal manifestations as a possible consequence of aHUS. Of interest, systemic involvement was still common ≥6 months after disease onset, emphasizing the importance of continued evaluation of organs in addition to the kidney. [Display omitted] DisclosuresScully:Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Johnson:Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Kupelian:Alexion Pharmaceuticals, Inc.: Employment. Greenbaum:Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Proteasome inhibitor associated thrombotic microangiopathy.

A variety of medications have been implicated in the causation of thrombotic microangiopathy (TMA). Recently, a few case reports have emerged of TMA attributed to the proteasome inhibitors (PI) bortezomib and carfilzomib in patients with multiple myeloma. The aim of this case series was to better characterize the role of PI in the etiology of drug-induced TMA. We describe eleven patients from six medical centers from around the world who developed TMA while being treated with PI. The median time between medication initiation and diagnosis of TMA was 21 days (range 5 days to 17 months). Median laboratory values at diagnosis included hemoglobin-7.5 gdL(-1) , platelet count-20 × 10(9) /L, LDH-698 UL(-1) , creatinine-3.12 mgdL(-1) . No patient had any other cause of TMA, including ADAMTS13 inhibition, other malignancy or use of any other medication previously associated with TMA. Nine patients had resolution of TMA without evidence of hemolysis after withdrawal of PI. Two patients had stabilization of laboratory values but persistent evidence of hemolysis despite medication withdrawal. One patient had recurrence of TMA with rechallenge of PI. There is a strong level of evidence that PI can cause DITMA. In evaluating patients with suspected TMA, PI use should be recognized as a potential etiology, and these medications should be discontinued promptly if thought to be the cause of TMA. Am. J. Hematol. 91:E348-E352, 2016. © 2016 Wiley Periodicals, Inc.

110 Thrombotic microangiopathy in pregnant kidney transplant recipients: A life-threatening condition for mother and child

Introduction Thrombotic microangiopathy (TMA) represents a spectrum of disorders characterized by thrombosis that affect small arterial vessels. Pregnancy is a potential trigger to acute episodes of TMA, which in turn, although rare, are associated with high maternal and perinatal morbidity and mortality. In renal transplant (RT) setting, fertility is increased by restoration of renal function, meanwhile RT patients are more susceptible to gestational complications, such as TMA syndromes. Objectives The aim of this study was to report our experience with RT recipients who developed TMA in allograft during pregnancy. Methods We describe four cases of pregnant RT recipients with TMA diagnosed by allograft biopsy, due to acute allograft dysfunction, at Hospital do Rim between 2011 and 2015. Their clinical and laboratory data were collected and are highlighted here. Results At conception, the average age was 21 ± 4 years. Their obstetric history revealed previous abortions in two patients and one previous uncomplicated pregnancy in another patient. All patients had chronic hypertension before conception and one patient also had preexisting proteinuria greater than 0.5 g. At the time of the confirmation of pregnancy, 75% of the patients were being maintained on immunosuppressive therapy with prednisone, tacrolimus and azathioprine, while one patient was receiving prednisone, tacrolimus and everolimus. The mean interval time of RT to pregnancy was 25 (9–45) months and the average baseline creatinine was 1.1 (0.9–1.4). The TMA diagnosis was established in the 14th week of gestation on average, and it was associated with thrombocytopenia and microangiopathic hemolytic anemia in only one patient. Moreover, concomitant acute cellular rejection (AR) occurred in one patient, and superimposed urinary tract infection in another. Except for the patient who had AR, in all cases the calcineurin inhibitor was withdrawn. Three patients developed preeclampsia with HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome. The mean gestational term at delivery was 23 ± 2 weeks and these resulted in two abortions and two stillbirths. Over a 6 month follow-up period post pregnancy, there was one case of graft loss and all patients had increased proteinuria and creatinine levels – median creatinine = 4.3 (1.5–11); median proteinuria = 1.1 (0.6–1.9). Conclusions Since HELLP syndrome was very prevalent in these cases we suggest that the TMA diagnosis demands careful surveillance for gestational hypertension complications. Apart from the poor pregnancy outcomes, TMA in pregnant RT patients is associated with deterioration of graft function.

Terminal Complement Blockade after Hematopoietic Stem Cell Transplantation Is Safe without Meningococcal Vaccination

Eculizumab inhibits terminal complement-mediated intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and complement-mediated thrombotic microangiopathy (TMA) in patients with atypical hemolytic uremic syndrome and is now used as a first-line therapy in these diseases. Eculizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) because of an increased risk of meningococcal infections in persons without adequate functional complement. Administration of meningococcal vaccine is required at least 2 weeks before administering the first dose of eculizumab, and this advice is included in the product label. Eculizumab use for treatment of TMA in hematopoietic stem cell transplantation (HSCT) recipients brings a significant dilemma regarding REMS required meningococcal vaccination. TMA after HSCT usually occurs within the first 100 days after transplantation when patients are severely immunocompromised and are not able to mount a response to vaccines. We evaluated 30 HSCT recipients treated with eculizumab for high-risk TMA without meningococcal vaccine. All patients received antimicrobial prophylaxis adequate for Neisseria meningitides during eculizumab therapy and for 8 weeks after discontinuation of the drug. Median time to TMA diagnosis was 28 days after transplant (range, 13.8 to 48.5). Study subjects received a median of 14 eculizumab doses (range, 2 to 38 doses) for HSCT-associated TMA therapy. There were no incidences of meningococcal infections. The incidences of bacterial and fungal bloodstream infections were similar in patients treated with eculizumab (n = 30) as compared with those with HSCT-associated TMA who did not receive any complement blocking therapy (n = 39). Our data indicate that terminal complement blockade in the early post-transplant period can be performed without meningococcal vaccination while using appropriate antimicrobial prophylaxis until complement function is restored after therapy completion.

How we manage thrombotic microangiopathies in pregnancy.

Differentiation between the thrombotic microangiopathies (TMAs) that present in pregnancy may be clinically challenging, but is critical to ensure correct management because of the impact on fetal and maternal outcomes. Thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS) are medical/obstetric emergencies that require specialist input, both at the time of acute diagnosis and follow-up in subsequent pregnancies. Features of preeclampsia and HELLP syndrome (haemolysis, elevated liver enzymes, low platelets) may precede or be present in evolving TTP or aHUS. Clinicians need to be mindful of how a presumed diagnosis of a specific TMA in pregnancy may evolve and be prepared to frequently reassess signs and symptoms and revise the diagnosis and management plan accordingly.

The Thrombotic Microangiopathy Registry of North America

The thrombotic microangiopathies (TMAs) are rare, life-threatening thrombotic disorders of diverse etiologies. Systematic studies of TMA have been difficult to perform due to their rare occurrence, disease heterogeneity and, lack of an organized research network in the United States. Whereas a multi-institutional approach has been used in Europe and Canada, TMA research in the US has been largely single-center based. To overcome the limitations of single institutional registries and to expand the number of TMA patients available for study, four academic centers convened during the 2013 ASFA annual meeting to establish the TMA Registry of North America (TRNA) with the following goals: (1) design and develop a registry to define "best practices" for the diagnosis, treatment, and management of TMA; (2) develop a platform for conducting observational and interventional clinical trials; (3) and, establish a national bio-repository of samples from patients with TMA to facilitate future studies. This abstract reports the first multi-institutional network in the United States designed to study TMA. Members met through bimonthly tele-conferences to develop a clinical registry using REDCap (Research Electronic Data Capture), a HIPAA-compliant, internet-based software program for data entry. To facilitate a cohesive and streamlined review of IRB applications, the TRNA utilized IRBshare, a portal for rapid approval of multi-site investigations. IRB consent included participation in a bio-repository arm for collecting blood and apheresate. Following approval through the Duke IRB in June 2014, study documents were uploaded to the IRBshare website. Since August 2015, 16 study participants with TMA have been consented, 13 of which have had their clinical information entered into the database. Preliminary data shows our population is 73% African-American and female. Average laboratory values at presentation included hemoglobin of 9.7 g/dL, platelets 53 x10^9/L, and LDH 1,150 u/L. ADAMTS13 testing was performed in 77% (10/13), of which 60% (6/10) measured at <10%. Current efforts include expansion of network sites to expand the registry and to develop clinical protocols for future studies. With its clinical and IRB infrastructure in place, the TRNA, which is the first U.S. research network designed to study TMA, is poised to perform cooperative observational and interventional trials in the near future. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Long-Term Management of Atypical Hemolytic Uremic Syndrome after Non-Renal Solid Organ Transplantation with Eculizumab

▪Thrombotic microangiopathy (TMA) defined as microangiopathic hemolytic anemia, thrombocytopenia and end organ damage has been described in the post transplant (PT) setting after solid organ and hematopoietic stem cell transplants (HSCT). The true incidence among non-renal solid organ transplant (NRSOT) recipients is unknown. Reported rates range from 2-30% (Verbiest 2014). Despite standard interventions such as plasma exchange and/or reduction in calcineurin inhibitor (CNI) therapy, 3-month mortality rates remain as high as 40% in NRSOT patients who develop PT-TMA.In HSCT and renal transplant recipients, it has been demonstrated that complement plays a central role in the development of PT-TMA, analogous to atypical hemolytic uremic syndrome (aHUS) (Zuber 2011; Jodele 2013). Based on similar clinical manifestations and etiology, PT-TMA should be defined by the same laboratory criteria as aHUS and treated with eculizumab (ECU), a monoclonal antibody directed against C5 (Sheth, ASH 2014). We previously reported the successful use of ECU for the acute treatment of PT-aHUS in NRSOT patients (Broome, ASH 2013). We report the long-term data on this cohort of patients here.Between January 2012-Novemeber 2013, 10 patients (8 small bowel, 2 liver), were diagnosed with PT-aHUS utilizing established clinical criteria for de novo aHUS. All patients were on CNI therapy at the time of diagnosis. The median time from transplant to TMA diagnosis was 10.5 months (range 1-53 months). All patients received standard aHUS dosing of ECU (with meningococcal vaccinations and antibiotic prophylaxis). By 1 month of ECU therapy, all patients demonstrated normalization of hematologic parameters and 4 of the 5 patients on hemodialysis (HD) at the time of ECU initiation were able to discontinue HD. At a median follow-up of 24 months, 7 patients remain on therapy (range 18-43 months). One patient had ECU discontinued at 3 months by the transplant team. Two patients have died: one at 3 months of therapy due to sepsis/multi-organ failure and the other at 6 months of therapy due to PT lymphoproliferative disorder/graft failure (GF). The 7 patients remaining on ECU had no clinical/laboratory evidence of recurrence of PT-aHUS (Table 1). No new HD has been initiated in the follow-up period. All remained on CNI therapy (tacrolimus) for prevention of transplant rejection. One patient on ECU therapy developed GF. No serious infections have been reported to date.ECU is an effective therapy for the long-term management of PT-aHUS in NRSOT recipients. Prompt initiation of ECU appears to result in an increased likelihood of reversal of end organ damage related to TMA. The 2 patients with GF (240 days, 572 days) and the 1 patient who remained on HD (180 days) had extended intervals from laboratory evidence of PT-aHUS to initiation of ECU, suggesting prolonged complement mediated TMA may contribute to irreversible organ damage. With early ECU therapy, 86% of patients have healthy graft function and 80% of patients were able to discontinue HD. Despite ongoing CNI therapy, renal function, as measured by serum creatinine, has continued to improve demonstrating the benefit of long-term ECU therapy. The observed decline in haptoglobin, an acute phase reactant, at 12 and 18 months suggests a decrease in systemic inflammation with constant complement regulation mediated by ECU, illustrating the systemic nature of PT-aHUS. All patients remained on both CNI and ECU without infectious complications, demonstrating the ability to successfully administer more than one immune mediator in NRSOT patients with PT-aHUS concurrently. The mortality rate in our cohort of NRSOT recipients with PT-aHUS is 20%, significantly less than prior reports of up to 70%. We propose treatment with ECU at the earliest clinical/laboratory signs of aHUS to prevent the morbidity and mortality associated with PT-aHUS in NRSOT patients. Future studies should prospectively evaluate ECU therapy in PT-aHUS to better define the risks and benefits of this therapy in NRSOT patients.Table 1Median Laboratory Values Post ECUAt diagnosis1 month3 months6 months12 months18 monthsPlatelets k/uL86151 p=.01175 p=.04177 p=.01191 p=.04168 p=.07Serum Creatinine mg/dL2.261.54 p=.031.42 p=.051.28 p=.040.97 p=.131.18 p=.13LDH units/L369302 p=.23206 p=.17186 p=.17235 p=.23158 p=.21Haptoglobin mg/dL<8115 p=.00154 p=.01136 p=.0267 p=.0390 p=.04 DisclosuresBroome:Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding.

P-194: Hypertension in Lupus Nephritis

Background Evaluate hypertension (HT) in a cohort with lupus nephritis (LN) and study its epidemiologic, clinical, histological and therapeutic characteristics. Methods The patients included in this study met the criteria fixed by the ARA for the diagnosis of systemic lupus erythematosus. The LN was selected based on the criteria of the International Society of Nephrology (ISN) and the Renal Pathology Society. We reviewed 120 cases of LES hospitalized in the Internal Medicine Department of the Military Hospital of Tunis during 13-year period from 1999 to 2012 and were selected 41 cases of LN. Results Hypertension was found in 10 patients among the 41 cases studied (25 %). There were 2 men and 8 women. The average age of our patients was 34 years. Threatening HT with hypertensive encephalopathy was observed in one patient. HT was associated with diffuse proliferative glomerulonephritis (Class IV) in 6 cases, associated with membranous glomerulopathy (IV + V) in a case. Four patients had clinical and biological signs of thrombotic microangiopathy. In one case, diagnosis of thrombotic microangiopathy was histologically confirmed. The others patients (4 cases) had HT secondary to corticosteroids treatment. The therapeutic strategies consisted of a low salt diet associated with antihypertensive medications in all cases. The angiotensin converting enzyme inhibitors were used in all cases, loop diuretic in 2 cases, beta blocking and calcium channel blockers in 2 others patients. After etiopathogenic treatment, evolution was marked by persistent HT in 4 cases. Conclusions HT in NL is a poor prognostic factor. It is multifactorial, treatment based on angiotensin converting enzyme inhibitors and its evolution is often favorable.

De novo post-transplant thrombotic microangiopathy localized only to the graft in autosomal dominant polycystic kidney disease with thrombophilia.

Introduction: Thrombotic microangiopathy (TMA) is a serious complication of renal transplantation and is mostly related to the prothrombotic effect of calcineurin inhibitors (CNIs). A subset of TMA (29%-38%) is localized only to the graft. Case 1: A young woman suffering from autosomal dominant polycystic kidney disease (ADPKD) underwent kidney transplant. After 2 months, she showed slow renal deterioration (serum creatinine from 1.9 to 3.1 mg/dl), without hematological signs of hemolytic-uremic syndrome (HUS); only LDH enzyme transient increase was detected. Renal biopsy showed TMA: temporary withdraw of tacrolimus and plasmapheresis was performed. The renal function recovered (serum creatinine 1.9 mg/dl). From screening for thrombophilia, we found a mutation of the Leiden factor V gene. Case 2: A man affected by ADPKD underwent kidney transplantation, with delay graft function; first biopsy showed acute tubular necrosis, but a second biopsy revealed TMA, while no altered hematological parameters of HUS was detected. We observed only a slight increase of lactate dehydrogenase (LDH) levels. The tacrolimus was halved and plasmapheresis was performed: LDH levels normalized within 10 days and renal function improved (serum creatinine from 9 to 2.9 mg/dl). We found a mutation of the prothrombin gene. Only a renal biopsy clarifies the diagnosis of TMA, but it is necessary to pay attention to light increasing level of LDH. Conclusion: Prothrombotic effect of CNIs and mTOR inhibitor, mutation of genes encoding factor H or I, anticardiolipin antibodies, vascular rejection, cytomegalovirus infection are proposed to trigger TMA; we detected mutations of factor II and Leiden factor V, as facilitating conditions for TMA in patients affected by ADPKD.