Transplant-associated Thrombotic Microangiopathy Diagnosis Research Articles

Easix Is Strongly Associated with Complement Activation and Overall Survival in Adult Allogeneic Hematopoietic Cell Transplantation Recipients

Introduction: Endothelial dysfunction is a common denominator of graft-versus-host disease (GVHD) and transplant-associated thrombotic microangiopathy (TA-TMA). The latter is also characterized by excessive complement activation. Recent studies have introduced the Endothelial Activation and Stress Index (EASIX) as a potential predictor of survival in patients with GVHD. We hypothesized that EASIX would predict complement activation and survival in patients with GVHD and TA-TMA. Methods: We enrolled consecutive adult TA-TMA (International Working Group/IWG criteria), acute and/or chronic GVHD and control allogeneic hematopoietic cell transplantation (HCT) recipients in a 1:1:1 ratio (January 2015-December 2018). Plasma was collected and stored immediately at -80oC at the first day of confirmed TA-TMA or GVHD diagnosis and at a similar post-transplant period in control recipients. EASIX [lactate dehydrogenase (U/L) × creatinine (mg/dL)/thrombocytes (10⁹ cells per L)] was calculated at day 0, 30, 100 and last follow-up. Complement activation was detected measuring soluble C5b-9/membrane attack complex (ELISA, Quidel). Results: We studied 20 TA-TMA, 20 GVHD and 20 control patients (Table 1). TA-TMA developed at a median of 125 post-transplant day (range 9-2931); whereas the first day of confirmed GVHD diagnosis was at a median of 78 post-transplant day (range 16-145). EASIX at day 100 and last follow-up differed significantly among groups (p=0.014 and p=0.001, Table 1), although there was no significant difference between TA-TMA and GVHD patients. In contrast, soluble C5b-9 was significantly higher in TA-TMA compared to GVHD (p=0.008) and control patients (p<0.001, Bonferroni's correction). Soluble C5b-9 levels were strongly associated with EASIX at day 100 and last follow-up (r=0.318, p=0.018 and r=0.321, p=0.020). Among laboratory values used to calculate EASIX (LDH, creatinine, platelets), C5b-9 was associated only with creatinine levels at day 100 (r=0.316, p=0.023), suggesting that the association between EASIX and C5b-9 is not driven by laboratory values per se. Furthermore, EASIX at day 0 and last follow-up was significantly associated with overall survival (p=0.013 and p=0.046). Among other pre-transplant factors studied (age, disease type and phase at transplant, donor), EASIX at day 0 was an independent predictor of overall survival (beta=2.627, p=0.029). Conclusion: Our study shows for the first time that EASIX predicts complement activation and overall survival in patients with endothelial dysfunction syndromes and control HCT recipients. Our findings suggest that EASIX may be a useful dynamic marker reflecting the course of endothelial dysfunction in these patients. Disclosures No relevant conflicts of interest to declare.

Clinical analysis of 9 patients with transplant-related thrombotic microangiopathy

Objective: To analyze the clinical features, efficacy and outcomes in patients with transplantation associated thrombotic microangiopathy (TA-TMA). Methods: The clinical data of 9 patients who developed TA-TMA after allogeneic hematopoietic stem cell transplantation (allo-HSCT) were retrospectively analyzed from January 2011 to August 2018 in Affiliated Tumor Hospital of Zhengzhou University. Results: There were 6 male and 3 female patiens with a median age of 31 (12-38) years. The median time from transplantation to TA-TMA was 76 (24-155) days. The baseline blood and biochemical parameters at diagnosis of TA-TMA included median hemoglobin (Hb) 66 (58-77) g/L,platelet (PLT) count 22 (4-38) × 10(9)/L,serum lactic dehydrogenase (LDH) 655 (305-4 238) U/L,blood urine nitrogen (BUN) level 15.9 (4.8-26.2) mmol/L,blood creatinine (Cr) level 118 (24-380) μmol/L. The proportion of median peripheral blood schistocytes was 2.6%(1.2%-9%). All patients had positive urinary occult blood tests,and urinary protein was seen in 4 patients. Three patients had mental symptoms. Coombs tests were all negative. The main treatments of TA-TMA composed of reduction and withdrawal of calcineurin inhibitor,steroids and plasma exchange. Response was seen in 4 patients. Patients who did not response to the treatment had a higher proportion of schistocytes,more severe acute graft-versus-host disease (aGVHD),more elevated serum LDH and other transplant-related complications. Conclusions: TA-TMA after allo-HSCT is a serious complication with high mortality rate. The proportion of schistocytes in peripheral blood, serum LDH level and comorbidities are prognostic factors of clinical outcome.

Largest Reported Series of Adults Who Received Treatment with Eculizumab (ECU) for Hematopoietic Cell Transplantation-Associated Thrombotic Microangiopathy (TA-TMA). a Single Center Experience

Background:TA-TMA is a life-threatening complication of hematopoietic cell transplantation (HCT), usually manifested as a combination of non-immune mediated hemolytic anemia, thrombocytopenia and end-organ dysfunction (renal, neurologic and/or hypertension). Reported mortality rates following TA-TMA are high (50-75%; Gavriilaki et al, Bone Marrow Transplantation 2017). It is more commonly associated with allogeneic HCT, however, may infrequently occur with autologous HCT. Traditionally, treatment for TA-TMA consisted in removing possible offending agents (calcineurin inhibitors, sirolimus) and/or instituting total plasma exchange (PLEX). These approaches have not resulted in significant improvement in the natural history of TA-TMA, with complete resolution in 12-20% of pts (Mulay et al, J Clin Apher 2015).Recent evidence of alternate complement pathway activation has been implicated in the pathophysiology of TA-TMA (Jodele et al, Blood 2013). Eculizumab (ECU) is an anti-C5 monoclonal antibody, approved for treatment of PNH and aHUS, which has been used anecdotally as treatment for TA-TMA. Most reports consist of pediatric patients. In this analysis, we evaluated consecutive cases of adult recipients of HCT who developed TA-TMA and have received ECU therapy at our institution.Methods:We reviewed electronic records of consecutive patients who presented with a diagnosis of TA-TMA (non-immune hemolytic anemia plus worsening thrombocytopenia and end-organ dysfunction) and were treated with ECU between 2015 and 2017 at our institution. Univariate and bivariate statistics were calculated for the sample; Fisher's exact tests and Wilcoxon rank sum tests were utilized to test for differences across groups.Results:Table 1 shows the baseline characteristics of these pts. A total of 15 pts were included in the analysis; 2/3 were female and the median age was 62. ECU was given according to the usual schedule for aHUS (900 mg IV weekly x 4, 1200 mg every other week starting on week 5). Median time from TA-TMA diagnosis to initiation of ECU was 2 days. All patients received prophylaxis for Neisseria meningitides with ciprofloxacin and antifungal prophylaxis at initiation of ECU. Three (20%) pts received PLEX prior to ECU. Seven (47%) patients were receiving tacrolimus at diagnosis, however, levels were not within toxic range (3.7-7.9 ng/mL). Median time post-HCT for development of TA-TMA was 135 days. Median LDH, hemoglobin, platelet count and creatinine at TA-TMA diagnosis were 1724 U/L, 7.3 g/dL, 33,000/mcL and 1.7 mg/dL, respectively. Ten (66.6%) patients had acute kidney injury and 7 (46.6%) pts had neurologic manifestations. Eight (53.3%) pts had evidence of GVHD concurrent with TA-TMA diagnosis. Ten (63.3%) pts developed systemic infections during their TA-TMA treatment. No pts developed meningitis or fungal infections.Median follow-up was 4.5 months after initiation of ECU. Eight (53.3%) patients had complete resolution of TA-TMA (i.e. resolution of hemolytic anemia, thrombocytopenia and end-organ damage), 4 of these 8 pts were recipients of autologous HCT. Median time to resolution was 98 days and median cumulative ECU dose was 10,200 mg (range 4800-36400mg). An additional 2 pts (13%) presented clinical improvement without complete resolution of TA-TMA.Mortality secondary to TA-TMA or its complications was 33%. Median time to death was 31 days. The most common cause of mortality were infectious complications. Median survival for the entire cohort was 130 days (range 6-833 days, Figure).LDH >1300 U/L; more than one organ involvement, allogeneic HCT, use of tacrolimus and early (<100 days) onset of TA-TMA post-HCT were associated with lower rates of TA-TMA resolution and higher mortality. PLEX prior to ECU did not correlate with improved outcomes.Conclusion:To our knowledge, this is the largest reported series of adult pts with TA-TMA who were treated with ECU. Treatment with ECU for TA-TMA is associated with higher rates of resolution and lower rates of cause-specific mortality than what has been previously reported with other approaches. We hypothesize that higher cumulative doses of ECU are warranted to achieve resolution of TA-TMA. A prospective study utilizing a more intensive schedule of ECU infusions is required to confirm such hypothesis. Based on our analysis, we conclude that ECU is an appropriate - and potentially better - option in the treatment of TA-TMA. [Display omitted] DisclosuresSkarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau.

Prospective Analysis of Complement Activation in Allogeneic Transplant Recipients and Correlation with Transplant Associated Thrombotic Microangiopathy (TA-TMA) and Acute Graft Versus Host Disease (aGVHD)

Background: Hematopoietic cell transplantation associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication and is associated with higher non-relapse mortality in allogeneic transplant (HCT) patients. Recent studies have indicated an association between complement activation of the terminal pathway (sC5b-9) and TA-TMA, leading to the utilization of complement blockade as a means for therapeutic intervention in cases of TA-TMA (Jodele, 2016, Bohl 2017). It is unknown, however, whether complement activation routinely occurs in the inflammatory milieu after transplant and whether such activation is associated with clinical outcomes. Therefore, we conducted a prospective analysis of complement activation from plasma samples drawn from HCT patients. We hypothesized that complement activation is associated with subsequent development of clinically relevant outcomes such as TA-TMA or aGVHD.Methods: We performed a prospective analysis of complement activation in 76 patients who underwent hematopoietic cell transplantation and reached day +90 between January 2017 and June 2018. Plasma samples were collected from patients at admission for the Pre-HCT timepoint, and subsequent samples were collected at day +30 (± 7 days). Complement markers included C5a (Terminal pathway), sC5b-9 (terminal pathway - membrane attack complex), C4d (Classical pathway), and BB Plus (Alternative pathway) were measured as previously described (Yang 2015). Following enrollment, transplant-related demographic data was collected, as well as any new cases or flares of aGVHD and/or TA-TMA, and patient survival. Changes in complement markers from pre-HCT to day +30 were categorized into four groups: 1. Normal - normal 2. Normal - elevated 3. Elevated - normal 4. Elevated - elevated. Time to TA-TMA was defined as days from transplantation to TA-TMA onset censoring those without TA-TMA at last follow up date, treating death as a competing risk. The cumulative incidence rate of TA-TMA was estimated and the Fine and Gray regression models accounting for competing risk were used to examine the association between change in complement markers and risk of TA-TMA. aGVHD was similarly analyzed. OS was defined from the date of transplantation to the date of death, censoring those alive at the last follow up date. Cox proportional hazard models were used to evaluate the associations with risk of death.Results: The median patient age at the time of transplant was 60 years (19-72) and 36.8% were female. Reduced-intensity conditioning was used in 76% of the patients and 58 of the 76 patients received tacrolimus as GVHD prophylaxis. Of the 76 patients, the cumulative incidence of aGVHD by Day 100 was 55.3% (95% Confidence Interval (CI): 43.4-65.6%) and the cumulative incidence rate of TA-TMA by Day 200 was 14.2% (95% CI: 7.2-23.5%). Median duration of follow-up was 270 days and overall survival was 81.4% by day +365.Complement Activation, TA-TMA, aGVHD, and Survival: At the pre-HCT time point, more than 25% of patients had evidence of complement activation (Figure 1A). However, pre-HCT complement activation was not associated with subsequent TA-TMA, aGVHD, or overall survival. We then evaluated changes in complement activation from pre-HCT to day +30 and correlated with incidence of aGVHD and TA-TMA (Figure 1B, Table 1). When compared to normal - normal group, patients in the normal-elevated sC5b-9 group had a higher risk of subsequent TA-TMA (Hazard Ratio (HR): 13.4, 95% CI: 1.6-109.9, p=0.02), and patients in the elevated - elevated C5a group had a higher risk of developing aGVHD (HR: 2.8, 95% CI: 1.01-7.6, p=0.049).Discussion: We show that complement activation can occur pre-HCT and is dynamic post-transplant. However complement activation pre-HCT does not correlate with clinical outcomes. Changes in terminal complement pathway between pre-HCT and day +30 correlate with subsequent development of TA-TMA or aGVHD. These results suggest that kinetics of complement activation may indicate a role of this pathway as a biomarker in diagnosis of TA-TMA and aGVHD. Further evaluation is necessary to explore whether complement inhibition might be effective as a therapeutic approach in aGVHD and TA-TMA. [Display omitted] DisclosuresCataland:Ablynx: Consultancy, Other: Member of Advisory Board; Shire: Consultancy; Alexion: Research Funding. Vasu:Boehringer Ingelheim Inc: Membership on an entity's Board of Directors or advisory committees.

Transplant-associated thrombotic microangiopathy: Incidence, prognostic factors, morbidity, and mortality in allogeneic hematopoietic cell transplantation.

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.

Eculizumab for transplant-associated thrombotic microangiopathy in adult allogeneic stem cell transplant recipients.

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). Patients were identified retrospectively and data collected through HSCT and pharmacy databases. Ten patients with TA-TMA after allogeneic HSCT were treated with ECU between 2013 and 2016. TA-TMA was diagnosed at a median of 93days 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 4days. 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. Early initiation of ECU may not alter the disease process enough to restore organ function, but it may prolong survival.

Bone marrow transplant-associated thrombotic microangiopathy without peripheral blood schistocytes: a case report and review of the literature

BackgroundBone marrow transplant-associated thrombotic microangiopathy (TA-TMA) is a relatively frequent but under-recognized and under-treated hematopoietic stem cell transplant (HSCT) complication that leads to significant post-transplant morbidity and mortality. Classic TMA-defining laboratory abnormalities appear at different times in the course of TA-TMA development, with schistocytes often appearing later in the disease course. In some severe TMA cases, schistocytes may be absent due to increased endothelial permeability. Unfortunately, many clinicians continue to perceive the presence of schistocytes as an absolute requirement for TA-TMA diagnosis, which leads to delayed recognition and treatment of this potentially fatal transplant complication.MethodsPatient chart review and PubMed literature search using the term, “transplant-associated thrombotic microangiopathy”.Case presentationA 54-year-old male IgG kappa multiple myeloma underwent a reduced intensity allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with fludarabine and melphalan. On day + 27, the patient developed acute kidney injury followed by repeated episodes of diarrhea and gastrointestinal bleeding attributed to graft versus host disease (GVHD) and cytomegalovirus (CMV) colitis. Repeated colonic biopsies suggested CMV infection and GVHD. Despite appropriate treatment with antiviral therapy and immunosuppressants, the patient’s condition continued to deteriorate. He experienced concomitant anemia and thrombocytopenia as well as elevated lactate dehydrogenase and low haptoglobin levels, but a TA-TMA diagnosis was not made due to an absence of schistocytes on peripheral smear. The patient expired secondary to uncontrolled gastrointestinal bleeding. A post-mortem analysis of the resection specimen revealed extensive TMA involving numerous arteries and arterioles in the ileal and colonic submucosa as well as in the muscularis propria and deep lamina propria of the mucosa.ConclusionsTA-TMA can occur in the absence of peripheral blood schistocytes. Our experience underscores the importance of considering the diagnosis of intestinal TA-TMA in patients with refractory post-transplant diarrhea and GI bleeding, even if all classic features are not present.

Transplant-Associated Thrombotic Microangiopathy: Prevalence, Prognostic Factors and Treatment Outcomes in Unrelated Allogeneic Transplant for Hematologic Diseases

Introduction: Transplant-associated thrombotic microangiopathy (TA-TMA) represents a devastating and life-threatening complication occurring more frequently in allogeneic compared to autologous hematopoietic cell transplantation (HCT). Although it has been a well-recognized syndrome for decades, our understanding in terms of epidemiology and more importantly, treatment options remains unclear. Therefore, we aimed to retrospectively investigate the incidence of TA-TMA in patients undergone HCT from unrelated donors and identify prognostic factors and treatment outcomes.Methods: We enrolled consecutive patients who underwent HCT from unrelated donors from 2003 to 2015. TA-TMA diagnosis was based on EBMT (European Bone Marrow Transplantation) criteria: increased (>4%) schistocytes in peripheral blood, thrombocytopenia, increased lactade dehydrogenase, decreased Hb. Anti-thymocyte globulin (ATG, rabbit) was used as standardised part of the conditioning in almost all patients (total dose of 5-7.5mg/kg). Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine or tacrolimus plus methotrexate in myeloablative and mycophenolate mofetil plus cyclosporine in reduced intensity conditioning transplants. Upon identification of TA-TMA, all possible causative factors were fully investigated. The mainstay of treatment strategy was withdrawal of calcineurin inhibitors, plasma infusion and plasma exchange combined with corticosteroid administration and in refractory cases, humanized anti-CD20 monoclonal antibody (Rituximab).Results: In total, we studied 179 patients, 74 male:105 female, aged 37±14 years, who underwent HCT from matched HLA A/B/C/DRB1 (8/8, n=88) and allele or antigen mismatched (n=91) grafts. Grafts derived from peripheral blood (157), bone marrow (18) and umbilical stem cells (4). Conditioning regimens were myeloablative (139), reduced intensity (28) and toxicity (12). Median follow-up was 11.5 (0.1-147.4) months.TA-TMA was diagnosed in 29 (16.2%) patients, 12 male:17 female, aged 34±12 years, 78 (9-721) days post-HCT for acute leukemia (21), Hodgkin (3) and non-Hodgkin (1), lymphoma, MDS (2), aplastic anemia (1) and MPN (1). Conditioning regimens were myeloablative in 24 (12 based on total body irradiation/TBI) and reduced intensity in 5 patients. Among patients with TA-TMA, 10 (34%) presented severe (grade III-IV) acute GVHD, 15 (52%) extensive chronic GVHD, 12 (41%) bacterial, 2 (7%) fungal and 21 (71%) viral (Cytomegalovirus and/or Epstein-Barr viremia) infectious episodes.In univariate analysis, age, gender, diagnosis, disease phase, previous lines of treatment, conditioning (intensity and TBI-based), ABO and HLA incompatibility, infections, acute and chronic GVHD were studied. The presence of TA-TMA was associated with severe acute and extensive chronic GVHD (p=0.001 and p=0.035 respectively) and TBI-based conditioning (p=0.043). In multivariate analysis, severe acute GVHD was the only independent factor associated with TA-TMA (β=3.4, p=0.038).Regarding treatment outcomes, 8 (28%) patients responded to cyclosporine cessation and plasma infusions. The rest 21 out of 29 patients underwent plasma exchange sessions; 14 (48%) of them responded to plasma exchange treatment. One patient that did not respond to plasma exchange received additional Rituximab treatment and the syndrome resolved. The other 6 (20.6%) patients were refractory and eventually succumbed. Treatment-related mortality was 33.3% (9/29) in TA-TMA patients and was directly associated with refractory microangiopathic syndrome in 6/29.Conclusion: Our results suggest that TA-TMA is not rare in unrelated transplant recipients and can be managed in a portion of patients that respond to cyclosporine cessation and plasma exchange. GVHD was the only independent predictor for the development of TA-TMA and therefore, successful prevention and treatment strategies for GVHD need to be timely employed to prevent complications. More importantly, transplanted patients with refractory microangiopathic syndrome showed increased TRM indicating that conventional treatment is inadequate. Recent data of increased complement activation in TA-TMA pave the way for targeted treatment with complement inhibitors in these patients. DisclosuresNo relevant conflicts of interest to declare.

Hematopoietic cell transplantation-associated thrombotic microangiopathy: a review of pathophysiology, diagnosis, and treatment

Transplant-associated thrombotic microangiopathy (TA-TMA) is a multifactorial disorder caused by systemic vascular endothelial injury that can be triggered by several mechanisms during the transplant process. Thrombotic microangiopathy may affect multiple systems and occurs in ~30% of patients undergoing hematopoietic stem cell transplantation. A subgroup of patients with thrombotic microangiopathy develop TA-TMA, and the other may develop other thrombotic microangiopathic disorders such as thrombotic thrombocytopenic purpura, a condition with similar finding but different pathophysiology involving ADAMTS-13. The mortality rates in patients who develop severe TA-TMA are in excess of 80%. Recent investigations show that complement system activation in patients with TA-TMA is a very poor prognostic sign and implicates complement dysregulation as a key pathway in the pathogenesis of TA-TMA and its disease phenotype. The original diagnostic criteria for TA-TMA included hematologic and renal injury markers, which are limited in their ability to detect only advanced disease, and therefore may result in delayed TA-TMA diagnosis in transplant patients. A recent set of diagnostic criteria added markers of complement activation, proteinuria, and hypertension, with predicted improved detection of early TA-TMA. Supportive care that includes elimination of potentially toxic agents such as calcineurin inhibitors and sirolimus, adequate antimicrobial treatment, and maintaining adequate renal functions using renal replacement therapy may be sufficient for treatment of mild-to-moderate TA-TMA. Plasma exchange, which is a potentially curative therapy in thrombotic thrombocytopenic purpura, has no proven efficacy in TA-TMA. Blocking the complement system with eculizumab is currently the most effective treatment to circumvent the poor outcome in patients with severe TA-TMA.

Eculizumab in Transplant-Associated Thrombotic Microangiopathy.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare entity with no standard of care and high mortality, despite the use of plasma exchange. Using specific search terms, all cases having TA-TMA treated with eculizumab and indexed in MEDLINE (English language only) by November 2014 were reviewed. A total of 26 cases, 53% men, had a median age of 33 years (range 2-61). Transplant-associated thrombotic microangiopathy occurred after stem-cell transplant (35%) or solid-organ transplant (65%), frequently associated with the use of cyclosporine or tacrolimus (96%). A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS 13) level was always >10%. After TA-TMA diagnosis, the following drug adjustments were made: discontinuation of cyclosporine or tacrolimus in 45%, dose reduction in another 27%, continuation of the drugs in 23%, and switch from cyclosporine to tacrolimus in remaining 5%. Plasma exchange was performed in ∼43%. The median interval between transplant and initiation of eculizumab was 63 days (range 11-512). A median of 5.5 doses (range 2-21) of eculizumab was utilized with 92% response occurring after a median of 2 doses (range 1-18). At a median follow-up of 52 weeks (range 3-113), the survivors (92%) were doing well. Within the limits of this retrospective analysis, our study demonstrates that eculizumab use may result in high response rate and 1-year survival in patients with TA-TMA refractory to discontinuation of calcineurin inhibitor and plasma exchange.

Histologic Features of Intestinal Thrombotic Microangiopathy in Pediatric and Young Adult Patients after Hematopoietic Stem Cell Transplantation

High-risk transplantation-associated thrombotic microangiopathy (TMA) can present with multisystem involvement and is associated with a poor outcome after hematopoietic stem cell transplantation (HSCT), with < 20% 1-year survival. TMA may involve the intestinal vasculature and can present with bleeding and ischemic colitis. There are no established pathologic criteria for the diagnosis of intestinal TMA (iTMA). The goal of our study was to identify histologic features of iTMA and describe associated clinical features. We evaluated endoscopic samples from 50 consecutive HSCT patients for 8 histopathologic signs of iTMA and compared findings in 3 clinical groups based on the presence or absence of systemic high-risk TMA (hrTMA) and the presence or absence of clinically staged intestinal graft-versus-host disease (iGVHD): TMA/iGVHD, no TMA/iGVHD, and no TMA/no iGVHD. Thirty percent of the study subjects had a clinical diagnosis of systemic hrTMA. On histology, loss of glands, intraluminal schistocytes, intraluminal fibrin, intraluminal microthrombi, endothelial cell separation, and total denudation of mucosa were significantly more common in the hrTMA group (P < .05). Intravascular thrombi were seen exclusively in patients with hrTMA. Mucosal hemorrhages and endothelial cell swelling were more common in hrTMA patients but this difference did not reach statistical significance. Patients with hrTMA were more likely to experience significant abdominal pain and gastrointestinal bleeding requiring multiple blood transfusions (P < .05). Our study shows that HSCT patients with systemic hrTMA can have significant bowel vascular injury that can be identified using defined histologic criteria. Recognition of these histologic signs in post-transplantation patients with significant gastrointestinal symptoms may guide clinical decisions.

Transplant-Associated Thrombotic Microangiopathy (TA-TMA) in Childhood - A literature review

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

Fragmented Red Cell as a Possible Favorable Prognostic Marker of Hematopoietic Stem Cell Transplantation Associated Thrombotic Microangiopathy

Fragmented red cell (FRC) by automated hematologic analyzer is known to detect schistocyte. In this study, it is noted that FRC might be a favorable prognostic marker of hematopoietic stem cell transplantation associated thrombotic microangiopathy (TA-TMA). The peripheral blood samples and clinical data of 89 patients were collected. The diagnosis of TA-TMA was defined by the Blood and Marrow Transplant Clinical Trials Network's criteria and schistocyte or both schistocyte- and FRC-positive cases and other parameters fulfilled are regarded as TA-TMA. Schistocyte and FRC displayed a correlation coefficient of 0.461 (P < 0.001) by Spearman's method. The diagnostic concordance of TA-TMA using schistocyte and FRC was 92.1% with kappa index of 0.531 (P < 0.001). The number of diagnosed patients and mean survival month were as follows: TA-TMA by schistocyte, 8 (8.9%), 13.5 month; TA-TMA by schistocyte and FRC, 7 (7.8%), 40.4 month; No TMA, 74 (83.1%), 38.3 month, respectively. Kaplan-Meier survival analysis by log-rank method of the patient with TA-TMA by schistocyte and rest of the group showed statistical significance (P < 0.01). As evidenced by the data, FRC might be a favorable prognostic marker for TA-TMA, but additional studies with larger patients groups are required for validation of clinical applications.

Transplant-Associated Thrombotic Microangiopathy (TA-TMA) and Consensus Based Diagnostic and Therapeutic Recommendations: Which TA-TMA Patients to Treat and When?

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is considered one of the most severe complications after hematopoietic stem cell transplantation. Unfortunately, controversial approaches on TA-TMA diagnostic criteria contribute to a delay in both diagnosis and treatment. Recommendations for TA-TMA based in the past on case reports or retrospective studies lack a reasonable level of evidence. One of the most promising drugs for TA-TMA likely induced by endothelium damage is Defibrotide, a polydisperse oligonucleotide. Auto-antibody depleting or complement blocking therapy has also emerged as new strategy to decrease TA-TMA-associated morbidity and mortality. Methods: A joint study group of experts on TA-TMA met during the 2013 ASH Meeting (New Orleans, USA) and the 2014 EBMT Meeting (Milan, Italy) with the aim of proposing a reliable treatment for this complication. Common diagnostic criteria for TA-TMA have been discussed and are described in the review. Factors influencing the outcome of TA-TMA are also addressed. Results: The panel agreed that an endothelial damage pathway is involved in the pathogenesis of TA-TMA. With emerging data, an updated version of TA-TMA diagnostic criteria is suggested. High or standard risk patients have been defined according to TA-TMA risk factors and a comprehensive therapeutic strategy for TA-TMA patients has been designed for a possible multicentre study. Conclusions: The panel focused primarily on high level of awareness about an early TA-TMA diagnosis and treatment before a TA-TMA-induced multi-organ failure. An important consensus was obtained to investigate whether Defibrotide or Eculizumab can improve the outcome of TA-TMA in a multicentre study.

Severe Gut Acute Graft Versus host Disease (GVHD) Influence Thrombotic Microangiopathy in 86 Allogeneic Hematopoietic Stem Cell Recipients Who Received Tacrolimus-Based Regimen for GVHD Prophylaxis

AbstractAbstract 1955 Background and aims:Transplantation-associated thrombotic microangiopathy (TA-TMA) is a significant complication of allogeneic stem cell transplantation (HSCT). Although endothelial injury represents the final common pathway of disease, the exact pathophysiology of TA-TMA remains unclear. A variety of potential risk factors have been proposed such as different conditioning regimens, the development of acute graft versus host disease (GVHD), concomitant infection, or the use of calcineurin inhibitor (cyclosporine, tacrolimus) and sirolimus. The recent use of both tacrolimus and sirolimus for GVHD prophylaxis suggest increasing the risk of TA-TMA, especially in patients receiving busulfan and cyclophosphamide. However, there are little studies in which tacrolimus/sirolimus GVHD prophylaxis was compared with other tacrolimus-based regimens in order to determine the really increased incidence of TA-TMA.The purpose of this study was to determine the incidence and risk factors of TA-TMA in 86 allogeneic-HSCT recipients who received tacrolimus-based regimens (with sirolimus or with methotrexate) for GVHD prophylaxis. Patients and Methods:We conducted a retrospective cohort study of 86 consecutive allogeneic-HSCT recipients (aged over 18 years) transplanted in our unit between September 2007 and July 2012; GVHD prophylaxis consisted on tacrolimus and methotrexate (N = 19) or tacrolimus and sirolimus (N= 64); 3 patients received tacrolimus and sirolimus for acute GVHD treatment. Median age was 51 years (range 20–68) and 59.3% male. 40.7% of patients were diagnosed of acute leukemia, 23.3% myelodisplastic syndrome, 23.2% lymphoproliferative disorders, 7% multiple myeloma, 5.9% other hematological malignancies. The EBMT status at the moment of HSCT was intermediate/advanced in 63% of patients. The source of stem cells was peripheral blood in 87.2% and bone marrow in 12.8%. 57% of patients receiving an unrelated donor transplant. Nineteen patients (22.1%) received a HLA-mismatch graft. Reduced intensity conditioning was administered in 74.4%. 67.4% developed acute GVHD, 58.1% grade II-IV acute GVHD. Median follow-up was 248 days (range 16–1357).The diagnosis of TA-TMA was considered according to probable TMA criteria as defined by validation study by Cho et al. Results:TA-TMA occurred in 9/86 patients (10,5%): 2/19 patients in the tacrolimus-methotrexate regimen group (10.5%) and 7/67 in the tacrolimus/sirolimus regimen group (10.4%). Median time until diagnosis of TA-TMA was 67 days (range, 37 – 405 days), and 8/9 patients were diagnosed before the day +110 post-HSCT; none of them developed chronic GVHD previously to the diagnosed of TA-TMA. Several variables have been analyzed but only acute GVHD (p=0.026) and acute gut GVHD (p=0.007) were significantly associated with TA-TMA in the univariate analysis. Of note, in the tacrolimus/sirolimus group, only acute gut GVHD (p=0.04) but not acute GVHD, was associated with TA-TMA. In the multivariate analysis, only grade ≥2 acute gut GVHD retained their association with TA-TMA development (OR = 13.33, 95% CI = 1.51 – 117.38). Conclusions:In contrast to previously published evidence, these data support that the use of tacrolimus/sirolimus GVHD prophylaxis does not increase the risk of TA-TMA compared to tacrolimus/methotrexate regimen. However, none of the patients included in our study have received busulfan-cyclophosphamide conditioning.On the other hand, the most important risk factor for TA-TMA in allogeneic-HSCT recipients who received tacrolimus-based GVHD prophylaxis regimens was grade ≥2 acute gut GVHD. Consequently we propose especially close monitoring for TA-TMA in these patients. Disclosures:No relevant conflicts of interest to declare.

Pulmonary Arterial Hypertension in Pediatric Patients with Hematopoietic Stem Cell Transplant–Associated Thrombotic Microangiopathy

Pulmonary arterial hypertension (PAH) is rarely included in the differential diagnosis of cardiorespiratory failure after pediatric hematopoietic stem cell transplant (HSCT) as the clinical presentation is nonspecific and may mimic other etiologies. The pathogenesis of PAH in HSCT is poorly understood and the diagnosis requires a high degree of suspicion. We describe 5 children diagnosed with PAH after allogeneic HSCT. All 5 patients had prolonged clinical signs of transplantation-associated thrombotic microangiopathy (TA-TMA) when they presented with hypoxemic respiratory failure and evidence of PAH. Four of the 5 patients had echocardiographic evidence of PAH, and 1 patient was diagnosed with PAH only on autopsy. PAH was diagnosed a median of 76 days (range, 56-101 days) after a diagnosis of TA-TMA. Despite aggressive medical management, including inhaled nitric oxide, 4 of the 5 patients died. One patient recovered from PAH after 11 months of sildenafil therapy. Three of the 4 deceased patients had an autopsy performed, demonstrating severe pulmonary vascular disease consistent with TA-TMA and severe PAH. We conclude that TA-TMA can be associated with significant pulmonary vascular injury presenting as hypoxemic respiratory failure with PAH after HSCT. Pediatric patients with unexplained hypoxemia after HSCT should be evaluated for both transplantation complications, TA-TMA and PAH, accordingly.

Does early initiation of therapeutic plasma exchange improve outcome in pediatric stem cell transplant–associated thrombotic microangiopathy?

The use of therapeutic plasma exchange (TPE) in hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA) is controversial because the exact mechanism of injury in TA-TMA is not yet understood. The study objective was to retrospectively review the outcome of children receiving TPE for TA-TMA at our institution. We hypothesized that patients initiating TPE earlier in their disease course would receive a greater benefit than those starting later, regardless of the therapeutic mechanism. We identified 10 consecutive pediatric patients with TA-TMA treated with TPE. Nine of these patients showed normalization of the laboratory variables associated with microangiopathy during their TPE course, but only five patients recovered renal function and survived TA-TMA. The five survivors started TPE a median of 17 days (range, 4-25 days) after TA-TMA diagnosis while the five patients who died started TPE a median of 32 days (range, 17-73 days) after TA-TMA was diagnosed. Three of the five survivors had multiorgan failure at TA-TMA diagnosis and completely recovered with early institution of TPE. These three survivors were able to discontinue renal replacement therapy, and all achieved a normal posttreatment creatinine. The five patients with later institution of TPE progressed to end-stage renal disease and all died. There were no serious TPE-related complications in either group. This is the first report evaluating TPE response in regard to procedure initiation time after TA-TMA diagnosis. Our data suggests that early initiation of TPE might be beneficial even in patients with multiorgan failure due to TA-TMA.

Evaluation the Risk Factor of Transplantation-Associated Thrombotic Microangiopathy.

AbstractAbstract 4527 Background:Transplantation-associated thrombotic microangiopathy (TA-TMA) is lifethrewten though rare complication of allogeneic hematopoietic stem cell transplantation (HSCT). Diagnosis of TA-TMA is difficult due to its variation of criteria. Recently two new diagnositic criteria for TA-TMA have recently been proposed: the Bone Marrow Transplant Clinical Trials Network (BMTCTN) and the International Working Group (IWG) criteria. Our purpose is to investigate the indence and risk facter of TA-TMA in our institute. Study design and methods:All 8 cases of TA-TMA previously diagnosed at our institution between October 2005 and August 2010 were retrospectively evaluated and analysised. Table I showed the transplant details and patients characteristics. Results:Six patients performed Matched Unrelated Donor HSCT, two were haploidentical donor HSCT. Four patients complicated with hypohepatia, but only three patients had renal insufficient. The incidence of central nervous symptom abnormalities or dysfunction was very high (sever of eight patients). Four of eight patients were CSA linked TA-TMA, withdrawing CSA resulted in complete response. The other four patients were no CSA linked TA-TMA and developed aGVHD or CMV infection before TA-TMA. They had badly response to common treatment including plasma exchange (PE), steroid treatment and immunosuppression decreased. All of them died of multiple organ failure. Table II showed TA-TMA manifestations and associated circumstance of the patient. Conclusion:Our experience suggests that CSA linked TA-TMA is totally different from no CSA linked TA-TMA. The former had good response and prognosis, the later were always associated with GVHD, hypohepatia and virus infectious. The mortality of no CSA linked TA-TMA is high, they had poor prognosis and badly response.Table I:Transplant details and patient characteristicsPatients No.SexAgeDiseaseConditioningDonorTA-TMA occurrence (days after SCT)Follow-up and Outcome (days after SCT)1M48ALLBUCY2MUD (HLA-B1, A->B)97144 died of TA-TMA2F28ALLBUCY2MUD (Matched, O->O)4765 died of TA-TMA3M42ALLBUCY2+ATGMUD (HLA-B, AB->O)3851 died of TA-TMA4M12ALLBUCY2+Ara-C+ATGHaploidentical (Mom->Son, O->O)33Survival>2705M17SAACTX+ATGMUD (HLA-CW, B->O)25Survival >2106F33MDSBUCY2MUD (Matched, AB->O)71Survival >11577F21ALLBUCY2+Ara-C+ATGHaploidentical (Dad->daughter, A->O)31Survival TA-TMA, but died of infection at 180+8F43ALLBUCY2MUD (Matched, A->O)6366 died of TA-TMATable II:TA-TMA manifestations and associated circumstancePatients No.Hb (g/L)PLT (*10E9/L)Schistocyte (%)LDH (U/L)Cr increasedCNS abnormalAntiglibulin testAssociated conditionsTreatment150<2011962>2 fold increasedNoNegCMV, AGVHD, III,PE*9 times, steroid259<2061243>2 fold increasedYesNegAGVHD, IVPE*4, steroid, Defibrotide Etanercept3863511481NoYesNegAGVHD, II; HypohepatiaPE*2, steroid, Defibrotide490793369NoYesNegCSA associatedPE*2, steroid Anti-CD25, withdraw CSA and recovery596405548NoYesNegCSA associatedwithdraw CSA and recovery689553340NoYesNegCSA associatedwithdraw CSA and recovery751<203398NoYesNegAGVHD, II; CMVsteroid, withdraw CSA and recovery861<2071838>2 fold increasedYesNegAGVHD, IV; CMV; Invasive fungal infection CSA associated,steroid Disclosures:No relevant conflicts of interest to declare.

Early clinical indicators of transplant-associated thrombotic microangiopathy in pediatric neuroblastoma patients undergoing auto-SCT

Patients undergoing auto-SCT for neuroblastoma present a unique population to study transplant-associated thrombotic microangiopathy (TA-TMA), due to standardized chemotherapy and later exposure to radiation and cis-retinoic acid (cis-RA). We retrospectively analyzed 20 patients after auto-SCT to evaluate early clinical indicators of TA-TMA. A total of 6 patients developing TA-TMA (30% prevalence) were compared with 14 controls. Four of six patients were diagnosed with TA-TMA by 25 days after auto-SCT. Compared with controls, TA-TMA patients had higher average systolic and diastolic blood pressure levels during high-dose chemotherapy and developed hypertension by day 13 after auto-SCT. Proteinuria was a significant marker for TA-TMA, whereas blood and platelet transfusion requirements were not. Serum creatinine did not differ between groups post transplant. However, patients with TA-TMA had a 60% decrease in renal function from baseline by nuclear glomerular filtration rate, compared with a 25% decrease in those without TA-TMA (P=0.001). There was no TA-TMA-related mortality. Significant complications included end-stage renal disease (n=1) and polyserositis (n=3). Patients with TA-TMA were unable to complete cis-RA therapy after auto-SCT. We suggest that careful attention to blood pressure and urinalysis will assist in the early diagnosis of TA-TMA, whereas serum creatinine seems to be an insensitive marker for this condition.

Posttransplant thrombotic microangiopathy: sensitivity of proposed new diagnostic criteria

Objective diagnosis of transplantation-associated thrombotic microangiopathy (TA-TMA) has traditionally been difficult due to the multiple potential etiologies of thrombocytopenia and red blood cell fragmentation occurring after allogeneic hematopoietic stem cell transplantation (SCT). To attempt to address this issue of diagnostic uncertainty, two new diagnostic criteria for TA-TMA have recently been proposed: the Bone Marrow Transplant Clinical Trials Network (BMT-CTN) and the International Working Group (IWG) criteria. However, both newly proposed criteria are yet to be clinically validated. All 15 cases of TA-TMA previously diagnosed at the authors' institution between December 2001 and March 2008 were retrospectively reclassified under the newly proposed BMT-CTN and IWG criteria. Potential diagnostic pitfalls were identified in both the BMT-CTN and the IWG TA-TMA criteria. The main limitation of the BMT-CTN criteria appeared to be need for concurrent renal and/or neurologic dysfunction to be manifest at TA-TMA diagnosis, which was present in only 73% of our patient cohort. For the IWG criteria, the main limitation to TA-TMA diagnosis appeared to be the requirement for schistocytosis of more than 4%, which was present in only 27% of these patients. Our experience suggests that potentially significant diagnostic pitfalls remain with both recently proposed TA-TMA diagnostic criteria, pitfalls that are likely to limit the diagnostic sensitivity of both. It is recommended that further clinical correlation of both the BMT-CTN and the IWG criteria be undertaken before either is routinely adapted into SCT practice.