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1.
Late transplant-associated thrombotic microangiopathy verified in bone marrow biopsy specimens is associated with chronic GVHD and viral infections
Hill, W., Sotlar, K., Hautmann, A., Kolb, H. J., Ullmann, J., Hausmann, A., Schmidt, M., Tischer, J., Pham, T. T., Rank, A., et al
European journal of haematology. 2024
Abstract
OBJECTIVES To describe late transplant-associated thrombotic microangiopathy (TA-TMA) as chronic endothelial complication in bone marrow (BM) after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS BM specimens along with conventional diagnostic parameters were assessed in 14 single-institutional patients with late TA-TMA (more than 100 days after HCST), including 11 late with history of early TA-TMA, 10 with early TA-TMA (within 100 days), and 12 non TA-TMA patients. Three non-HSCT patients served as control. The time points of BM biopsy were +1086, +798, +396, and +363 days after HSCT, respectively. RESULTS Late TA-TMA patients showed an increase of CD34+ and von Willebrand Factor (VWF)+ microvascular endothelial cells with atypical VWF+ conglomerates forming thickened VWF+ plaque sinus in the BM compared to patients without late TA-TMA and non-HSCT. Severe chronic (p = .002), steroid-refractory GVHD (p = .007) and reactivation of HHV6 (p = .002), EBV (p = .003), and adenovirus (p = .005) were pronounced in late TA-TMA. Overall and relapse-free survival were shorter in late TA-TMA than in patients without late TA-TMA (5-year OS and RFS: 78.6% vs. 90.2%, 71.4% vs. 86.4%, respectively). CONCLUSION Chronic allo-immune microangiopathy in BM associated with chronic, steroid-refractory GVHD and/or viral infections are key findings of late, high-risk TA-TMA, which deserves clinical attention.
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2.
Epidemiology, Outcomes, and Complement Gene Variants in Secondary Thrombotic Microangiopathies
Werion, A., Storms, P., Zizi, Y., Beguin, C., Bernards, J., Cambier, J. F., Dahan, K., Dierickx, D., Godefroid, N., Hilbert, P., et al
Clinical journal of the American Society of Nephrology : CJASN. 2023
Abstract
BACKGROUND The identification of complement defects as major drivers of primary atypical hemolytic uremic syndrome (HUS) has transformed the landscape of thrombotic microangiopathies (TMA), leading to the development of targeted therapies and better patients' outcomes. In contrast, little is known about the presentation, genetics and outcomes of TMA associated with specific diseases or conditions, also referred to as secondary TMA. METHODS Here we assessed the relative incidence, clinical and genetic spectra, and long-term outcomes of secondary TMA vs. other TMAs in consecutive patients hospitalized with a first episode of TMA from 2009 to 2019 at two European reference centers. RESULTS During the study period, 336 patients were hospitalized with a first episode of TMA. Etiologies included atypical HUS in 49 (15%); thrombotic thrombocytopenic purpura in 29 (9%); shigatoxin-associated HUS in 70 (21%), and secondary TMA in 188 (56%). The main causes of secondary TMA were hematopoietic stem cell transplantation (n=56, 30%), solid organ transplantation (n=44, 23%) and malignant hypertension (n=25, 13%). Rare variants in complement genes were identified in 32/49 (65%) patients with atypical HUS and 8/64 (13%) with secondary TMA; pathogenic or likely pathogenic variants were found in 24/49 (49%) and 2/64 (3%) of them, respectively (P<0.001). After a median follow-up of 1157 days, death or kidney failure occurred in 14 (29%), 8 (28%), 5 (7%) and 121 (64%) patients with atypical HUS, thrombotic thrombocytopenic purpura, shigatoxin-associated HUS and secondary TMA, respectively. Unadjusted and adjusted Cox regressions showed that patients with secondary TMA had the highest risk of death or kidney failure (unadjusted hazard ratio 3.35, 95% confidence interval 1.85-6.07, P<0.001; adjusted hazard ratio 4.11, 95% confidence interval 2.00-8.46, P<0.001; considering atypical HUS as reference). CONCLUSIONS Secondary TMA represent the main cause of TMA and are independently associated with a high risk of death and progression to kidney failure.
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3.
Endothelial Injury Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation: Angiopetin-2 as a Novel Predictor of the Outcome and the Role of Functional Autoantibodies against Angiotensin II Type 1 and Endothelin A Receptor
Vythoulkas, D., Lazana, I., Kroupis, C., Gavriilaki, E., Konstantellos, I., Bousiou, Z., Chondropoulos, S., Griniezaki, M., Vardi, A., Gkirkas, K., et al
International journal of molecular sciences. 2023;24(8)
Abstract
Transplant-associated thrombotic microangiopathy (TMA) occurs in a significant percentage of patients after allogeneic stem cell transplantation (allo-SCT) and is associated with significant morbidity and mortality. The aim of the present study was to examine the association of serum angiopoetin-2 (Ang2) levels and the presence of antibodies against angiotensin II type 1 (AT1R) and ndothelin A Recreptor (ETAR) with the outcome of patients with TMA and/or graft-versus-host disease (GVHD) after allo-SCT. Analysis of our data showed that elevated serum Ang2 levels at the time of TMA diagnosis are significantly associated with increased non-relapse mortality and decreased overall survival. To our knowledge, this is the first study demonstrating an association between raised Ang2 levels and poor outcomes in patients with TMA. Antibodies against AT1R (AT1R-Abs) and ETAR (ETAR-Abs) were detected in 27% and 23% of the patients, respectively, but there was no association between the presence of autoantibodies and the outcome of patients with TMA. However, a significant finding was the strong positive correlation between the presence of AT1R-Abs with the occurrence of chronic fibrotic GVHD, such as scleroderma and cryptogenic organizing pneumonia, raising the possibility of the contribution of autoantibodies in the pathogenesis of fibrotic GVHD manifestations.
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4.
Prospective clinical and biomarker validation of the ASTCT consensus definition for transplant-associated thrombotic microangiopathy (TA-TMA)
Ma, S., Bhar, S., Guffey, D., Kim, R. B., Jamil, M., Amos, C. I., Lee, S. J., Hingorani, S. R., Sartain, S. E., Li, A.
Transplantation and cellular therapy. 2023
Abstract
INTRODUCTION Transplantation-associated thrombotic microangiography (TA-TMA) is a disorder that causes severe complications post-allogeneic hematopoietic cell transplantation (allo-HCT). Diagnosing TA-TMA is challenging due to non-standardized criteria. In this study, we aimed to evaluate the new TA-TMA consensus definition from the American Society for Transplantation and Cellular Therapy (ASTCT) panel as part of an ongoing prospective pediatric cohort study and to compare the impact and outcomes of employing the current clinical TMA definition (cTMA) versus the new consensus definition. METHODS We included patients aged 0 to 18 years who underwent their first allo-HCT from May 2021 to January 2023 at Texas Children's Hospital. We compared the incidence, biomarkers, and outcomes of TA-TMA applying the previous and recently proposed screening algorithms and definitions. RESULTS While the classic microangiopathic hemolytic anemia (MAHA)-based cTMA definition led to an incidence of 12.7%, the ASTCT-HR definition doubled the incidence to 28.5% by day 100. In contrast to patients with concordant diagnosis (+/+) who had significantly worse post-transplant survival, those reclassified as TA-TMA by the new definition only (-/+) had significantly different prognosis (100% survival at day 100) despite the lack of TMA-directed therapy. Furthermore, biomarkers of the terminal and alternative complement pathways (sC5b9 and Ba, respectively) were significantly elevated around day 15 in the concordant group (+/+) but not in the discordant group (-/+) when compared to the non-TMA patients. CONCLUSIONS The recently proposed ASTCT consensus TA-TMA diagnosis is more sensitive and allows earlier recognition of manifestation that requires closer clinical monitoring but risks over-diagnosis and over-treatment. We recommend additional prospective validation.
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5.
[Efficacy and Prognosis of Transplant-Associated Thrombotic Microangiopathy Based on Different Prognostic Risk Models]
Xu, Y. F., Wei, Y., Guo, J. Y., Xu, S., Zhang, L. L., Wang, L. J., Bo, J., Dou, L. P., Liu, D. H., Li, M., et al
Zhongguo shi yan xue ye xue za zhi. 2023;31(5):1501-1508
Abstract
OBJECTIVE To investigate the clinical features of transplant-associated thrombotic microangiopathy (TA-TMA) and the prognostic value of different prognostic risk models for TA-TMA. METHODS The clinical characteristics of 32 TA-TMA patients diagnosed at the First Medical Center of the PLA General Hospital from January 2018 to February 2022 in terms of short-term prognosis and influencing factors were retrospectively analyzed. In addition, the risk population composition ratio, treatment response, and overall survival between the BATAP risk model and the TMA index model were compared, as well as the efficacy of two prognostic risk models for predicting death in patients with TA-TMA. RESULTS Independent risk factors affecting the short-term prognosis of TA-TMA include III-IV aGVHD prior to TA-TMA diagnosis (P=0.001), renal or neurological dysfunction (P=0.006), and Hb<70 g/L (P=0.043). In the TMA index model, treatment response was worst in the high-risk group (P=0.008), while there was no significant difference in treatment response between different risk groups in the BATAP model (P=0.105). In the BATAP model, there was a statistically significant difference in the OS between the three groups of low risk, intermediate risk, and high risk (87.5% vs 61.1% vs 16.7%, χ(2)=6.7, P=0.014). In the TMA index model, there was a statistically significant difference in the OS between the three groups of low risk, intermediate risk, and high risk (77.8% vs 45.5% vs 0.0%, χ(2)=7.3, P=0.017). The area under the ROC curve (AUC) of the TMA index model was 0.745 (95%CI: 0.56-0.88, P<0.05), and the AUC of the BATAP model was 0.743 (95%CI: 0.56-0.88, P<0.05), indicating that both prognostic risk models have good predictive value. CONCLUSION The short-term prognosis of TA-TMA patients might be accurately determined using both the BATAP model and the TMA index model. When predicting the efficacy of TA-TMA in different risk groups, the TMA index model may perform better than the BATAP model.
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6.
Pathway-driven rare germline variants associated with transplant-associated thrombotic microangiopathy (TA-TMA)
Zhang, Z., Hong, W., Wu, Q., Tsavachidis, S., Li, J. R., Amos, C. I., Cheng, C., Sartain, S. E., Afshar-Kharghan, V., Dong, J. F., et al
Thrombosis research. 2023;225:39-46
Abstract
The significance of rare germline mutations in transplant-associated thrombotic microangiopathy (TA-TMA) is not well studied. We performed a genetic association study in 100 adult TA-TMA patients vs. 98 post-transplant controls after matching by race, sex, and year. We focused on 5 pathways in complement, von Willebrand factor (VWF) function and related proteins, VWF clearance, ADAMTS13 function and related proteins, and endothelial activation (3641variants in 52 genes). In the primary analysis focused on 189 functional rare variants, no differential variant enrichment was observed in any of the pathways; specifically, 29 % TA-TMA and 33 % controls had at least 1 rare complement mutation. In the secondary analysis focused on 37 rare variants predicted to be pathogenic or likely pathogenic by ClinVar, Complement Database, or REVEL in-silico prediction tool, rare variants in the VWF clearance pathway were found to be significantly associated with TA-TMA (p = 0.008). On the gene level, LRP1 was the only one with significantly increased variants in TA-TMA in both analyses (p = 0.025 and 0.015). In conclusion, we did not find a significant association between rare variants in the complement pathway and TA-TMA; however, we discovered a new signal in the VWF clearance pathway driven by the gene LRP1 among likely pathogenic variants.
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7.
Pediatric Transplant Associated Thrombotic Microangiopathy Healthcare Utilization and Implications of Eculizumab Therapy
Schoettler, M. L., Lehmann, L. E., Kao, P. C., Chen, N., Jodele, S., Chonat, S., Williams, K. M., London, W. B., Duncan, C., Dandoy, C. E.
Blood advances. 2023
Abstract
The healthcare utilization (HCU) burden of transplant associated thrombotic microangiopathy (TA-TMA) and its treatments are unknown. The objective of this study was to investigate inpatient costs associated with meeting criteria for transplant associated thrombotic microangiopathy (TA-TMA) in the first-year post-HCT. This IRB-approved retrospective multicenter study included serial children who underwent HCT from 1/1/2015 to 7/1/2019. A standardized unit cost (adjusted for geographic location, differences in cost of living, and inflation) for inpatient hospitalization was extracted from the Pediatric Health Information System data and linked to clinical data. Both total cost and cost-per-day from 15 days before stem cell infusion to 1-year post-HCT were calculated. Among children with neuroblastoma who underwent autologous HCT (n=60), 17 (28%) developed TA-TMA; there were no apparent differences in costs for TA-TMA versus no TA-TMA. Among allogeneic (allo) recipients, after adjusting for severe grade III/IV acute graft versus host disease (GVHD), infections, and HLA mismatch, costs were not different in TA-TMA (n=137) vs. no TA-TMA (n=238). Among allo HR-TMA-TMA, unadjusted costs were significantly higher in the eculizumab treated cohort (n=19, median $1,419,823, range $286,175 to $7,217,095) than supportive care (n=36, median $672,578 range $156,379 to $3,911,402, p=0.001). However, after adjusting for GI bleeding which occurred disproportionately in the eculizumab (n=6) versus supportive care (n=0) cohort, eculizumab treatment was not associated with increased total costs. More studies are needed to determine the etiology of increased HCU costs in those with HR-TA-TMA and to predict those more likely to benefit from eculizumab, reducing HCU and improving outcomes.
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8.
Upregulation of HIF-1α contributes to complement activation in transplantation-associated thrombotic microangiopathy
Qi, J., Pan, T., You, T., Tang, Y., Chu, T., Chen, J., Fan, Y., Hu, S., Yang, F., Ruan, C., et al
British journal of haematology. 2022
Abstract
Transplantation-associated thrombotic microangiopathy (TA-TMA) is a severe complication of haematopoietic stem cell transplantation (HSCT). Complement activation is involved in the development of TA-TMA. However, the underlying mechanism is unclear. Therefore, 21 samples of TA-TMA and 1:1 matched controls were measured for hypoxia-inducible factor-1α (HIF-1α) and complement protein. The mechanism was investigated both in vitro and in vivo. In this study, we found that levels of HIF-1α were significantly higher in TA-TMA patients than that in non-TA-TMA controls. Upregulation of HIF-1α induced an increase in membrane-bound complement C3 and dysfunction of human umbilical vein endothelial cells (HUVECs) in vitro. Increasing HIF-1α in vivo led to C3 and C5b-9 deposition in the glomerular endothelial capillary complex, thrombocytopenia, anaemia, and increased serum lactate dehydrogenase (LDH) levels in wild-type (WT) but not in C3(-/-) mice subjected to HSCT. High platelet aggregation in peripheral blood and CD41-positive microthrombi in the kidney were also found in dimethyloxallyl glycine (DMOG)-treated mice, recapitulating the TA-TMA phenotype seen in patients. Comprehensive analysis, including DNA array, luciferase reporter assay, chromatin immunoprecipitation (ChIP)-seq, and quantitative polymerase chain reaction (PCR), revealed that HIF-1α interacted with the promoter of complement factor H (CFH) to inhibit its transcription. Decreased CFH led to complement activation in endothelial cells.
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9.
Acute graft-versus-host disease increase risk and accuracy in prediction model of transplantation-associated thrombotic microangiopathy in patients with myelodysplastic syndrome
Zhang, Z., Wang, H., Qi, J., Tang, Y., Cai, C., Zhou, M., Pan, T., Wu, D., Han, Y.
Annals of hematology. 2022
Abstract
Allogeneic hematopoietic stem cell transplantation is the only curative therapy for patients with myelodysplastic syndrome. Transplantation-associated thrombotic microangiopathy (TA-TMA) remains a cause of death after transplantation. This study assessed the risk factors of TA-TMA and established a prediction model for this complication. We launched a real-world study from 303 MDS patients after allo-HSCT from Dec 1, 2007, to Jun 1, 2018. Logistic regression was used to analyze risk factors and to establish a nomogram. The accuracy of the model was assessed by C-index and calibration curve. TA-TMA class was associated with an over twofold increase in the risk of death (HR 2.66, 95% CI 1.39-5.09, p = 0.003). Stage III or IV acute graft-versus-host disease (aGVHD) (OR: 6.17, 95% CI: 2.19-17.18, p < 0.001) and occurrence time of aGVHD were the risk factors for TA-TMA. Next, we put these two variants and the other three variants into the prediction model via multivariate Lasso regression. In order to quantify the contribution of each factor, a nomogram was generated and displayed (C index of 0.783). TA-TMA predicts worsened outcomes of overall survival. A cross-validated multivariate score including aGVHD occurrence showed excellent concordance and efficacy of predicting TA-TMA in HSCT patients.
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10.
Sickle cell disease is a risk factor for transplant-associated thrombotic microangiopathy in children
Schoettler, M., Stenger, E. O., Spencer, K., Lutterman, D., Rumbika, S., Jones, J. A., Haight, A. E., Parikh, S. H., Qayed, M., Watkins, B., et al
Blood advances. 2022
Abstract
Transplant associated thrombotic microangiopathy (TA-TMA) and sickle cell disease (SCD) share features of endothelial and complement activation. Thus, we hypothesized that SCD is a risk factor for TA-TMA and that pre-hematopoietic cellular transplantation (HCT) markers of endothelial dysfunction and complement activation would be higher in SCD patients. Children who underwent haploidentical or matched sibling donor (MSD) first HCT between January 2015- June 2020 were included in this IRB approved, single institution, retrospective study. Of 115 children, 52 had SCD and 63 underwent HCT for non-SCD indications. There were no significant differences in severe grade III-IV acute graft versus host disease (GVHD) in SCD vs. non-SCD HCT recipients. The non-SCD cohort had significantly more CMV positive recipients, radiation containing preparative regiments, and PBSC graft sources (p=0<0.05); all described risk factors for developing TA-TMA. Despite this, 7/52 (13%) of SCD patients developed TA-TMA compared to 1/63 (2%) non-SCD patients (p=0.015). Risk was highest in those who underwent haploidentical HCT (OR 33, 95% CI 1.4 - 793.2). Adjusting for HLA match, GVHD, post HCT viral infection, stem cell source and myeloablation, SCD remained a risk for developing TA-TMA (OR 12.22, 95% CI 1.15- 129.6). In available pre-HCT samples, there were no differences in complement biomarkers in those with SCD and those without, though SCD patients did have significantly higher markers of endothelial activation, sVCAM-1 and p-selectin levels. In conclusion, children with SCD merit careful screening for TA-TMA post HCT, particularly those receiving a haploidentical HCT.