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.

Introduction: ADAMTS13 (A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats) activity remains a key tool in differential diagnosis of thrombotic microangiopathies (TMAs). However, ADAMTS13 testing is not readily available in many hospitals. Recently, PLASMIC and PLASIC scores have been developed to facilitate rapid recognition of TTP. We aimed to evaluate their usefulness compared to ADAMTS13 testing in a real-world cohort of TMA patients. Methods: We enrolled consecutive patients with samples referred to our Center for ADAMTS13 measurement due to TMA over the last 2 years. Samples were collected either at first diagnosis or relapse before initiation of treatment. ADAMTS13 activity was measured with a commercially available and validated ELISA kit (Technozym, Diapharma). Clinical data were retrospectively collected from referring centers. Management was based on treating physicians' decisions. TTP was defined as severe ADAMTS13 deficiency (activity≤10%); while secondary TMAs were diagnosed in patients with cancer, connective tissue disorders or hematopoietic cell transplantation recipients (transplant-associated TMA). Atypical hemolytic uremic syndrome (aHUS) remained a diagnosis of exclusion in patients with ADAMTS13>10%. PLASMIC was calculated based on seven variables: platelets, hemolysis, cancer, transplant, MCV, INR, creatinine; while MCV was not included in PLASIC, as previously described. ROC curve analysis was performed to determine the sensitivity and specificity of scores. Multivariate binary or logistic regression models were performed when appropriate. Results: We studied 50 TMA patients. Combined clinical and laboratory data conferred the following TMA classification: TTP in 36 patients (72%), transplant-associated TMA in 7 (14%), other secondary TMA in 5 and aHUS in 2. PLASMIC score was intermediate in 2 and high in another 4 patients without TTP. The PLASIC score was high in 5 patients without TTP, leading to less false positive results compared to PLASMIC (p<0.001). These patients suffered from secondary TMAs. In the ROC curve analysis, both PLASMIC and PLASIC significantly predicted TTP diagnosis (p<0.001 and area under the curve/AUC 0.891 and 0.892, Figure 1). In patients without secondary TMAs, PLASMIC and PLASIC had an excellent performance (p<0.001 and AUC 1). Plasma exchange was commenced in the majority of patients (42/50, 84%). Among TTP patients, the majority (77%) received rituximab as salvage or prophylactic treatment. Rituximab administration was associated with platelet (p=0.003) and ADAMTS13 (p=0.015) levels at diagnosis. The complement inhibitor eculizumab was administered in 3 patients with TA-TMA, who achieved TMA resolution. With a median follow-up of 2.9 years (range 0.3-26.3), overall survival was significantly lower in patients with secondary TMAs (p<0.001). PLASMIC or PLASIC score were not associated with clinical outcomes in our cohort. Conclusion: PLASMIC and PLASIC scores are excellent tools in TMA patients without secondary causes. While PLASMIC and PLASIC scores conferred similar outcomes, the PLASIC score requires six instead of seven variables, is classified as low/high omitting the intermediate category and leads to less false positive results. Further validation of the PLASIC score might confirm its clinical value. In addition, the role of ADAMTS13 levels in guiding rituximab administration needs to be further investigated. When an underlying etiology is detected, ADAMTS13 testing is necessary to exclude TTP and facilitate further therapeutic decisions. Figure 1 Disclosures Panayiotidis: Bayer: Other: Support of clinical trial.

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Dear Editor, Acquired severe aplastic anemia (SAA) remains a diagnostic and therapeutic challenge, despite advances in the field that have led to improved survival rates. 1 Allogeneic hematopoietic cell transplantation (alloHCT) is a cornerstone in the therapeutic algorithm of the disease even in patients with coexisting paroxysmal nocturnal hemoglobinuria (PNH) clones. Nevertheless, literature on patients with SAA and PNH clones post alloHCT is scarce.Complement inhibition with eculizumab has shown effectiveness in patients with PNH and high disease activity, with or without aplastic anemia. 2 However, the role of eculizumab in the transplant setting has not been clarified yet. Recently, DeZern et al reported successful outcomes with eculizumab bridging before alloHCT in 8 SAA patients. 3 Two recent studies have also explored outcomes of patients with PNH clones in the age of eculizumab. 4,5 Although both studies present the potential benefits of eculizumab post alloHCT in 8 and 2 patients respectively, there is no clear comparison with a historical control group that did not receive eculizumab. 4,5 This comparison would clarify the role of complement inhibition, given that alloHCT mortality in SAA patients with PNH clones has been reported at approximately 30%. 6 Given the renewed interest in the field, we conducted a retrospective analysis of alloHCT outcomes in patients transplanted for SAA with or without PNH clones.