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

Abstract

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.

Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) and Growth Differentiation Factor-15 (GDF-15) Levels Are Significantly Associated with Endothelial Injury Indices in Adult Allogeneic Hematopoietic Cell Transplantation Recipients

“…In our study, we found significantly higher suPAR and GDF-15 levels in HSCT-TMA and GVHD patients compared to allo-HSCT and healthy controls. Moreover, both GDF-15 and suPAR concentrations were associated with EASIX at day 100 and the last follow-up, and these findings are comparable with our previous study where EASIX at the same time points was significantly higher in HSCT-TMA and GVHD compared with controls [ 63 ]. Interestingly, suPAR was associated with creatinine and platelets at day 100 and last follow-up, while GDF-15 was only associated with platelets at both time points.…”

“…To date, there is a lack of standardized laboratory parameters that specifically address endothelial dysfunction in these patients. The EASIX score, which is based on the calculation of LDH multiplied by Cr, divided by platelet count, has emerged as a potential prognostic biomarker of endothelial dysfunction in patients with HSCT-TMA and GVHD [ 63 , 64 ].…”

Biomarkers for Early Complications of Endothelial Origin After Allogeneic Hematopoietic Stem Cell Transplantation: Do They Have a Potential Clinical Role?

“…EASIX score combines three routine laboratory tests that are used as diagnostic parameters of TA-TMA and is calculated using the following formula: (Lactate Dehydrogenase (U/L)) x (Creatinine (mg/dL))/Thrombocytes (10 9 cells per L). Elevated EASIX score at days 0 after HCT has been showed to predict the risk of mortality in patients with acute GVHD and TA-TMA ( 86 , 107 ). This easy-to-calculate index can be used by clinicians as a tool for clinical management of decision in patient with GVHD in the reduced conditioning regimen setting, since this index was not predictive in case of myeloablative conditioning regimens ( 86 ).…”

Role of the lectin pathway of complement in hematopoietic stem cell transplantation-associated endothelial injury and thrombotic microangiopathy

“…The Endothelial Activation and Stress Index (EASIX)a composite measure of LDH, creatinine, and platelet levels-has demonstrated prognostic value for risk of death in patients with GVHD [114][115][116]. In adult patients with GVHD and HSCT-TMA, soluble C5b-9 levels were strongly associated with EASIX score 100 days after transplant and at last follow-up [115].…”

“…The Endothelial Activation and Stress Index (EASIX)a composite measure of LDH, creatinine, and platelet levels-has demonstrated prognostic value for risk of death in patients with GVHD [114][115][116]. In adult patients with GVHD and HSCT-TMA, soluble C5b-9 levels were strongly associated with EASIX score 100 days after transplant and at last follow-up [115]. When EASIX was calculated before conditioning, the score was a significant prognostic factor for HSCT-TMA and was predictive of overall survival after HSCT, independent of other assessments [114].…”