Easix, a new tool to predict response and refractoriness in immune-mediated thrombotic thrombocytopenic purpura

Abstract

Abstract Background Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 deficiency due to autoantibodies. It presents with microangiopathic hemolytic anemia, thrombocytopenia, and organ ischemia. Caplacizumab, combined with plasma exchange (TPE), corticosteroids (CE), and rituximab, has improved outcomes. However, 10–15% of patients remain refractory, and up to 20% may relapse. Platelet count and ADAMTS13 activity guide response, but caplacizumab leads to rapid platelet recovery while ADAMTS13 may stay severely reduced despite apparent remission. Thus, there is a need for dynamic biomarkers reflecting actual disease activity and endothelial damage. The Endothelial Activation and Stress Index (EASIX), calculated as (LDH×creatinine)/platelets, indirectly reflects endothelial stress and has shown predictive value in other hematologic contexts. However, its role in iTTP is still unknown. Objectives To evaluate EASIX behavior during treatment and follow-up of iTTP patients and assess its predictive value for refractoriness and mortality. Methods This international, multicenter, and retrospective study included 55 adult patients diagnosed with iTTP between 2015-2024. Adults with iTTP and treated with at least two therapies among TPE, CE, rituximab, and caplacizumab, were included. Clinical data were collected by chart review. Laboratory data and EASIX values were calculated at baseline and on days 1–2, 7, 14, 21, 28, and 35, as well as on the day of last targeted-therapy discontinuation. If it occurred, laboratory data was also collected at any relapse (clinical or ADAMTS13). Definitions of remission, exacerbations, refractoriness, and relapse were according to Cuker et al. (2021). Data were analyzed using Wilcoxon rank sum test, logistic regression models and ROC analysis. ResultsOverall, the median age was 47 years (range: 21-77), with 62% female. At diagnosis, all patients had thrombocytopenia (100%), and most had concomitant anemia (96%). Neurological symptoms were seen in 56% of patients, and gastrointestinal involvement in 23%. Most patients received CE (98%), TPE (96%), rituximab (78%), and caplacizumab (75%). Refractoriness occurred in 13%, clinical relapses in 24%, ADAMTS13 relapses in 11%, and mortality during the acute phase in 7%.At onset, the median EASIX was 103.7 (IQR 41.1-290.9). After treatment initiation, EASIX declined rapidly, reaching values <1 by day 7. Similarly, creatinine, LDH, and platelet counts normalized by day 7; however, substantial inter-individual variability was observed in these parameters compared to EASIX values. ADAMTS13 activity reached values >20% at day 21.Median EASIX at day 0 was significantly higher in refractory vs. non-refractory patients (752 vs. 91; p=0.007), remaining so at day 7 (median 45 vs. 1; p<0.001) and day 14 (1.61 vs. 0.49; p=0.003). A non-significant trend toward higher EASIX values was also observed in the refractory group at day 1 (63 vs. 19; p=0.069).Relapse episodes also showed distinct EASIX dynamics. Clinical relapses were marked by sharp EASIX rises (median 13.24, IQR 5.0-27.5), while ADAMTS13 relapses did not show significant EASIX changes.Logistic regression showed that EASIX at day 0 significantly predicted refractoriness (OR 1.003, 95% CI: 1.001–1.005; p=0.021). ROC analysis revealed an area under the curve (AUC) of 0.811. A cut-off value of 129.1 yielded a sensitivity of 100% and a specificity of 58.7% for identifying refractory patients. EASIX outperformed platelet count or LDH alone: platelet count did not show significant association and LDH exhibited moderate predictive value (AUC 0.714), but requiring markedly elevated thresholds above normal clinical ranges to achieve this performance. Similarly, higher baseline EASIX values were linked with increased mortality risk (OR 1.004, 95% CI: 1.001–1.009; p=0.027). ConclusionsEASIX is a dynamic, easily applicable, and accessible biomarker that reflects endothelial stress in iTTP. Its rapid decline in responders and rise during clinical relapses adds value beyond traditional markers. Notably, higher baseline EASIX values strongly predicted refractoriness and were also associated with mortality. Despite the small sample size, these findings support its incorporation into routine monitoring and justify prospective validation for early risk stratification and potentially guide treatment intensity.