Validation of Early Increase in Complement Activation Marker sC5b-9 as a Predictive Biomarker for the Development of Thrombotic Microangiopathy After Stem Cell Transplantation.

ABSTRACT

Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is a multifactorial complication. Complement dysregulation may play an important role in the pathogenesis of TA-TMA. Our previous observations suggested that early increase of soluble C5b-9 (sC5b-9), before the development of other complications, can predict the development of later TA-TMA. The present study aims to validate our earlier findings in an independent cohort enrolling 67 pediatric patients who underwent allogeneic HSCT during the study period (October 2015-January 2019). Five different TA-TMA diagnostic criteria were applied, and all important clinical and laboratory parameters of TA-TMA activity were registered. Complement pathway activities, components and sC5b-9 levels were systematically measured before transplantation and on days 28, 56, and 100 after HSCT. A strong and remarkable association still have been found between early increase of sC5b-9 (10 of 10 patients with TA-TMA vs. 27 of 57 without TA-TMA; P = 0.002) and the development of TA-TMA during 100 days post-transplantation. An increase in sC5b-9 concentration had 100% sensitivity and 53% specificity for TA-TMA in the cohort. All TA-TMA cases have been observed during cyclosporine immunosuppression, no TA-TMA was diagnosed during tacrolimus or mycophenolat mofetil therapy. In the majority of patients TA-TMA was mild and self-limiting, without any signs of organ damage. No additional complement parameters were closely associated with the development of TA-TMA. Early raise of the sC5b-9 activation marker was predictive for later development of TA-TMA throughout the whole study period. In patients with a marked increase, early and frequent monitoring of TA-TMA activity markers should be attempted, to facilitate subsequent therapy decisions in time. However, patients with TA-TMA were only identified during or after cyclosporine immunosuppression. Further studies enrolling higher number of patients are necessary to determine the role of immunosuppression in the pathogenesis of TA-TMA.