Early Elevation of Complement Factor Ba Is a Predictive Biomarker for Transplant-Associated Thrombotic Microangiopathy

Abstract

Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous reports suggest that TA-TMA is caused by complement activation by complement-related genetic variants; however, this needs to be verified, especially in adults. Here, we performed a nested case-control study of allo-HSCT-treated adults at a single center. Fifteen TA-TMA patients and 15 non-TA-TMA patients, matched according to the propensity score, were enrolled. Based on a previous report showing an association between complement-related genes and development of TA-TMA, we first sequenced these 17 genes. Both cohorts harbored several genetic variants with rare allele frequencies; however, there was no difference in the percentage of patients in the TA-TMA and non-TA-TMA groups with the rare variants, or in the average number of rare variants per patient. Second, we measured plasma concentrations of complement proteins. Notably, levels of Ba protein on Day 7 following allo-HSCT were abnormally and significantly higher in TA-TMA than in non-TA-TMA cases, suggesting that complement activation via the alternative pathway contributes to TA-TMA. All other parameters, including soluble C5b-9, on Day 7 were similar between the groups. The levels of C3, C4, CH50, and complement factors H and I in the TA-TMA group after Day 28 were significantly lower than those in the non-TA-TMA group. Complement-related genetic variants did not predict TA-TMA development. By contrast, abnormally high levels of Ba on Day 7 did predict development of TA-TMA and non-relapse mortality. Thus, Ba levels on Day 7 after allo-HSCT are a sensitive and prognostic biomarker of TA-TMA.

Early vascular endothelial complications after hematopoietic cell transplantation: Role of the endotheliopathy in biomarkers and target therapies development

“…In the setting of TA-TMA, NETs and soluble C5b-9 have been postulated as potential biomarkers for diagnosis confirmation (100,124), and it might be used to foresee the development of TA-TMA ( 126) and of aGvHD (98). Also, the early assessment of some coagulation factors, such as VWF and TM, together with soluble vascular CAM protein 1 (sVCAM-1), or biomarkers belonging to the complement cascade, such as sC5b-9 or Factor Ba, can predict TA-TMA development (128)(129)(130) and even guide the treatment (131). Jodele et al recently demonstrated that activated terminal complement, measured by elevated blood soluble C5b-9, alone, is a valuable indicator of reduced survival in a prospective study including 130 patients undergoing HCT with a diagnosis of TA-TMA published in 2022 A "dose effect" was observed between higher sC5b-9 levels, higher risk for developing multiorgan dysfunction syndrome, and worse outcomes.…”

Endothelial Dysfunction after Hematopoietic Stem Cell Transplantation: A Review Based on Physiopathology

“…The concentration of soluble products derived from complement activation (C5b-9, C3a) may be measured in plasma. It could help in predicting the diagnosis and severity of TA-TMA [164,[172][173][174].…”

Complement System as a New Target for Hematopoietic Stem Cell Transplantation-Related Thrombotic Microangiopathy

“…Moreover, an association between sC5b-9 plasma levels and an index of endothelial activation/injury was also reported [ 28 ]. Moreover, Okamura et al found a significant predictive value of early (at 7 days after transplant) high plasma levels of the Ba, a fragment released from complement factor B upon activation of the complement alternative pathway [ 29 ].…”

“…The finding of ADAMTS13 gene variants seems to be consistent with the experimental results obtained by Zheng et al in a mouse model of TMA, which supported a synergistic effect of ADAMTS13 deficiency and complement activation in the pathogenesis of TMA [ 34 ]. However, the importance of complement-related genetic variants in TA-TMA was denied by Okamura et al [ 29 ]. In their nested case-control study of 15 TA-TMA patients and 15 non-TA-TMA patients, no significant differences were identified between the two groups as far as variants in 17 complement system-related genes.…”

“…In their nested case-control study of 15 TA-TMA patients and 15 non-TA-TMA patients, no significant differences were identified between the two groups as far as variants in 17 complement system-related genes. Nevertheless, according to the authors, early high levels of the complement activation biomarker Ba are predictive of TA-TMA [ 29 ].…”