The alternative complement pathway activation product Ba as a marker for transplant‐associated thrombotic microangiopathy

Abstract

BackgroundTransplant‐associated thrombotic microangiopathy (TA‐TMA) occurs after hematopoietic stem cell transplantation (HSCT) and is characterized by microvascular thrombosis and end‐organ injury particularly of the kidneys. TA‐TMA is challenging to diagnose and treat, which can lead to long‐term complications and death in patients with severe disease. Studies have shown that genetic abnormalities of the alternative complement pathway (AP) are associated with TA‐TMA. We hypothesized that patients with TA‐TMA may generate elevated levels of the AP activation product, Ba, compared with HSCT patients without TA‐TMA.ProcedureWe longitudinally measured plasma levels of complement activation products C3a, Ba, and C5a in 14 HSCT patients: 7 with TA‐TMA and 7 without TA‐TMA. We assessed renal function by calculating estimated glomerular filtration rate (eGFR) and correlated the extent of AP activation with renal dysfunction in both patient populations.ResultsThe median days from HSCT to study enrollment were 154 (39‐237) in the TA‐TMA group and 84 (39‐253) in the HSCT group without TA‐TMA. Median Ba levels (ng/mL) at enrollment were 1096.9 (826.5‐1562.0) in the TA‐TMA group and 725.7 (494.7‐818.9) in the HSCT group without TA‐TMA (P = 0.007). Over the study duration, Ba levels inversely correlated with eGFR. There were no differences in C3a, C5a, or sC5b9 levels between the two populations at any measured interval.ConclusionsWe conclude in this preliminary study that Ba protein may serve as a marker for TA‐TMA, and furthermore, that components generated in the early phase of AP activation may be involved in the pathogenesis of renal endothelial injury in TA‐TMA.

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

“…Previous studies report an association between TA-TMA and various complement proteins. Recently, Sartain et al reported that Ba might be a diagnostic marker for TA-TMA in pediatric patients (11). They suggested that alternative pathway activation contributes to the pathogenesis of TA-TMA.…”

“…Previous reports show that human leukocyte antigen (HLA)mismatched donors, conditioning intensity, acute graft-versushost disease (aGVHD), calcineurin inhibitors, and viral infection are risk factors for TA-TMA; thus TA-TMA is a multifactorial and heterogeneous disorder (4)(5)(6). Interestingly, recent studies indicate that the complement system may contribute to development of TA-TMA (7)(8)(9)(10)(11)(12). First, a pediatric cohort suggested an association between genetic abnormalities of complement-related genes and TA-TMA (9).…”

Characterization of Novel P-Selectin Targeted Complement Inhibitors in Murine Models of Hindlimb Injury and Transplantation

“…Although the focus here was on VCA transplants, it is likely B.PSel-Crry would be an equally suitable therapy in solid organ transplantation. Microvascular thrombosis is a common complication early and late post-transplantation (40)(41)(42)(43), particularly in extended criteria donors, and thus application of B.PSel-Crry could represent a novel therapeutic intervention.…”

Microvascular thrombosis: experimental and clinical implications

“…Severe ADAMTS13 deficiency is not a hallmark of TMA-TA; the etiology is thought be related to endothelial damage from chemotherapy and the post-transplant inflammatory state leading to classical and alternative complement activation. 173,176,177 Alterative pathway dysfunction is supported by complement regulatory mutations and anti-factor H antibodies in a subset of patients. 178 TMA-TA also frequently co-occurs with other insults including infection and graft versus host disease so it can be challenging to assess the relative severity of TMA-TA.…”