Linking Complement Activation, Coagulation, and Neutrophils in Transplant-Associated Thrombotic Microangiopathy

Abstract

Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe and life-threatening complication of hematopoietic cell transplantation (HCT) that often coincides with graft-versus-host-disease (GVHD). Although endothelial damage seems to be the common denominator for both disorders, the role of complement system, neutrophils, and coagulation has not been clarified. In an effort to distinguish the pathogenesis of TA-TMA from GVHD, we evaluated markers of complement activation, neutrophil extracellular trap (NET) release, endothelial damage, and activation of coagulation cascade in the circulation of patients with these two disorders, as well as control HCT recipients without TA-TMA or GVHD. We observed that the terminal complement product C5b-9 levels, the levels of markers of NET formation, and thrombin–antithrombin complex levels were significantly increased in the TA-TMA group compared with patients without complications, whereas there was no significant difference between the GVHD and the control group. On the other hand, the levels of circulating thrombomodulin, an endothelial damage marker, were significantly increased in both TA-TMA and GVHD patients. These findings propose a role for the interplay between complement system, neutrophil activation through NET release, and activation of the coagulation cascade in TA-TMA.

Endothelial and Complement Activation As Predictors of Survival in Adult Allogeneic Hematopoietic Cell Transplantation

“…Furthermore, our group has also proposed a cutoff value for distinguishing complement activation in TA-TMA from GVHD by the degree of complement activation. 15 In line with our previous findings, the present study confirms for the first time that EASIX is associated with sC5b-9.…”

Kidney Disease after Allogeneic Hematopoietic Cell Transplantation: In Search of the Truth

“…These changes are similar to those previously observed in TA-TMA [11,12]. Similar to TA-TMA [13], complement also seems to play a role in GVHD-associated organ injury following alloHCT [14,15]. In a recent study, Ma et al [16] have also confirmed that complement is involved in renal damage following alloHCT.…”

Endothelial Dysfunction in COVID-19: Lessons Learned from Coronaviruses

“…Taking into account previous experience from other coronaviruses, several recent studies have implicated complement activation as part of the vicious cycle of endothelial dysfunction in COVID-19 [ 37 ]. Complement is a major regulator of endothelial injury syndromes, such as thrombotic microangiopathies [ 38 , 39 ]. Severe COVID-19 appears to resemble complement-mediated thrombotic microangiopathies in both pathophysiology and clinical phenotype [ 40 ].…”