Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis

Abstract

Thrombosis is a common complication of end-stage renal disease, particularly in patients on hemodialysis. Although substantial progress has been made in preventing thrombotic complications in various other groups of patients, the mechanisms of thrombosis during hemodialysis require clarification. In this report, we demonstrate that complement activation triggered by hemodialysis biomaterials, and the subsequent generation of the complement anaphylatoxin C5a, results in the expression of functionally active tissue factor (TF) in peripheral blood neutrophils. Because TF is a key initiator of coagulation in vivo, we postulate that the recurring complement activation that occurs during long-term hemodialysis contributes to thrombosis in dialyzed end-stage renal disease patients. Furthermore, we found that complement contributed to the induction of granulocyte colony-stimulating factor, which has been implicated in the pathogenesis of thrombosis in patients treated with the recombinant form of this molecule. Importantly, the inhibition of complement activation attenuated the TF expression and granulocyte colony-stimulating factor induction in blood passing through a hemodialysis circuit, suggesting that the complement system could become a new therapeutic target for preventing thrombosis in patients with chronic renal failure who are maintained on hemodialysis.

Complement in disease: a defence system turning offensive

“…The generation of C5a during haemodialysis-induced complement activation is associated with neutrophil activation and an increase in TF expression as a primary initiator of coagulation. Indeed, patients on haemodialysis have an elevated risk of thrombosis and exhibit increased expression of oxidative stress markers and proinflammatory cytokines — factors that are all strongly correlated with mortality in this population 147,148 . The impact of haemodialysis-induced complement activation on overall inflammation, or even mortality, is difficult to assess given the complexity of the underlying diseases and treatments.…”

Complement in Immune and Inflammatory Disorders: Therapeutic Interventions

“…Currently, the peptide compstatin and its analogs are the only inhibitors that act on native C3; by preventing activation of C3 by convertases, compstatin blocks C3b opsonization, amplification and generation of effectors. Despite specificity for human/primate C3, compstatin analogs have been tested in models ranging from sepsis to hemodialysis-induced thromboinflammation (11, 22, 23). In a primate model of AMD, intravitreal compstatin suppressed or reversed drusen formation (24), and a compstatin analog (AL-78898A, Alcon) is in clinical development for the treatment of AMD.…”

From orphan drugs to adopted therapies: Advancing C3-targeted intervention to the clinical stage

“…Patients suffering from end-stage renal disease (ESRD) are often forced to rely for many years on periodic sessions of hemodialysis (HD) because of their deterioration of kidney function and the shortage of donor replacement organs (Santoro et al , 2013). Interestingly, studies have shown that even modern “biocompatible” HD filters can trigger appreciable levels of complement activation and also induce TF expression, thereby contributing to a thromboinflammatory milieu that can increase morbidity in ESRD patients (Kourtzelis et al , 2010). Notably, this thromboinflammatory reaction has been shown to be attenuated ex vivo by the earlier compstatin analog 4(1MeW) (Kourtzelis et al , 2010).…”

“…Interestingly, studies have shown that even modern “biocompatible” HD filters can trigger appreciable levels of complement activation and also induce TF expression, thereby contributing to a thromboinflammatory milieu that can increase morbidity in ESRD patients (Kourtzelis et al , 2010). Notably, this thromboinflammatory reaction has been shown to be attenuated ex vivo by the earlier compstatin analog 4(1MeW) (Kourtzelis et al , 2010). Recently, these findings were recapitulated in a refined, clinically relevant NHP model of HD-induced inflammation (Reis et al , 2014).…”