More than a century ago, Rudolf Virchow called attention to an association between inflammation and thrombosis; the more we learn about the interface between the two processes, the more we have to admire his prescience. Another piece of that story grows more convincing and more mature with recent observations of patients with chronic renal failure.
Thrombotic events in end-stage renal disease (ESRD), particularly in hemodialysis patients, are common. The two-year death rate of ESRD dialysis patients who sustain an acute myocardial infarction is 73 percent.1 These are not limited to the consequences of accelerated atherogenesis (about which much has been written); thrombosis of vascular access grafts, pulmonary emboli, and deep-venous thromboses are seen as well. The mechanisms contributing to increased risk of thrombosis point to the nexus of inflammation and coagulation. For example, TNFα, IL-6, CRP, and fibrinogen levels are elevated in dialysis patients. In 1977, Craddock and Jacob demonstrated that the transient leukopenia and hypoxemia seen in patients upon initiating hemodialysis were due to the activation of complement, especially the generation of C5a, by dialyzer cellophane.2 C5a activates neutrophils leading to their aggregation, adhesion, and oxidative burst, which subsequently can injure vascular endothelial cells.3 These authors speculated that complement-induced leukocyte activation played a role in diverse disease states, including acute respiratory distress syndrome (ARDS) and atherosclerosis. Today, Kourtzelis et al. in the laboratory of John Lambris at the University of Thrace in Greece return to the issue of hemodialysis-associated thrombosis, demonstrating that complement anaphylotoxin C5a can induce tissue factor (TF) in peripheral blood neutrophils.
They found that serum from patients undergoing hemodialysis stimulated neutrophils and monocytes to produce functionally active TF. The increase was observed in sera removed immediately after initiating hemodialysis, reaching a maximum after 15 minutes and returning to baseline at 240 minutes. This TF activity was inhibited by an antibody to TF and associated with an increase in TF gene expression in neutrophils and monocytes. TF is expressed in blood leukocytes obtained from ESRD patients, and hemodialysis transiently enhances its expression. As previously shown, hemodialysis induces significant complement activation reaching a maximum after 60 minutes.
The complement anaphylatoxin C5a appears to be an important actor in the process; an antibody directed against its receptor on neutrophils was able to block the ability of hemodialysis serum to promote TF expression by neutrophils. In vitro, hemodialyis-induced complement activation and subsequent TF up-regulation in neutrophils could be reduced by inhibiting C3 cleavage with a complement inhibitor (compstatin) analog. White blood cell-derived inflammatory mediators, including G-CSF, IFN-γ, and IL-1RA, were also reduced when complement was inhibited.
In Brief
This manuscript exemplifies the intricate balance that inflammation and thrombosis play in disease states, such as sepsis, anti-phospholipid syndrome, and ARDS. Limiting complement activation with eculizumab in PNH has been shown to decrease not only hemolysis but also thrombotic events. With new, improved biomaterials for hemodialysis, complement activation is minimized in ESRD patients, yet thrombotic events continue to be a source of significant morbidity and mortality. Possibly new complement inhibitors can lessen thrombotic events in ESRD and other processes.
References
Competing Interests
Dr. Vercellotti indicated no relevant conflicts of interest.
