In vivo–generated thrombin and plasmin do not activate the complement system in baboons

• Published in: Blood Vol. 130; no. 24; pp. 2678 - 2681
• Main Authors: Keshari, Ravi S., Silasi, Robert, Lupu, Cristina, Taylor, Fletcher B., Lupu, Florea
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.12.2017; American Society of Hematology
• Subjects: Animals; Brief Report; Complement Activation - drug effects; Complement Activation - immunology; Complement System Proteins - immunology; Complement System Proteins - metabolism; Escherichia coli - immunology; Escherichia coli - metabolism; Factor Xa - immunology; Factor Xa - pharmacology; Fibrinolysin - immunology; Fibrinolysin - metabolism; Humans; Lipopolysaccharides - immunology; Lipopolysaccharides - pharmacology; Papio; Phosphatidylcholines - immunology; Phosphatidylcholines - pharmacology; Phosphatidylserines - immunology; Phosphatidylserines - pharmacology; Thrombin - immunology; Thrombin - metabolism; Thrombosis and Hemostasis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2017-06-788216

Sepsis concurrently activates both coagulation and complement systems. Although complement activation by bacteria is well documented, work in mice and in vitro suggests that coagulation proteases can directly cleave complement proteins. We aimed to determine whether generation of coagulation proteases in vivo can activate the complement cascade in 2 highly coagulopathic models. We compared temporal changes in activation biomarkers of coagulation (thrombin-antithrombin [TAT]), fibrinolysis (plasmin-antiplasmin [PAP]), and complement (C3b, C5a, C5b-9) in baboons infused with factor Xa (FXa) and phospholipids (FXa/phosphatidylcholine-phosphatidylserine [PCPS]) vs LD100 Escherichia coli. We found that, albeit with different timing, both FXa/PCPS and E coli infusion led to robust thrombin and plasmin generation. Conversely, only E coli challenge activated the complement system, reaching a maximum at 2 hours postchallenge during the peaks of lipopolysaccharide and bacteremia but not of TAT and PAP. Despite inducing a strong burst of thrombin and plasmin, FXa/PCPS infusion did not produce measurable levels of complement activation in vivo. Similarly, ex vivo incubation of baboon serum with thrombin, plasmin, or FXa did not show noticeable complement cleavage unless supraphysiologic amounts of enzymes were used. Our results suggest that in vivo–generated thrombin and plasmin do not directly activate the complement in nonhuman primates. •In vivo–generated thrombin and plasmin do not contribute to complement activation in nonhuman primates.•Bacteria and lipopolysaccharide are the main drivers of in vivo complement activation in E coli sepsis in baboons.