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

Area of Science:

• Biochemistry
• Immunology
• Hematology

Background:

• Sepsis activates both coagulation and complement systems.
• Coagulation proteases may directly cleave complement proteins, but in vivo evidence is limited.
• Investigating direct protease-complement interactions is crucial for understanding sepsis pathogenesis.

Purpose of the Study:

• To determine if in vivo generated coagulation proteases activate the complement cascade.
• To compare complement activation in response to coagulation proteases versus bacterial challenge.
• To investigate the role of thrombin, plasmin, and factor Xa in complement activation.

Main Methods:

• Comparison of coagulation (TAT, PAP) and complement (C3b, C5a, C5b-9) biomarkers in baboons.
• Infusion of factor Xa/phospholipids (FXa/PCPS) versus LD100 Escherichia coli.
• Ex vivo serum incubation with coagulation enzymes.

Main Results:

• Both FXa/PCPS and E. coli induced thrombin and plasmin generation.
• Only E. coli challenge activated the complement system.
• FXa/PCPS infusion did not lead to measurable complement activation in vivo.
• Ex vivo studies showed complement cleavage only with supraphysiologic enzyme concentrations.

Conclusions:

• In vivo-generated thrombin and plasmin do not directly activate the complement cascade in nonhuman primates.
• Bacterial challenge, not coagulation proteases, drives complement activation in this sepsis model.
• These findings challenge the hypothesis of direct protease-mediated complement activation in vivo.