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

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Coagulation proteases like thrombin and plasmin do not directly activate the complement system in vivo. Bacterial infection, however, triggers complement activation during sepsis, independent of coagulation protease activity.

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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.