Peritoneal lavage with activated protein C alters compartmentalized coagulation and fibrinolysis and improves survival in polymicrobial peritonitis.
OBJECTIVE
During peritonitis, intra-abdominal fibrin entraps bacteria and hampers their elimination. Systemic administration of anticoagulant activated protein C improves survival in patients with severe sepsis, but its precise mode of action is unclear. This study in polymicrobial peritonitis assessed the effects of local activated protein C administration in peritoneal lavage fluid on coagulation, fibrinolysis, and survival.


METHODS
Prospective, randomized study.


METHODS
University-based research laboratory.


METHODS
C57BL/6 mice.


METHODS
Twenty-four hours after induction of peritonitis by cecal ligation and puncture, mice underwent peritoneal lavage with activated protein C (1.0 microg/mL) or saline. Peritoneal lavage fluid, blood, and lungs were sampled after 24, 48, or 72 hrs (n = 8/group/time point). For survival analysis, maximum observation was 96 hrs (n = 22/group). Clotting time, tissue factor expression, thrombin-antithrombin complexes, fibrin degradation products (D-dimers), plasminogen activator, and plasminogen activator inhibitor were used to assess coagulation and fibrinolysis responses.


RESULTS
Activated protein C lavage reduced abdominal bacterial load, abdominal and pulmonary clotting times, D-dimers (p < .05 vs. saline), pulmonary tissue factor expression, and fibrin depositions, without clear effects on systemic thrombin generation. Activated protein C lavage decreased plasma and abdominal tissue plasminogen activator levels with increased inhibitor plasminogen activator inhibitor-1 levels (p < .05) but had reverse effects on pulmonary fibrinolysis. Survival improved from 55% (saline) to 80% after intra-abdominal activated protein C administration (p = .03).


CONCLUSIONS
Peritoneal lavage with activated protein C may rebalance coagulation and fibrinolysis within compartments and improve survival in polymicrobial peritonitis.
van Veen
Suzanne Q
SQ
Department of Surgery (Surgical Laboratory), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Levi
Marcel
M
van Vliet
Arlène K
AK
Florquin
Sandrine
S
van Gulik
Thomas M
TM
Boermeester
Marja A
MA
D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D005342:Fibrinolysis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008168:Lung / Q000098:blood supply; D051379:Mice; D008810:Mice, Inbred C57BL; D010533:Peritoneal Lavage; D010538:Peritonitis / Q000188:drug therapy* / Q000382:microbiology; D011486:Protein C / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D011486:Protein C; D011994:Recombinant Proteins