Peritoneal lavage with activated protein C alters compartmentalized coagulation and fibrinolysis and improves survival in polymicrobial peritonitis

Department of Surgery (Surgical Laboratory), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Critical Care Medicine (Impact Factor: 6.31). 11/2006; 34(11):2799-805. DOI: 10.1097/01.CCM.0000243795.04284.2A
Source: PubMed


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.
Prospective, randomized study.
University-based research laboratory.
C57BL/6 mice.
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.
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).
Peritoneal lavage with activated protein C may rebalance coagulation and fibrinolysis within compartments and improve survival in polymicrobial peritonitis.

6 Reads
  • Source
    • "*P b 0.05 vs. 0 h. e243 P. Raeven et al. / Thrombosis Research 129 (2012) e238–e245 Author's personal copy post-CLP), but these changes were likely influenced by lavage [34]. Additionally, the latter study assessed only the active circulating PAI-1, and active PAI-1 is prone to serious measurement/handling errors due to its instability (in contrast to total PAI-1) [35]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Plasminogen activator inhibitor type 1 (PAI-1) co-induces septic coagulopathy. We aimed to characterize spatiotemporal PAI-1 gene/protein changes occurring in acute sepsis and tested whether PAI-1 fluctuations correlate with sepsis severity and early outcome. Female mice underwent cecal ligation and puncture (CLP) in three experiments. I: mild (23 G needle) CLP to compare circulating PAI-1 to its organ gene expression within 0-24h. II: mild or severe (17 G) CLP to asses differences in PAI-1 organ-specific expression and in coagulation/fibrinolysis. III: moderate (18 G) CLP to characterize circulating PAI-1 in survivors (SUR), and to retrospectively compare it to dying (DIE) mice. In mild sepsis, the trajectory of circulating PAI-1 (1089 ng/ml peak at 24h) was identical to PAI-1 gene expression in the left cranial vena cava (LCVC; 39-fold peak at 24h). PAI-1 expression rise was immediate (60-fold at 6h) and sustained in the liver, but marginal in the kidney, lungs and heart. Body temperature decrease correlated with the PAI-1 expression increase in the liver (rho = -0.79), and blood (protein, rho = -0.53). Regardless of severity, PAI-1 gene expression remained unaltered except the LCVC where it was >3-fold higher in 17G (vs. 23 G). Severe sepsis extended activated partial thromboplastin/pro-thrombin time and increased circulating PAI-1, while antithrombin and fibrinogen decreased at 6 and/or 24h (vs. 23 G). Within 24h of death, circulating PAI-1 in DIE was >3-fold higher versus SUR. Polymicrobial sepsis caused a gradual circulating PAI-1 release and highly variable gene expression response pattern in organs. Only circulating PAI-1 and PAI-1 expression in the LCVC correlated with response severity and/or outcome.
    Thrombosis Research 02/2012; 129(5):e238-45. DOI:10.1016/j.thromres.2012.02.004 · 2.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A new approach to analyze directional couplers of arbitrary cross section is presented. The ultimate objective is to obtain accurate coupling coefficients for various coupler parameters and to establish the optimal conditions for practical applications of polarization-preserving fiber-optic couplers (PFDCs). The even and odd super-modes for each polarization are obtained using a recently developed Yee's mesh finite-difference vectorial-beam-propagation method (YMFD-VBPM). Subsequently, the coupling coefficient for each polarization is then obtained
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In acute respiratory distress syndrome or pneumonia, a procoagulant shift is observed in bronchoalveolar lavage fluid (BALF). The effect of a primarily extrapulmonary infection on coagulation and fibrinolysis in the pulmonary compartment is unclear. In 35 patients, 87 bronchoalveolar lavages were performed on the day of operation for secondary peritonitis (day 0) and on days 2 and 3 after surgery. Two noninfectious control groups were included: subjects undergoing bronchoalveolar lavage after elective surgery (n=8) and those undergoing long-term mechanical ventilation (n=10). In BALF from patients with peritonitis, a tissue factor (TF)/factor VIIa-mediated activation of coagulation was shown (high levels of thrombin-antithrombin complexes). Levels of fibrinolysis activators decreased rapidly after day 0, whereas levels of inhibitors increased. The net effect was reduced fibrinolysis (plasminogen activator activity). The sequential comparison of plasma levels of TF pathway inhibitor showed higher levels in patients who died (28-day mortality; P<.001). Sequential levels of TF in BALF were higher in patients with low PaO2 : FiO2 ratios (<200; P=.039). Differences between patients and control subjects were more pronounced in BALF than in plasma. Secondary peritonitis induces an early activation of the coagulation and inhibition of fibrinolysis in the systemic and bronchoalveolar compartments, possibly via a compartmentalized response. This imbalance may be associated with reduced oxygen delivery and an adverse outcome in secondary peritonitis.
    The Journal of Infectious Diseases 12/2006; 194(9):1331-9. DOI:10.1086/508290 · 6.00 Impact Factor
Show more