Peritoneal lavage with activated protein C alters compartmentalized coagulation and fibrinolysis and improves survival in polymicrobial peritonitis
ABSTRACT 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.
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.
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ABSTRACT: OBJECTIVE: To characterize derangements in the hemostatic profiles of dogs with naturally occurring septic peritonitis and determine if such derangements were predictive of survival. DESIGN: Prospective, observational single cohort study. SETTING: University veterinary teaching hospital. ANIMALS: A total of 27 client-owned dogs with naturally occurring septic peritonitis. INTERVENTIONS: Standard treatment included fluid resuscitation, antimicrobial therapy, supportive care, and surgery provided at the discretion of the primary clinician. Blood was collected preoperatively and on days 1 and 3 postoperatively for platelet count, prothrombin time, activated partial thromboplastin time, D-dimer and fibrinogen concentrations, total protein C (PC) and antithrombin (AT) activities, and thromboelastography. MEASUREMENTS AND MAIN RESULTS: Sixteen of 27 (59%) dogs survived. Preoperative PC deficiency was identified in 10 of 11 (91%) nonsurvivors and 2 of 15 (13%) survivors. Preoperative AT deficiency was identified in 10 of 11 (91%) nonsurvivors and 14 of 15 (93%) survivors. Compared to survivors, nonsurvivors had lower mean preoperative PC (98 ± 24% versus 49 ± 26%; P < 0.001) and AT (53 ± 9% versus 32 ± 16%; P < 0.001) activities. Anticoagulant activities decreased on day 1 postoperatively. As a predictor of survival, preoperative PC activity of more than 60% achieved a sensitivity of 93% and specificity of 82%. Preoperative AT activity of more than 41.5% achieved a sensitivity of 100% and specificity of 82%. The maximum amplitude, α angle, and coagulation index from preoperative thromboelastograms of survivors were significantly greater (more hypercoagulable) than nonsurvivors (P < 0.01), with the maximum amplitude being the most specific predictor of survival (100%). CONCLUSIONS: Deficiencies of PC and AT and hypercoagulability appear to be consistent features of naturally occurring canine sepsis and may be useful prognostic indicators in canine septic peritonitis.01/2013; 23(1). DOI:10.1111/vec.12013
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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
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ABSTRACT: Background: The role of plasminogen activator inhibitor type-1 (PAI-1) in abdominal sepsis remains elusive. Objectives: To study the influence of inhibition and over-expression of PAI-1 upon survival in cecal ligation and puncture (CLP) sepsis. Methods: I) mice underwent moderate CLP and received 10mg/kg of either monoclonal anti- PAI-1 (MA-MP6H6) or control (MA-Control) antibody intravenously at 0h, 18h or 30h post- CLP. The 30h treatment group was additionally stratified into mice predicted to survive (PSUR) or die (P-DIE) based on IL 6 measured at 24h post-CLP. II) PAI-1 expression was induced with pLIVE.PAI-1 plasmid administered 72h pre-CLP. Blood was sampled for 5 and survival was monitored for 28 days. Results: MA-MP6H6 effectively neutralized active PAI-1 and fully restored fibrinolysis while PAI-1 overexpression was liver-specific and correlated with PAI-1 increase in the blood. Without stratification, MA-MP6H6 co-/post-treatment conferred no survival benefit. Prospective stratification (IL-6 cut-off: 14ng/ml) suggested increased mortality by MAMP6H6 treatment in P-SUR that reached 30% difference (vs. MA-Control; p<0.05) after a retrospective cut-off readjustment to 3.3ng/ml for better P-SUR homogeneity. Subsequent prospective anti-PAI-1 treatment in P-SUR mice with 3.3ng/ml cut-off demonstrated a negative but statistically insignificant effect: mortality was higher by 17% after MA-MP6H6 vs. MA-Control. Over-expression of PAI 1 did not alter post-CLP survival. Neither PAI-1 inhibition nor overexpression meaningfully modified inflammatory response and/or organ function. Conclusions: Restoration of fibrinolysis in early abdominal sepsis was not beneficial and it may prove detrimental in subjects with the lowest risk of death, while preemptive PAI-1 upregulation at the current magnitude was not protective.Journal of Thrombosis and Haemostasis 06/2014; DOI:10.1111/jth.12565 · 5.55 Impact Factor