Plasma-derived human antithrombin attenuates ventilator-induced coagulopathy in a Streptococcus pneumoniae pneumonia model in rats

Introduction

Pneumonia is characterized by local activation of coagulation leading to alveolar fibrin deposition. Lung injurious mechanical ventilation (LI-MV) with conventional tidal volumes (V_T) and no positive end-expiratory pressure (PEEP) aggravates pulmonary coagulopathy. We hypothesized administration of anti-thrombin (AT), a natural anticoagulant, to attenuate ventilator-induced coagulopathy and inflammation in a rat model of Streptococcus pneumoniae pneumonia.

Methods

Rats challenged intratracheally with bacteria were ventilated 40 hours later (V_T = 12 ml/kg/no PEEP) after systemicadministration of plasma-derived human AT (250 U/kg) or placebo for 3 hours. Endpoints: BALF levels of thrombin-antithrombin complexes (TATc), fibrin degradation products (FDP), AT, plasminogen activator activity (PAA), plasminogen activator inhibitor-1 (PAI-1), pulmonary cytokines and blood cultures. Data are presented as the mean ± SD. Statistics: one-way ANOVA with Dunn's multiple comparison test.

Results

S. pneumoniae pneumonia was characterized by activation of coagulation (TATc, in pneumonia vs. healthy control, 3.7 ± 0.3 vs. 1.2 ± 0.5 ng/ml; FDP: 291 ± 40 vs. 15 ± 5 ng/ml; AT: 3.7 ± 0.3 vs. 20.0 ± 5.2 IU/ml - all P < 0.05) and inhibition of fibrinolysis (PAA: 99.2 ± 5.9 vs. 73.3 ± 5.7% of normal, P < 0.05, PAI-1: 1.9 ± 0.6 vs. 10.0 ± 1.4 ng/ml, P < 0.05). Systemic administration of AT resulted in supraphysiologic levels of BALF AT levels (25.4 ± 4.9 vs. 5.3 ± 1.0 IU/ml) and prevented further activation of coagulation by MV (TATc, in LI-MV with AT vs. placebo, 3.9 ± 0.3 vs. 6.5 ± 0.8 ng/ml - P < 0.05). No changes in pulmonary cytokines were observed between the infected and mechanically ventilated animals (TNF: LI-MV with AT vs. placebo, 1.6 ± 0.4 vs. 1.9 ± 1.3 ng/ml and IL-6: 2.5 ± 1.3 vs. 2.4 ± 1.4 ng/ml- P = NS). The infected animals showed similar numbers of bacteria in blood samples at the start of the experiment, which did not change during the experiment.

Conclusion

Systemic administration of AT attenuated ventilator-induced coagulopathy but not inflammation.