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Activated Protein C Inhibits Local Coagulation after Intrapulmonary Delivery of Endotoxin in Humans

Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; and Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Tom van der Poll, M.D., Academic Medical Center, Room G2-130, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands. E-mail: t.vanderpoll{at}amc.uva.nl

Rationale: Acute lung injury and pneumonia are associated with pulmonary activation of coagulation and suppression of fibrinolysis, resulting in fibrin deposition in the lung. Activated protein C (APC) has systemic anticoagulant effects in patients with sepsis. Objective: To determine the effect of systemic administration of recombinant human APC on endotoxin-induced hemostatic alterations in the bronchoalveolar space in humans. Methods: Healthy humans received intravenous APC (24 µg/kg/hour; n = 8) or vehicle (n = 7); all subjects were administered saline in one lung subsegment and endotoxin (4 ng/kg) into the contralateral lung. Bronchoalveolar lavage was performed 16 hours after saline and endotoxin administration. Measurements and Main Results: Endotoxin induced local activation of coagulation, as reflected by elevated levels of thrombin–antithrombin complexes (1.9 ± 0.1 ng/ml) and soluble tissue factor (15.0 ± 0.6 pg/ml) in bronchoalveolar lavage fluid, which was inhibited by APC (1.4 ± 0.1 ng/ml and 12.3 ± 0.4 pg/ml, respectively; both p < 0.01). Concurrently, endotoxin suppressed fibrinolysis, as indicated by reduced bronchoalveolar levels of plasminogen activator activity accompanied by elevated levels of plasminogen activator inhibitor type I activity. APC diminished the rise in plasminogen activator inhibitor type I activity (from 3.9 ± 0.1 to 3.0 ± 0.2 ng/ml, p = 0.002), while not significantly influencing plasminogen activator activity levels. Endotoxin reduced bronchoalveolar protein C concentrations, which was prevented by APC. Protein C did not influence the endotoxin-induced rise in local soluble thrombomodulin levels. Conclusion: APC exerts an anticoagulant effect in the human lung challenged with endotoxin.

Key Words: fibrinolysis • lipopolysaccharide • lung

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