Activated protein C inhibits local coagulation after intrapulmonary delivery of endotoxin in humans

Am J Respir Crit Care Med. 2005 May 15;171(10):1125-8. doi: 10.1164/rccm.200411-1483OC. Epub 2005 Mar 4.


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 microg/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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Blood Coagulation / drug effects*
  • Bronchoalveolar Lavage Fluid / chemistry
  • Endotoxins
  • Fibrinolysis / drug effects
  • Humans
  • Infusions, Intravenous
  • Lung / drug effects*
  • Pneumonia / chemically induced
  • Pneumonia / physiopathology
  • Protein C / administration & dosage*
  • Protein C / analysis
  • Recombinant Proteins / administration & dosage*
  • Recombinant Proteins / analysis


  • Endotoxins
  • Protein C
  • Recombinant Proteins