In the lung, alveolar and interstitial
fibrin deposition are the hallmarks of early phase ALI. Local procoagulant activity and reduced fibrinolysis constitute the rationale for
anticoagulant use in the treatment of ALI. An activated complex of
tissue factor and
factor VIIa triggers procoagulant activity in the lung, with subsequent
thrombin formation and
fibrin deposition. Increased pulmonary vascular permeability and leukocyte accumulation have been successfully prevented in animals treated with
tissue factor/
activated factor VII pathway inhibitor. In humans, a phase II study evaluating
tissue factor pathway inhibitor in the treatment of
severe sepsis suggested that lung function in
acute respiratory distress syndrome patients was improved. However, the phase III trial failed to demonstrate a survival benefit; data regarding respiratory dysfunction have not yet been published.
Heparin, despite effectively inhibiting
thrombin formation, has not shown consistent benefits in reducing
lung injury, and its efficacy has not yet been evaluated in a controlled study.
Antithrombin administration in animals has shown consistent benefits with ALI, but clinical studies have failed to demonstrate reductions in mortality and
lung injury. Activated
protein C administration has been shown to improve survival and lung function in both animal and clinical studies. Soluble
thrombomodulin has been shown to improve ALI in animals, and it is currently being evaluated in humans with
sepsis. Finally,
plasminogen activators may improve gas exchange in ALI, but studies in humans are limited.