Alveolar fibrin deposition commonly occurs in the lungs of patients with the adult respiratory distress syndrome (ARDS). Bronchoalveolar lavage (BAL) from patients with ARDS, control patients with interstitial lung disease (ILD), congestive heart failure, or exposure to hyperoxia, and normal healthy subjects was studied to determine whether local alterations in procoagulant activity favor alveolar fibrin deposition in the lungs in ARDS. Procoagulant activity capable of shortening the recalcification time of plasma deficient in either factor VII or factor VIII was observed in unconcentrated BAL of all patients, but was significantly greater in BAL from patients with ARDS when compared with that of control subjects (p < 0.001). Unconcentrated BAL from patients with ARDS shortened the recalcification time of plasma deficient in factor X, but not functional thrombin was detectable. BAL procoagulant from patients with ARDS was inhibited by concanavalin A, an inhibitor of tissue factor. The hydrolysis of purified human factor X by BAL from the ARDS and other patient groups was determined by measuring the amidolytic activity of generated factor Xa on its N-benzoyl-L-isoleucyl-L-glutamyl-glycyl-L-arginine-p-nitroanilide substrate. The procoagulant activity of BAL was associated with the development of amidolytic activity, indicating activation of factor X. BAL from patients with ARDS contained more factor X activating activity than did BAL from control groups (p < 0.001). This activity was calcium dependent and was maximal at 1 mM ionized calcium. The BAL factor X activating activity was most active at neutral pH and was sedimented by ultracentrifugation at 100,000 x g. Cleavage of purified human 125l-labeled factor X by ARDS was demonstrated by SDS-polyacrylamide gel electrophoresis and autoradiography. The appearance of a 55,000 M(r) cleavage product, identical to factor Xa produced by activation of human factor X by Russell's viper venom, strongly correlated with simultaneously performed amidolytic determinations of factor Xa formed by activation of factor X by BAL. The activation of factor X by BAL was dependent on tissue factor and factor VII, since activation was inhibited by monospecific antibodies to human factor VII and tissue factor. Immunoblots demonstrated the presence of both tissue factor and factor VII in BAL from patients with ARDS. These studies demonstrate that increased procoagulant activity occurs in BAL from patients with ARDS, that procoagulant activity in unconcentrated BAL from patients with ARDS may activate factor X, and that the activation of factor X by BAL is effected mainly by a complex of tissue factor and factor VII. Augmented activity of the extrinsic coagulation pathway may occur in the alveolar compartment during human inflammatory lung injury and could contribute to extravascular fibrin deposition in ARDS.
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine