Disordered pathways of fibrin turnover in lung lavage of premature infants with respiratory distress syndrome

Premature infants who have self-limited respiratory distress syndrome (RDS) rapidly improve, whereas infants with a complicated respiratory course are more likely to develop bronchopulmonary dysplasia (BPD), a chronic lung disorder that is the result of prolonged lung injury and impaired healing. The balance of competing activities of coagulation and fibrinolysis may contribute to the premature lung's response to acute injury and determine, in part, whether there is early resolution or protracted alveolar inflammation. To determine the relative activities of the coagulation and fibrinolytic pathways in neonatal lung injury, procoagulant (PC) and plasminogen activator (PA) activities were measured in undiluted cell-free lung lavage samples obtained serially over the first 28 days of life from 11 infants with self- limited RDS, 11 infants with evolving BPD, and 5 mechanically ventilated control infants without lung disease. Lung lavage from all three groups contained readily detectable procoagulant activity due mainly to the tissue factor-Factor VII complex. Plasminogen activator activity was relatively high in control lavage samples but depressed on the first day of life in the two groups of infants with lung disease: median, 0.3814 IU/ml (control); 0.0541 IU/ml (RDS); and 0.0454 IU/ml (BPD), p < 0.05 in each case compared with control. Two infants with severe lung disease had no detectable plasminogen activator activity in lung lavage on the first day of life. Depressed fibrinolytic activity correlated with severity of lung disease assessed radiographically and by pulmonary function measurements. Plasminogen activator activity was due to both tissue plasminogen activator and urokinase. Significant concentrations of plasminogen activator inhibitors were detected, predominantly PAI-2. Antiplasmin activity was present in ≥ 90% of RDS and BPD samples compared to 43% of control samples. There was a trend toward higher procoagulant and lower plasminogen activator activities in BPD infants compared to the RDS group. In the normal infant lung, high procoagulant and fibrinolytic activities indicate a capability for local rapid fibrin turnover. Infants with lung disease initially express procoagulant activity similar to that of control infants but lower levels of fibrinolytic activity. We speculate that these early differences in the balance of coagulation and fibrinolysis in the lung may influence the clearance of the fibrinous alveolar exudate and may promote the development of alveolar septal organization in those infants who progress to BPD.