Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome

Abstract

Objective: The coagulation and inflammatory cascades may be linked in the pathogenesis of acute lung injury and acute respiratory distress syndrome. However, direct evidence for the contribution of abnormalities in coagulation and fibrinolysis proteins to outcomes in patients with acute lung injury/acute respiratory distress syndrome is lacking.

Design: Retrospective measurement of plasma levels of protein C and plasminogen activator inhibitor-1 in plasma samples that were collected prospectively as part of a large multicenter clinical trial. The primary outcome was hospital mortality. To evaluate the potential additive value of abnormalities of these biomarkers, the excess relative risk of death was calculated for each combination of quartiles of protein-C and plasminogen activator inhibitor-1 levels.

Setting: Ten university medical centers.

Patients: The study included 779 patients from a multicenter clinical trial of a protective ventilatory strategy in acute lung injury/acute respiratory distress syndrome and 99 patients with acute cardiogenic pulmonary edema, as well as ten normal controls.

Measurements and main results: Compared with plasma from controls and patients with acute cardiogenic pulmonary edema, baseline protein-C levels were low and baseline plasminogen activator inhibitor-1 levels were elevated in acute lung injury/acute respiratory distress syndrome. By multivariate analysis, lower protein C and higher plasminogen activator inhibitor-1 were strong independent predictors of mortality, and ventilator-free and organ-failure-free days. Plasminogen activator inhibitor-1 and protein C had a synergistic interaction for the risk of death.

Conclusions: Early acute lung injury/acute respiratory distress syndrome is characterized by decreased plasma levels of protein C and increased plasma levels of plasminogen activator inhibitor-1 that are independent risk factors for mortality and adverse clinical outcomes. Measurement of plasminogen activator inhibitor-1 and protein-C levels may be useful to identify those at highest risk of adverse clinical outcomes for the development of new therapies.

Figure 1

Association between plasma levels of protein C (top) and plasminogen activator inhibitor-1 (PAI-1) (bottom) and hospital mortality in 779 patients with acute lung injury/acute respiratory distress syndrome. p < .05 for linear-dose-response trend for both protein C and PAI-1.

Figure 2

Combined effects of protein C and plasminogen activator inhibitor-1 (PAI-1) on mortality as measured by the excess relative risk of death. The probability of death was calculated from the logistic-regression model. The excess probability of death was calculated by subtracting the probability for the best combination of protein C (highest quartile) and PAI-1 (lowest quartile) (18, 19).