Therapeutic modulation of coagulation and fibrinolysis in acute lung injury and the acute respiratory distress syndrome

Abstract

Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are characterized by excessive intraalveolar fibrin deposition, driven, at least in part by inflammation. The imbalance between activation of coagulation and inhibition of fibrinolysis in patients with ALI/ARDS favors fibrin formation and appears to occur both systemically and in the lung and airspace. Tissue factor (TF), a key mediator of the activation of coagulation in the lung, has been implicated in the pathogenesis of ALI/ARDS. As such, there have been numerous investigations modulating TF activity in a variety of experimental systems in order to develop new therapeutic strategies for ALI/ARDS. This review will summarize current understanding of the role of TF and other proteins of the coagulation cascade as well the fibrinolysis pathway in the development of ALI/ARDS with an emphasis on the pathways that are potential therapeutic targets. These include the TF inhibitor pathway, the protein C pathway, antithrombin, heparin, and modulation of fibrinolysis through plasminogen activator- 1 (PAI-1) or plasminogen activators (PA). Although experimental studies show promising results, clinical trials to date have proven unsuccessful in improving patient outcomes. Modulation of coagulation and fibrinolysis has complex effects on both hemostasis and inflammatory pathways and further studies are needed to develop new treatment strategies for patients with ALI/ARDS.

Fig. (1)

The extrinsic coagulation pathway, the anticoagulant pathway and the fibrinolytic pathway. Activation of TF results in activation of coagulation factors and generation of thrombin from prothrombin ultimately leading to fibrin formation and deposition. The endogenous inhibitor TFPI limits the action of TF. AT degrades Factor Xa and thrombin while heparin sulfate inhibits thrombin-mediated activation of fibrinogen. The anticoagulant mediator Protein C is activated by thrombin binding to TM to generate APC which, along with Protein S, degrades Factor Va. APC also limits PAI-1 activity which inhibits the fibrinolytic mediators u-PA and t-PA from generating plasmin which degrades fibrin into FDPs. TF, tissue factor; TFPI, tissue factor pathway inhibitor; Factor VIIa, activated Factor VII; Factor Xa, activated Factor X; Factor Va; activated Factor V; AT, antithrombin; TM, thrombomodulin; APC, activated protein C; PAI-1, plasminogen activator inhibitor-1; u-PA, urokinase plasminogen activator; t-PA, tissue plasminogen activator; FDP, fibrin degradation product.

Fig. (2)

Comparison of plasma and pulmonary oedema fluid levels of tissue factor (TF) and clot time in patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and control patients with hydrostatic pulmonary edema (HYDRO). (A, B) Boxplots of TF protein levels in (A) edema fluid and (B) plasma measured by ELISA. TF protein levels in pulmonary edema fluid were significantly higher in ALI/ARDS vs HYDRO (*p = 0.012, Mann - Whitney U test) and TF protein levels in plasma were significantly higher in ALI/ARDS vs HYDRO (**p = 0.02, Mann - Whitney U test). Note that TF levels in edema fluid (A) are more than 100 - fold higher than simultaneous levels in plasma (B) in both patient groups. (C, D) Boxplots of clot time measured by recalcification time of normal plasma mixed with pulmonary edema fluid from patients with ALI/ARDS or HYDRO in the absence (C) or presence (D) of a TF blocking antibody. Clot time was significantly longer in plasma mixed with edema fluid from patients with HYDRO vs ALI/ARDS (†p = 0.006, Mann - Whitney U test), and this difference was negated when TF activity was blocked (p = 0.095, Mann - Whitney U test). Reproduced with permission from [The alveolar epithelium can initiate the extrinsic coagulation cascade through expression of tissue factor, JA Bastarache, L Wang, T Geiser, Z Wang, K Albertine, M Matthay and LB Ware, 62(7), 608-16, 2007] BMJ Publishing Group LTD.¹⁶

Fig. (3)

Fibrinolytic activity in human serial ARDS BAL samples. Fibrinolytic activity measured by the ¹²⁵I-fibrin plate assay is indicated in box plot format. Data from 7 normal control patients are shown for comparison. Reproduced with permission from Serial abnormalities of fibrin turnover in evolving adult respiratory distress syndrome, S Idell, KB Koenig, DS Fair, TR Martin, J McLarty and RJ Maunder, 261, L240-248, 1991] from AJP [87].