Pulmonary coagulopathy: a potential therapeutic target in different forms of lung injury

The role and source of tissue factor A large body of evidence has shown that systemic coagulopathy is a key event in severe systemic inflammation, such as that which occurs in sepsis. 1 Systemic coagulopathy is the net result of activation of coagulation and defective systems of natural inhibition of coagulation, on the one hand, and attenuation of fibrinolysis on the other. Activation of coagulation is primarily driven by the extrinsic coagulation pathway which starts with expression of tissue factor (TF) on mononuclear cells and endothelial cells. TF then binds and activates factor VII which activates downstream coagulation cascades. 2 3 Mechanisms that regulate the coagulation pathway under normal conditions involve natural inhibitors of coagulation, including activated protein C (APC), antithrombin (AT) and tissue factor pathway inhibitor (TFPI). In general, they all interfere with the TFfactor VIIa-induced activation of coagulation, but on different levels. In patients with sepsis, increased coagulant activity is not sufficiently counterbalanced by these natural inhibitors. In addition, a rapid sustained increase in synthesis of plasminogen activator inhibitor (PAI)-1 is present during the septic response. PAI-1 is the main inhibitor of tissue-type and urokinase-type plasminogen activator (tPA and uPA) which activate the fibrinolytic system. The importance of systemic coagulopathy with sepsis has been established in experimental studies and in the randomised, prospective, doubleblind, placebo-controlled PROWESS trial in which infusion of recombinant human (rh)-APC resulted in improved survival of patients with severe sepsis.