Roles played by tissue factor and tissue factor pathway inhibitor in coagulation

Patients with severe infections almost invariably exhibit evidence of activation of the coagulation system. The lungs are amongst the most frequently affected organs during severe infection and sepsis. The abundant presence of intravascular and extravascular fibrin appears to be a specific hallmark of acute lung injury after sepsis. Tissue factor (TF) is regarded to be the primary initiator of coagulation in severe infection. Effective blockade of the TF pathway, either by recombinant TF pathway inhibitor or by anti-TF antibodies in experimental sepsis, attenuates lung injury and partially prevents pulmonary dysfunction. In addition, inhibition of the activity of TF prevents local activation of coagulation in models of pneumonia. The TF pathway can influence inflammatory signaling by activation of protease activated receptor-1 and -2. This review presents the most recent data on the crosstalk between TFmediated coagulation and inflammation, with a specific emphasis on these processes in the lung. Introduction Disseminated intravascular coagulation (DIC) is an acquired syndrome that is characterized by intravascular activation of coagulation and loss of localization, and complications that compromise blood supply to organs. Bacterial infection is the most common cause of DIC, and both Gram-negative and Gram-positive organisms have been identified as causative pathogens, although coagulopathy may be more pronounced in infections caused by Gram-negative bacteria [1]. DIC is commonly seen in sepsis, and particularly in septic shock, in which the incidence is somewhere between 30% and 50% [2]. Understanding the pathogenetic mechanisms of the coagulation imbalance seen in DIC is particularly important, because of the role played by DIC in the development of multiple organ failure. Several concurrent mechanisms contribute to the pathogenesis of DIC. Bacterial lipopolysaccharide (LPS) and other bacterial products, as well as proinflammatory cytokines, all promote fibrin deposition through three main pathways [3,4]: tissue factor (TF)mediated thrombin generation; dysfunctional physiological anticoagulant mechanisms; and impaired fibrin removal due to depression of the fibrinolytic system by plasminogen activator inhibitor-1. All three of these mechanisms contribute to fibrin deposition in DIC. Severely reduced anticoagulant capacity and inhibited fibrinolysis, in conjunction with a massive activation of coagulation, lead to excessive fibrin formation and consumption of clotting factors and inhibitors. In recent years it has become clear that tightly regulated interactions exist between coagulation and inflammation during sepsis. In this review we focus on the role played by TF in the activation of coagulation and inflammation that occurs during severe infection, with a particular emphasis on these processes in the lungs. Roles played by tissue factor and tissue factor pathway inhibitor in coagulation Coagulation activation in sepsis is primarily driven by the TF pathway. TF, a 47 kDa transmembrane glycoprotein, is a potent stimulator of the extrinsic coagulation cascade and an essential mediator of coagulation [5,6]. It is not exposed to circulating blood in a resting state, but it becomes exposed on the surface of mononuclear cells and endothelial cells when they are stimulated by bacteria or by bacterial products such as LPS and proinflammatory cytokines. Alternatively, TF located at extravascular sites, such as on adventitial fibroblasts and vascular smooth muscle cells, can become exposed to blood at sites of vascular injury or disruption of the endothelium. Review Tissue factor as an initiator of coagulation and inflammation in the lung