The multivalent activity of the tissue factor-thrombin pathway in thrombotic and non-thrombotic disorders as a target for therapeutic intervention

Importance of the field: Tissue factor (TF) is the key initiator of the coagulation cascade. The exposure of subendothelial TF after vessel injury to blood is a critical step in hemostasis and in the pathogenesis of arterial and venous thrombotic disorders. Moreover, an additional role for TF overexpression and subsequent generation of TF: FVIIa complex, FXa and thrombin have been recently emerged, contributing in non-thrombotic manifestations such as inflammation, cancer growth and fibrosis. Areas covered in this review: The multivalent role of TF and the above mentioned proteases in disease is reviewed, with focus on their implication in non-thrombotic disorders, as suggested by clinical and experimental data. Moreover, potential therapeutic interventions using anticoagulation agents are discussed. What the reader will gain: A better understanding of the pathogenic role of the TF-thrombin pathway in the pathogenesis of disease and the effect of anticoagulants in the treatment of such disorders. Take home message: The TF-thrombin pathway, apart from the initiation of hemostasis and thrombosis, exert intracellular signaling activity through protease-activated receptors, participating in inflammation and tumor biology. Both low-molecular-weight heparins and recently developed anticoagulants rise as candidates for the modification of biological functions associated with disorders like sepsis, ischemia-reperfusion or cancer growth and metastasis.