Heparanase in the Coagulation System.

Abstract

The hemostatic cascade is initiated by the transmembrane coagulation protein- tissue factor (TF) and eventuates in fibrin formation. Heparanase protein was demonstrated to directly enhance TF activity resulting in increased activation of the coagulation system. In addition, heparanase was found to increase hemostatic system activation via two other mechanisms: up-regulating TF expression in endothelial cells and releasing the protein tissue factor pathway inhibitor (TFPI) from the cell surface. Peptides derived from TFPI-2, a protein similar to TFPI, were shown to inhibit the TF/heparanase complex as well as attenuate sepsis and tumor growth. Increased heparanase procoagulant activity was observed in several clinical settings, including women using oral contraceptives, women at delivery, patients following orthopedic surgery and patients with diabetic foot, shift work female nurses, patients with lung cancer, retinal vein thrombosis and prosthetic heart valve thrombosis. Remarkably, the heparanase profile was significantly different across the tested groups. Inhibition of TF / heparanase interaction may represent a new target for attenuating coagulation, cancer and inflammation.