Abstract Heparanase is an endo-b-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains of heparan sulfate proteoglycans (HSPG) on cell surfaces and the extracellular matrix, activity that is strongly implicated in tumor metastasis and angiogenesis. Evidence was provided that heparanase over-expression in cancer cells results in a marked increase in tissue factor (TF) levels. Likewise, TF was induced by exogenous addition of recombinant heparanase to tumor cells and primary endothelial cells, induction that was mediated by p38 phosphorylation and correlated with enhanced procoagulant activity. TF induction was further confirmed in heparanase over-expressing transgenic mice and correlated with heparanase expression levels in leukemia patients. Heparanase was also found to be involved in the regulation of tissue factor pathway inhibitor (TFPI). A physical interaction between heparanase and TFPI was demonstrated, suggesting a mechanism by which secreted heparanase interacts with TFPI on the cell surface, leading to dissociation of TFPI from the cell membrane and increased coagulation activity, thus further supporting the local pro-thrombotic function of heparanase. Data indicate a possible involvement of heparanase in early miscarriages and point to a regulatory effect on TFPI and TFPI-2 in trophoblasts. As heparins are strong inhibitor of heparanase, in view of the effect of heparanase on TF, the role of heparins anticoagulant-activity may potentially be expanded. Taking into account the pro-metastatic and pro-angiogenic functions of heparanase, its over-expression in human malignancies and abundance in platelets, its involvement in the coagulation machinery is an intriguing novel arena for further research.