*2.1.2. Suppression of natural anticoagulant mechanisms*

Protein C (PrC)—inactivates Va and VIIIa in the presence of thrombin, and its functions are mediated by specific endothelial receptor. PrC performs cytoprotective and antimetastatic effects independently of coagulation [37]. Association between increased incidence of throm‐ botic events and acquired resistance to PrC (APC), unrelated to factor V Leiden, has been observed in multiple myeloma and colorectal cancer [38, 39]. There could be mechanisms of cell resistance due to the modification of the endothelial receptor and induction of APC under the influence of tumor proinflammatory cytokines [39, 40].

Protein S—cofactor PrC whose activity can be inhibited by circulating paraproteins [24].

Antithrombin III (ATIII)—a major serpin that inactivates factors IIa, IXa, Xa, XIa, XIIa, kallikrein, plasmin. Decreased levels of ATIII are found in patients with malignant diseases and decreased survival [41, 42].

Tissue factor pathway inhibitor (TFPI)—main inhibitor of the complex TF:VIIa. Overexpres‐ sion of heparanase induces increase of functionally inactive TFPI in plasma (36), a putative role of a tumor suppressor gene [43, 44].
