**2. Tumor prothrombotic mechanisms**

Factors that enhance thrombogenicity of neoplasms are complex and reflect the interaction of a variety of mechanisms that can be summarized on the basis of the classical triad suggested by Virchow: hypercoagulability, vascular endothelial injury, and stasis.

#### **2.1. Changes in hemostasis factors**

Tumor cells have the properties to qualitatively and quantitatively modify plasma and cellular components of hemostasis either directly by synthesis and secretion of procoagulant substan‐ ces or indirectly by intracellular cytokine-mediated mechanisms (**Table 1**).

#### *2.1.1. Synthesis and secretion of procoagulant substances*

Production of procoagulant components by the tumor cells enhances fibrin deposition at the sites of extravasation and extracellularly within the tumor microenvironment.

Tissue factor (TF)—cellular procoagulant and the main initiator of coagulation. Under physiological conditions, procoagulant active form of TF cannot be detected in circulation and on the surface of intact endothelium [1]. TF overexpression is considered a hallmark of the malignant phenotype, identified for the first time in the description of thromboplastin properties of leukemic cells [2]. Subsequently, high activity of TF was observed in the super‐ natant samples from patients with promyelocytic leukemia [3]. Constitutive expression of TF on neoplastically transformed cells has been confirmed by other authors. TF was found overexpressed on tumor cell surface of a number of cancers. TF overexpression is found on the surface of microparticles or is secreted into the tumor microenvironment [3, 4]. Increased TF-dependent procoagulant activity is observed in circulating tumor cells with stem cell phenotype [5]. By inducing proinflammatory response through synthesis and secretion of tumor cytokines: IL-1β, TNF-α, vascular endothelial growth factor (VEGF), malignant cells upregulate TF expression on the surface of monocytes/macrophages, endothelium [6–9], and the degree of tissue expression of TF in the primary tumor correlates with levels of the circulating antigen [10]. Overexpression of TF has a specific biological role in mediating tumor growth and metastasis [11].

**1. Introduction**

4 Tumor Metastasis

strategies.

**2. Tumor prothrombotic mechanisms**

*2.1.1. Synthesis and secretion of procoagulant substances*

**2.1. Changes in hemostasis factors**

Malignancy is associated with derangement of the dynamic homeostasis of hemostatic system. Associated perturbations are characterized by various clinical manifestations with some of them infrequently being indicative of an occult cancer. The interaction between the presence of hemostatic imbalance and cancer has long been recognized. Starting first with the clinical observations by the French surgeon Armand Trousseau of increased thrombotic tendency in patients with advanced gastric cancer knowledge of the interrelationship between malignan‐ cy and hemostasis has since evolved conceptually into understanding its intrinsic biology. Relationship between hemostasis and cancer is bidirectional. On the one side, it is viewed as a process where the innate defense system of hemostasis modulates cancerous develop‐ ment. On the other side, tumor itself manipulates hemostatic system via paracrine regulato‐ ry mechanisms and utilizes hemostatic functions to induce host tolerance for its development and evasion of immune surveillance. Knowledge of the molecular and cellular processes involved in thrombosis in cancer and their differentiation from the physiological hemostasis is essential for understanding the factors driving the increased tumor-associated prothrom‐ botic tendency. It also allows for identifying the certain hemostatic components as determi‐ nants of the neoplastic process and their incorporation into development of antitumor

Factors that enhance thrombogenicity of neoplasms are complex and reflect the interaction of a variety of mechanisms that can be summarized on the basis of the classical triad suggested

Tumor cells have the properties to qualitatively and quantitatively modify plasma and cellular components of hemostasis either directly by synthesis and secretion of procoagulant substan‐

Production of procoagulant components by the tumor cells enhances fibrin deposition at the

Tissue factor (TF)—cellular procoagulant and the main initiator of coagulation. Under physiological conditions, procoagulant active form of TF cannot be detected in circulation and on the surface of intact endothelium [1]. TF overexpression is considered a hallmark of the malignant phenotype, identified for the first time in the description of thromboplastin properties of leukemic cells [2]. Subsequently, high activity of TF was observed in the super‐ natant samples from patients with promyelocytic leukemia [3]. Constitutive expression of TF

by Virchow: hypercoagulability, vascular endothelial injury, and stasis.

ces or indirectly by intracellular cytokine-mediated mechanisms (**Table 1**).

sites of extravasation and extracellularly within the tumor microenvironment.

Cysteine proteinase (CP)—endopeptidase with a molecular weight of 68 KDa, whose only known substrate is f.X. CP can directly activate f.X to f.Xa without involving f.VII, and unlike other activators of f.X, CP proteolytically cleaves its molecule at several sites [12]. It has been identified in extracts from embryonic tissues (amnion and chorion), solid tumors, and leukemic blasts [13–15]. CP has not been detected in extracts from normal tissues as well as in patients in complete remission. Its expression in acute promyelocytic leukemia is inhibited by treatment with all-trans-retinoic acid, which confirms the hypothesis that undifferentiated cells express CP and upon recovery of differentiation its expression is suppressed [16].

F.VII—a cofactor of tissue factor required for its procoagulant activity. Endogenously synthe‐ sized f.VII from non-hepatic tumor cells capable of activating the coagulation via f.Xa mediates proinvasive signaling pathways [17]. Proteolytically active f.VII in combination with TF induces anti-apoptotic effects and inhibits anoikis [18].

Prothrombin/thrombin—a key proteolytic enzyme of coagulation. It is produced by different tumor types and exerts pleiotropic biological effects in the processes of angiogenesis and tumor proliferation [19]. In patients with low-grade carcinoma, f.II induces intravascular coagulation, increases tumor platelet adhesion in vitro, and the formation of metastases in vivo [20].

F.VIII: vWF—various cancers are associated with elevated levels of von Willebrand factor (vWF) and f.VIII as a consequence of tumor-induced proinflammatory cytokine response (TNF-α, IL-6) [21–25].

F.V—cofactor of f.X. By expressing f.V receptor, activity tumor cells are functionally involved in catalyzing the prothrombinase complex [26]. Increased coagulation activity in patients with breast cancer is correlated with the presence of single nucleotide polymorphisms in the gene of f.V and increased thrombotic risk [27].

F.XIII—fibrin stabilizing factor. Tumor cells from breast cancer have f.XIII-like activity. By catalyzing fibrin cross-linking and deposition, they potentiate tumor growth and metastasis [28].

Fibrinogen/fibrin—electron microscopy analysis demonstrated that fibrin is an integral component of the examined tumors [29]. Fibrin deposition potentiates formation of metastatic emboli that trap circulating tumor cells in the vascular bed and promote adhesion to the endothelium [30]. Plasma fibrinogen levels are significantly elevated in patients with multiple myeloma and breast cancer at the time of diagnosis and during follow-up compared to healthy controls [31, 32].

Procoagulant microparticles (MP)—submicron extracellular vesicles. Their procoagulant capacity is determined by the expression of negatively charged phosphatidylserine and functionally active TF [33]. Increased MP-associated procoagulant activity was detected in patients with myeloproliferative neoplasms [34]. By intracellular exchange of MP, tumor cells transfer oncogenic signal and amplify the angiogenic phenotype [35].

Heparanase—endoglucuronidase that degrades heparan sulfate. Overexpressed in almost all known malignancies but has not been detected in normal tissue adjacent to the tumor. Tumor cells secrete heparanase, which induces the expression of TF, activates directly f.X, and inactivates tissue factor pathway inhibitor [36].
