**2. The epidemiology and pathophysiology of venous thrombosis in cancer patients**

#### **2.1 Cancer cells and the haemostatic mechanisms**

The haemostatic system is a complex, multifaceted mechanism that participates in maintaining the integrity of the vascular system and fluidity of blood. In coordination with the mechanisms of inflammation and repair, the haemostatic mechanism produces a coordinated response. Haemostatic systems are normally quiescent and are only activated after injury and results in the production of a platelet plug, fibrin-based clot, deposition of white cells at the site of injury, and activation of inflammatory and repair processes.

Tumor cells can activate blood coagulation through multiple mechanisms, including (a) production of procoagulant, fibrinolytic, and proaggregating activities; (b) release of proinflammatory and proangiogenic cytokines and (c) direct interaction with host vascular and blood cells through adhesion molecules.

Miller et al (1) studied the link between the haemostatic systems and cancer where the authors evaluated haemostatic status every year for 4 years in a population of approximately 3000 middle-aged men without cancer. Among patients with the activation

Venous Thromboembolism in Cancer Patients 75

and provide a degree of protection to the cancer cells from the immune system. Fibrin has also been shown to increase expression of TF and induce expression of IL-8 and vascular

The TF–factor VIIa complex can signal through cleavage of protease-activated receptors, which, in turn, induce the mitogen-activated protein kinase (MAPK) signal transduction cascade (11). The MAPK pathway is involved in the induction of genes involved in angiogenesis, migration, and proliferation. In addition, phosphorylation of the cytoplasmic tail of the TF receptor has also been shown to indirectly activate transcription of VEGF, downregulate thrombospondin (an antiangiogenic protein), and induce cell migration. Expression of TF by malignant cells also seems to support metastatic process and is

The first description of deep vein thrombosis (DVT) in patients with cancer was made by Bouillard in 1823(12) although this was popularly first credited to Armand Troussean, the French Physician, in 1865 (13-14). Since that time, hundreds of studies have provided solid data on the clinical association between VTE and cancer, and delineated the elevated risk for VTE particularly during the first few months following the diagnosis of cancer and in the

The incidence of DVT or PE in patients with cancer varies widely because of the heterogeneity of the patients' population and the difficulty of conducting large epidemiological studies. Based on a prospective medical database in the United States, the annual incidence of a first episode of DVT or PE in the general population is 0.1% (15), while the estimated annual incidence of VTE in the cancer population is 0.5%. (19-21) The prevalence of cancer-associated thrombosis may be underestimated by more than 10-fold as autopsy studies in cancer patients have demonstrated even higher rates of VTE (17-22). In a large population-based epidemiological study, approximately 20% of all new cases of VTE are associated with

The risk of VTE associated with different malignancies has more recently been quantified in NHL (23), colonic cancer (24) ovarian (25) lung (26) and breast cancer (27). It was generally thought that solid tumors, such as pancreatic, ovarian and brain cancer carry a much higher risk for VTE than haematological malignancies. However, recent studies suggest that the incidence of VTE in patients with haematological malignancies may be similar to that observed in patients with solid tumors (28). In a population based case-control study of patients with a first episode of VTE, Blom et al found that the odds ratio of developing VTE among patients with haematological malignancies was approximately 26 compared to the

general population (18). Similar results were also reported by other authors (29-31).

Prospective studies has shown that VTE have inflicted a higher risk of several adverse complications on patients with cancer including recurrent VTE, bleeding complications while on anticoagulant treatment, increase in both short-term and long-term mortality (32- 33) and increased mortality during first 3 month of therapy. The risk of VTE is markedly different for cancer patients throughout the course of the disease and this variable incidence of VTE comorbidity in cancer patients can be attributed to a combination risk factors related

endothelium growth factor (VEGF) and thereby, enhancing angiogenesis (9-10).

dependent on the formation of the TF-factor VIIa complex (11).

presence of distant metastasis (15-18).

**2.2 The incidence of venous thromboembolism in cancer patients** 

underlying cancer, whereas 26% of incident cases had idiopathic VTE (15).

to the patient, the cancer itself and treatment (34).

of the haemostatic system (defined as persistent elevation of fibrinopeptide A and prothrombin fragment 1+2 levels), total mortality was significantly higher in participants with persistent activation (17.1/1000 person-years) than in patients without activation (9.7/1000 person-years; p=0.015). This difference was attributed to an increased incidence of death from cancers (11.3/1000 vs. 5.1/1000 person-years).

The majority of patients with cancer has increased levels of procoagualnt factors V, VIII, IX, and XI, as well as increased levels of markers of coagulation activation (e.g., thrombin– antithrombin, prothrombin fragment 1*+*2, fibrinopeptide and D-dimer (2). In addition, patients with some disseminated malignancies seem to have a deficient activity of von Willebrand's factor-cleaving protease (ADAMTS-13), resulting in unusually large von Willebrand factor multimers leading to platelet thrombosis (3).

Many tumors have been shown to activate blood coagulation through an abnormal expression of high levels of the procoagulant molecule tissue factor (TF). In normal vascular cells, expression of TF is not expressed, except when induced by inflammatory cytokines such as interleukin 1*β* and tumor necrosis factor *α* (TNF-*α*) or by bacterial lipopolysaccharides. In tumor cells, TF is expressed and causes activation of the extrinsic pathway. In the elegant study conducted by Kakkar et al (4) plasma levels of TF, factor VIIa, factor XIIa, the thrombin–antithrombin complex, and prothrombin fragments were elevated in patients with cancer compared with healthy controls. Tissue factor and factor VIIa levels were both significantly higher, suggesting significant activation of the extrinsic pathway. On the other hand, levels of factor XIIa were only marginally elevated, indicating that the intrinsic pathway is not involved to a significant degree in the hypercoagulable state seen in patients with cancer (5).

Tumor cells express cancer procoagulant, a cysteine protease expressed only on malignant tissues. Cancer procoagulant directly activates factor X in the common pathway independent of factor VII (6). The activity of this protease seems to be driven by the stage of cancer. The onset of cancer is usually associated with high levels of protease slowly declines thereafter (7), partially explaining the tendency of thromboembolic events to occur during the first three month following the diagnosis of cancer.

In addition to the expression of TF and cancer procoagulant, tumor cells enhance coagulation in patients with cancer by expressing proteins that regulate the fibrinolytic system, including plasminogen activators, plasminogen activator inhibitors 1 and 2, and plasminogen-activator receptor, leading to an imbalance of fibrinolytic mechanism (8) Tumor cells may elicit platelet activation and aggregation through direct cell–cell interactions or through the release of soluble mediators, including ADP, thrombin, and other proteases. Furthermore, expression of certain cytokines by tumor cells, including TNF*α* and interleukin 1*β*, induces expression of TF on endothelial cells and simultaneously downregulates the expression of thrombomodulin, resulting in a prothrombotic state at the vascular wall.Multiple studies have provided considerable evidence for a bidirectional clinical association between VTE and cancer, in that cancer elicits expression of procoagulant activities, contributing to the prothrombotic state in these patients, and the procoagulant activities themselves seem to elicit cancer growth, proliferation, and metastasis. Fibrin and platelet deposition around solid tumor cells promotes angiogenesis through platelet-derived proangiogenic factors, and may seal immature tumor vasculature Pathophysiology and Clinical Aspects of 74 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

of the haemostatic system (defined as persistent elevation of fibrinopeptide A and prothrombin fragment 1+2 levels), total mortality was significantly higher in participants with persistent activation (17.1/1000 person-years) than in patients without activation (9.7/1000 person-years; p=0.015). This difference was attributed to an increased incidence of

The majority of patients with cancer has increased levels of procoagualnt factors V, VIII, IX, and XI, as well as increased levels of markers of coagulation activation (e.g., thrombin– antithrombin, prothrombin fragment 1*+*2, fibrinopeptide and D-dimer (2). In addition, patients with some disseminated malignancies seem to have a deficient activity of von Willebrand's factor-cleaving protease (ADAMTS-13), resulting in unusually large von

Many tumors have been shown to activate blood coagulation through an abnormal expression of high levels of the procoagulant molecule tissue factor (TF). In normal vascular cells, expression of TF is not expressed, except when induced by inflammatory cytokines such as interleukin 1*β* and tumor necrosis factor *α* (TNF-*α*) or by bacterial lipopolysaccharides. In tumor cells, TF is expressed and causes activation of the extrinsic pathway. In the elegant study conducted by Kakkar et al (4) plasma levels of TF, factor VIIa, factor XIIa, the thrombin–antithrombin complex, and prothrombin fragments were elevated in patients with cancer compared with healthy controls. Tissue factor and factor VIIa levels were both significantly higher, suggesting significant activation of the extrinsic pathway. On the other hand, levels of factor XIIa were only marginally elevated, indicating that the intrinsic pathway is not involved to a significant degree in the hypercoagulable state seen in

Tumor cells express cancer procoagulant, a cysteine protease expressed only on malignant tissues. Cancer procoagulant directly activates factor X in the common pathway independent of factor VII (6). The activity of this protease seems to be driven by the stage of cancer. The onset of cancer is usually associated with high levels of protease slowly declines thereafter (7), partially explaining the tendency of thromboembolic events to occur during

In addition to the expression of TF and cancer procoagulant, tumor cells enhance coagulation in patients with cancer by expressing proteins that regulate the fibrinolytic system, including plasminogen activators, plasminogen activator inhibitors 1 and 2, and plasminogen-activator receptor, leading to an imbalance of fibrinolytic mechanism (8) Tumor cells may elicit platelet activation and aggregation through direct cell–cell interactions or through the release of soluble mediators, including ADP, thrombin, and other proteases. Furthermore, expression of certain cytokines by tumor cells, including TNF*α* and interleukin 1*β*, induces expression of TF on endothelial cells and simultaneously downregulates the expression of thrombomodulin, resulting in a prothrombotic state at the vascular wall.Multiple studies have provided considerable evidence for a bidirectional clinical association between VTE and cancer, in that cancer elicits expression of procoagulant activities, contributing to the prothrombotic state in these patients, and the procoagulant activities themselves seem to elicit cancer growth, proliferation, and metastasis. Fibrin and platelet deposition around solid tumor cells promotes angiogenesis through platelet-derived proangiogenic factors, and may seal immature tumor vasculature

death from cancers (11.3/1000 vs. 5.1/1000 person-years).

Willebrand factor multimers leading to platelet thrombosis (3).

the first three month following the diagnosis of cancer.

patients with cancer (5).

and provide a degree of protection to the cancer cells from the immune system. Fibrin has also been shown to increase expression of TF and induce expression of IL-8 and vascular endothelium growth factor (VEGF) and thereby, enhancing angiogenesis (9-10).

The TF–factor VIIa complex can signal through cleavage of protease-activated receptors, which, in turn, induce the mitogen-activated protein kinase (MAPK) signal transduction cascade (11). The MAPK pathway is involved in the induction of genes involved in angiogenesis, migration, and proliferation. In addition, phosphorylation of the cytoplasmic tail of the TF receptor has also been shown to indirectly activate transcription of VEGF, downregulate thrombospondin (an antiangiogenic protein), and induce cell migration. Expression of TF by malignant cells also seems to support metastatic process and is dependent on the formation of the TF-factor VIIa complex (11).
