**5. Pathogenesis of cancer-associated venous thromboembolism**

Stasis of blood flow, hypercoagulability, and endothelial injury are known as Virchow's triad, and they are involved in thrombus formation. Stasis of blood flow caused by several factors, such as poor performance status, indwelling CVC, and venous compression by tumor, is thought to be involved in the pathogenesis of VTE in cancer patients.

Blood cells also play an important role in the occurrence of VTE in cancer patients. Leukocyte count 11 × 109 /L or above is a risk factor of VTE in cancer patients [21]. Increased leukocyte is found in 20–30% of cancer patients, and it is common in colon and lung cancer patients. Increased expression of granulocyte colony stimulating factor, granulocyte-macrophage colony stimulating factor, and interleukin-6 causes leukocyte increase in cancer patients [22, 23]. Neutrophils may enhance thrombosis through formation of neutrophil extracellular traps (NETs), which take in erythrocytes and platelets, and bind to tissue factor (TF) resulting in activation of coagulation [24, 25]. Increased incidences of VTE are reported both in cancer patients with thrombocytosis prior to cancer diagnosis and thrombocytosis at cancer diagnosis [11, 26, 27]. Higher expression of platelet factor 4, which activates platelets, in cancer patients may be related to the development of VTE [28, 29]. Platelets also play a regulatory role in NETs formation. These may play an important role in the pathogenesis of cancer-associated VTE.

Some proteins also have been reported to be involved in the pathogenesis of cancer-associated VTE. TF plays an important role in hemostasis and activates factor IX and factor X to initiate extrinsic coagulation pathway by forming a complex with factor VII or activated factor VII. VTE most frequently occurs in pancreatic cancer patients, and pancreatic cancer expresses TF. Expression levels of TF correlate with histologic grades of cancer, and the incidence of VTE is higher in patients with pancreatic cancer with high TF expression level [30, 31]. Podoplanin is a protein which activates platelets by binding to platelet C-type lectin receptor 2 (CLEC-2) [32, 33]. The relationships between podoplanin and VTE are proven in patients with glioblastoma multiforme (GBM). Expression levels of podoplanin vary by GBM subtype. GBM with high podoplanin expression level has a high number of platelet aggregates in tumor vessels and is reported to have high incidence of VTE [34].

P-selectin is a protein that exists in platelets and endothelial cells, and soluble form of P-selectin exists in plasma. P-selectin induces leukocytes to damaged endothelium for thrombus formation. The incidence of VTE is reported to be higher in cancer patients with high levels of soluble P-selectin [35]. Inhibition of P-selectin reduces thrombus formation in animal models [36].

Plasminogen activator inhibitor-1 (PAI-1) inhibits plasmin, which is synthesized from plasminogen to dissolve thrombus. Increased level of PAI-1 causes thrombotic tendency. The incidence of VTE is high in pancreatic cancer patients with increased levels of PAI-1 [37]. It is reported that administration of bevacizumab to mice transplanted with lung cancer cells increases PAI-1 expression and enlarges the size of thrombus. Administration of PAI-1 inhibitor to these mice decreases the thrombus size [38]. These findings suggest that increased PAI-1 may be related to the occurrence of cancer-associated VTE (**Figure 1**).

**127**

*Etiology of Cancer Associated Thromboembolism (CAT), and Diet, Lifestyle and Medicine…*

Considering the pathogenesis of cancer-associated VTE described in the previous section, it is unlikely that certain diets and nutrition can suppress the development of cancer-associated VTE specifically. Then, are there any diets and nutrition which may prevent the development of VTE in general, not just cancer-associated? The association between diet and nutrition and thrombosis has not necessarily been well analyzed for VTE, but it has been well analyzed for arterial thrombosis such as ischemic heart disease or cerebral infarction. In 2010, the American College of Cardiology announced seven lifestyles to reduce deaths caused by cardiovascular and cerebral infarction by 20% by 2020: (1) nonsmoking, (2) body mass index <25 kg/m2

*Pathogenesis of cancer-associated venous thromboembolism. Cancer cells express and release various proteins. These induce leukocytosis and thrombocytosis and activate coagulation resulting in thrombus formation.*

physical activity at goal levels, (4) pursuit of a diet consistent with the current guideline recommendations, (5) untreated total cholesterol <200 mg/dL, (6) untreated blood pressure < 120/<80 mm Hg, and (7) fasting blood glucose <100 mg/dL [39]. Do these lifestyles also reduce the incidence of VTE? Hypertension, hypercholesterolemia, diabetes (these are related to diet and nutrition), and smoking are risk factors for atherosclerotic cardiovascular disease, and meta-analysis of nine clinical trials revealed that only smoking is a risk factor for VTE among them [40]. These results suggest that diets and nutrition to prevent arterial thrombosis are not necessarily effective for VTE prevention. On the other hand, obesity, one of the risk factors for arterial thrombosis, is also known to be one of the risk factors for the development of VTE. Analysis of the association between 95 BMI-related gene polymorphisms and VTE development proves that five of the polymorphisms are associated with VTE development [41]. Therefore, taking a diet without too much calories or carbohydrates to maintain proper body weight is considered to be useful for VTE prevention. Other reports examining the relationship between diet and nutrition and VTE are as follow. The incidence of VTE is 22% lower for those who eat fish three or more times a week than for those who eat twice or less a week [42] and is low for those who eat enough fish, vegetables, and fruits and eat less red meat and processed meat [43]. These reports suggest that diets to prevent arterial

, (3)

*DOI: http://dx.doi.org/10.5772/intechopen.92379*

**6. Diet, nutrition, and VTE**

**Figure 1.**

*Etiology of Cancer Associated Thromboembolism (CAT), and Diet, Lifestyle and Medicine… DOI: http://dx.doi.org/10.5772/intechopen.92379*

**Figure 1.**

*New Insights into Metabolic Syndrome*

and body mass index of 35 kg/m2

patients. Leukocyte count 11 × 109

/L or more, hemoglobin less than 100 g/L (10 g/dL) and/or the

or more (1 point each). Rates of VTE have been

/L or above is a risk factor of VTE in cancer

/L,

use of erythropoiesis-stimulating agents, leukocyte count more than 11 × 109

and 6.7% in high-risk (score ≥ 3) category over a median of 2.5 months.

**5. Pathogenesis of cancer-associated venous thromboembolism**

reported to be 0.3% in low-risk (score = 0), 2% in intermediate-risk (score = 1–2),

Stasis of blood flow, hypercoagulability, and endothelial injury are known as Virchow's triad, and they are involved in thrombus formation. Stasis of blood flow caused by several factors, such as poor performance status, indwelling CVC, and venous compression by tumor, is thought to be involved in the pathogenesis of VTE

Blood cells also play an important role in the occurrence of VTE in cancer

patients [21]. Increased leukocyte is found in 20–30% of cancer patients, and it is common in colon and lung cancer patients. Increased expression of granulocyte colony stimulating factor, granulocyte-macrophage colony stimulating factor, and interleukin-6 causes leukocyte increase in cancer patients [22, 23]. Neutrophils may enhance thrombosis through formation of neutrophil extracellular traps (NETs), which take in erythrocytes and platelets, and bind to tissue factor (TF) resulting in activation of coagulation [24, 25]. Increased incidences of VTE are reported both in cancer patients with thrombocytosis prior to cancer diagnosis and thrombocytosis at cancer diagnosis [11, 26, 27]. Higher expression of platelet factor 4, which activates platelets, in cancer patients may be related to the development of VTE [28, 29]. Platelets also play a regulatory role in NETs formation. These may play an

Some proteins also have been reported to be involved in the pathogenesis of cancer-associated VTE. TF plays an important role in hemostasis and activates factor IX and factor X to initiate extrinsic coagulation pathway by forming a complex with factor VII or activated factor VII. VTE most frequently occurs in pancreatic cancer patients, and pancreatic cancer expresses TF. Expression levels of TF correlate with histologic grades of cancer, and the incidence of VTE is higher in patients with pancreatic cancer with high TF expression level [30, 31]. Podoplanin is a protein which activates platelets by binding to platelet C-type lectin receptor 2 (CLEC-2) [32, 33]. The relationships between podoplanin and VTE are proven in patients with glioblastoma multiforme (GBM). Expression levels of podoplanin vary by GBM subtype. GBM with high podoplanin expression level has a high number of platelet aggregates in tumor vessels and is reported to have high incidence of VTE [34]. P-selectin is a protein that exists in platelets and endothelial cells, and soluble form of P-selectin exists in plasma. P-selectin induces leukocytes to damaged endothelium for thrombus formation. The incidence of VTE is reported to be higher in cancer patients with high levels of soluble P-selectin [35]. Inhibition of P-selectin

Plasminogen activator inhibitor-1 (PAI-1) inhibits plasmin, which is synthesized from plasminogen to dissolve thrombus. Increased level of PAI-1 causes thrombotic tendency. The incidence of VTE is high in pancreatic cancer patients with increased levels of PAI-1 [37]. It is reported that administration of bevacizumab to mice transplanted with lung cancer cells increases PAI-1 expression and enlarges the size of thrombus. Administration of PAI-1 inhibitor to these mice decreases the thrombus size [38]. These findings suggest that increased PAI-1 may be related to the occur-

important role in the pathogenesis of cancer-associated VTE.

reduces thrombus formation in animal models [36].

rence of cancer-associated VTE (**Figure 1**).

count of 350 × 109

in cancer patients.

**126**

*Pathogenesis of cancer-associated venous thromboembolism. Cancer cells express and release various proteins. These induce leukocytosis and thrombocytosis and activate coagulation resulting in thrombus formation.*
