Cancer-Associated Thrombosis: Risk Factors, Molecular Mechanisms, Future Management

Abstract

Venous thromboembolism (VTE) is a major health problem in patients with cancer. Cancer augments thrombosis and causes cancer-associated thrombosis (CAT) and vice versa thrombosis amplifies cancer progression, termed thrombosis-associated cancer (TAC). Risk factors that lead to CAT and TAC include cancer type, chemotherapy, radiotherapy, hormonal therapy, anti-angiogenesis therapy, surgery, or supportive therapy with hematopoietic growth factors. There are some other factors that have an effect on CAT and TAC such as tissue factor, neutrophil extracellular traps (NETs) released in response to cancer, cancer procoagulant, and cytokines. Oncogenes, estrogen hormone, and thyroid hormone with its integrin αvβ3 receptor promote angiogenesis. Lastly, patient-related factors can play a role in development of thrombosis in cancer. Low-molecular-weight heparin and direct oral anticoagulants (DOACs) are used in VTE prophylaxis and treatment rather than vitamin K antagonist. Now, there are new directions for potential management of VTE in patients with cancer such as euthyroid, blockade of thyroid hormone receptor on integrin αvβ3, sulfated non-anticoagulant heparin, inhibition of NETs and stratifying low and high-risk patients with significant bleeding problems with DOACs.

Keywords: angiogenesis; anticoagulants; cancer; coagulation; heparins; inflammation; integrin αvβ3; non-anticoagulant heparin; oral anticoagulant; thrombosis; thyroid hormone.

Figure 1.

Representation of the reciprocal links between cancer and thrombosis. Tumor cells can express procoagulant factors, such as tissue factor (TF), that trigger the cascade of coagulation, which would be suppressed by mechanisms that induce endothelial tissue factor pathway inhibitors (TFPI). Tumor cells interact with endothelial cells, platelets, and leukocytes and these interactions induce inflammatory cytokines and pro-angiogenic factors such as vascular endothelial growth factor (VEGF). Neutrophil attraction contributes to the accumulation of neutrophil extracellular traps (NETs) and triggers adhesion, activation, and generation of thrombin. In general, the adherence of cancer to the endothelium causes the release of procoagulants and formation of thrombus, leading to CAT occurrence. TF also triggers the generation of factor VIIa, factor Xa, and thrombin (IIa), which activate platelets and induce protease-activated receptor-mediated signaling. The plasminogen activator (PA) system is expressed on platelets and it consists of plasminogen activators: urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), cell membrane receptor for uPA (uPAR), and the plasminogen activator inhibitors plasminogen activator inhibitor 1 (PAI-1) and plasmin. The PA system has an effect on cell adhesion and migration, which is particularly important in cancer progression. Also, TF suppress vasculoprotective molecules, such as thrombomodulin (TM). Release of von willebrand factor (VWF) promotes recruitment, adhesion, and activation of platelets and leukocytes with formation of NETs. abbreviations: APC, activated protein C; GAGS, glycosaminoglycans heparin sulfate; PC, protein C; PCI, protein C inhibitor; TNF, tumor necrosis factor-alpha.

Figure 2.

Relationship between integrin αvβ3, thyroid hormones, TF/FVIIa, angiogenesis, inflammation, and thrombus formation. When TF is released, it activates factor VII (VIIa) forming a complex that activates thrombus formation. TF is expressed on vascular endothelial cells, circulating monocyte and platelet where its activation upregulates VEGF that promotes angiogenesis. Non-genomic actions of thyroid hormones are initiated on integrin αvβ3. Thyroid hormones activate the NF-kB pathway, thus promoting the production of VEGF, cell proliferation and angiogenesis. Thrombus formation and angiogenesis stimulation affect inflammation pathway and vice versa. Either sulfated non-anticoagulant LMWH (SNACH) or integrin αvβ3 receptor blockade suppresses inflammation, angiogenesis, and indirectly the thrombosis processes. abbreviations: ABP-280, actin-binding protein 280; NF-KB, nuclear factor kappa B; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TREs, thyroid hormone response elements; TRs, thyroid hormone receptors. (Modified with permission from Mousa SA. Heparin and low-molecular weight heparins in thrombosis and beyond. Methods Mol Biol 2010;663:109-132.).