Cancer-Associated Thrombosis: An Overview of Mechanisms, Risk Factors, and Treatment

Abstract

Cancer-associated thrombosis is a major cause of mortality in cancer patients, the most common type being venous thromboembolism (VTE). Several risk factors for developing VTE also coexist with cancer patients, such as chemotherapy and immobilisation, contributing to the increased risk cancer patients have of developing VTE compared with non-cancer patients. Cancer cells are capable of activating the coagulation cascade and other prothrombotic properties of host cells, and many anticancer treatments themselves are being described as additional mechanisms for promoting VTE. This review will give an overview of the main thrombotic complications in cancer patients and outline the risk factors for cancer patients developing cancer-associated thrombosis, focusing on VTE as it is the most common complication observed in cancer patients. The multiple mechanisms involved in cancer-associated thrombosis, including the role of anticancer drugs, and a brief outline of the current treatment for cancer-associated thrombosis will also be discussed.

Keywords: cancer; thrombosis; venous thromboembolism.

Figure 1

Direct mechanisms involved in cancer-associated thrombosis. Direct activation of coagulation and platelets can occur through several factors expressed on or released from cancer cells. These include the expression of tissue factor (TF), the key initiator of the coagulation cascade, which can also be released by TF-positive microparticles. Podoplanin (PDPN) expression can directly cause platelet activation and aggregation via the C-type lectin-like receptor 2 (CLEC-2) receptor on platelets. Plasminogen activation inhibitor-1 (PAI-1), a key inhibitor of fibrinolysis, is highly expressed in cancer cells. Cancer cells also secrete platelet agonists such as ADP and thrombin, thus further promoting platelet activation through P2Y12 and protease-activated receptors 1 and 4 (PAR1/4), respectively. Phosphatidyl serine (PS) expressed on tumour microparticles may also promote coagulation as PS serves as a surface for formation of coagulation complexes. Cancer procoagulant (CP) has been shown to directly activate coagulation by activating Factor X.

Figure 2

Indirect mechanisms promoting thrombosis in cancer. Tumours can be highly metastatic, resulting in cancer cell dissemination and intravasation into nearby blood vessels. Inflammatory cytokine secretion from tumour cells can cause activation of platelets and promote a procoagulant phenotype in endothelial cells. Cancer-derived factors also stimulate neutrophils to release neutrophil extracellular traps (NETs). NETs serve as a scaffold that can physically entrap platelets, or activate platelets through NET-associated histones, ultimately leading to profound platelet activation, fibrin deposition, and entrapment of red blood cells, exacerbating clot formation.