Mechanisms and biomarkers of cancer-associated thrombosis

Abstract

Cancer-associated thrombosis is a leading cause of non-cancer death in cancer patients and is comprised of both arterial and venous thromboembolism (VTE). There are multiple risk factors for developing VTE, including cancer type, stage, treatment, and other medical comorbidities, which suggests that the etiology of thrombosis is multifactorial. While cancer-associated thrombosis can be treated with anticoagulation, benefits of therapy must be balanced with the increased bleeding risks seen in patients with cancer. Although risk models exist for primary and recurrent VTE, additional predictors are needed to improve model performance and discrimination of high-risk patients. This review will outline the diverse mechanisms driving thrombosis in cancer patients, as well as provide an overview of biomarkers studied in thrombosis risk and important considerations when selecting candidate biomarkers.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Figure 1.. Graphical summary of key mechanisms driving cancer-associated thrombosis.

Interleukin-8 (IL-8), tumor necrosis factor-α (TNF- α), and granulocyte-colony stimulating factor (G-CSF) stimulate neutrophils to form neutrophil extracellular traps (NETs) containing cell free DNA (cfDNA) and citrullinated histone H3 (H3Cit). Extracellular vesicles (EVs), derived from tumor or host cells, express negatively charged phosphatidylserine (PS) which bind histones in NETs. EVs also express tissue factor (TF) which binds factor VIIa (FVIIa) to initiate the extrinsic pathway of coagulation and generate thrombin. Tumor cells can also secrete exosomes expressing polyphosphate (polyP) to activate the contact pathway. Similarly, platelets can express polyP to initiate contact pathway activation, as well as interact with cfDNA and histones present in NETs for thrombin and thrombus formation. Podoplanin-expressing activated endothelial cells can bind C-type lectin-like receptor 2 (CLEC-2) on platelets to induce platelet activation and aggregation. Inhibitory microRNAs (miRNAs) can be secreted extracellularly in a protein- or EV-bound form. Platelets and other host cells can take up miRNAs which regulate gene expression of coagulation factors and re-secrete miRNAs into plasma. FXIIa, factor XIIa; RBC, red blood cell.