The role of coagulation and platelets in colon cancer-associated thrombosis

Abstract

Cancer-associated thrombosis is a common first presenting sign of malignancy and is currently the second leading cause of death in cancer patients after their malignancy. However, the molecular mechanisms underlying cancer-associated thrombosis remain undefined. In this study, we aimed to develop a better understanding of how cancer cells affect the coagulation cascade and platelet activation to induce a prothrombotic phenotype. Our results show that colon cancer cells trigger platelet activation in a manner dependent on cancer cell tissue factor (TF) expression, thrombin generation, activation of the protease-activated receptor 4 (PAR4) on platelets and consequent release of ADP and thromboxane A2. Platelet-colon cancer cell interactions potentiated the release of platelet-derived extracellular vesicles (EVs) rather than cancer cell-derived EVs. Our data show that single colon cancer cells were capable of recruiting and activating platelets and generating fibrin in plasma under shear flow. Finally, in a retrospective analysis of colon cancer patients, we found that the number of venous thromboembolism events was 4.5 times higher in colon cancer patients than in a control population. In conclusion, our data suggest that platelet-cancer cell interactions and perhaps platelet procoagulant EVs may contribute to the prothrombotic phenotype of colon cancer patients. Our work may provide rationale for targeting platelet-cancer cell interactions with PAR4 antagonists together with aspirin and/or ADP receptor antagonists as a potential intervention to limit cancer-associated thrombosis, balancing safety with efficacy.

Metabolomic, transcriptomic and genetic integrative analysis reveals important roles of adenosine diphosphate in haemostasis and platelet activation in non‐small‐cell lung cancer

“…Amongst the key metabolites, adenosine diphosphate (ADP), a pro‐angiogenic regulator and platelet agonist, is produced by cancer cells and by activated platelets. ADP is required for adhesion of platelets to cancer cells (Mitrugno et al ., ), inducing platelet activation and aggregation through the purinergic P2Y1 and P2Y12 receptors. P2YR12 represents a potential target for an anticancer therapy due to its involvement in platelet‐cancer cell crosstalk, and P2YR12 ‐ mediated platelet activation has been demonstrated to promote metastasis in mouse model of melanoma ( Zhu et al ., ) .…”

Prognostic evaluation of colorectal cancer using three new comprehensive indexes related to infection, anemia and coagulation derived from peripheral blood

“…Peripheral blood test is commonly used in clinical practice. Blood routine test (BRT), as one of the most basic peripheral blood biochemical tests, can quickly and accurately detect the values of blood components such as white blood cells (WBC), lymphocytes (LY), red blood cells (RBC), hemoglobin (HGB) and platelets (PLT), as well as other related indicators, in order to effectively indicate abnormalities of infection, anemia and cruor [7][8][9] . In recent years, a wide variety of blood indicators with different changes were concerned and discussed in the study of malignant tumor diseases including CRC: Qian W, et al reported that the post-/pre-treatment MPV (Mean Platelet Volume) ratio were prognostic factors for OS in resectable CRCs [10] ; Preoperative neutrophil-lymphocyte ratio (NLR) and red blood cell distribution width (RDW), especially the independent prediction of NLR, were confirmed as effective biomarkers for clinical diagnosis and prognosis evaluation of esophageal cancers [11] ; In patients with pathologic stage I non-small cell lung cancer undergoing surgical resection, high LY and PLT count from peripheral blood could provide poor prognostic value independently [12] ; Even the ratios between indicators were developed into new indexes, which had fairly good prognostic significance, including NLR, Platelet-to-Lymphocyte Ratio (PLR), Lymphocyte-to-Monocyte ratio (LMR).…”

Protease‐activated receptor signaling in intestinal permeability regulation

“…model selection, influence of different proteases). Conversely, other studies suggested that colon cancer cells can induce cancer‐associated thrombosis by thrombin via PAR‐4 activation on platelets and subsequent amplification . Not only PAR‐1 and PAR‐2 are expressed by colon cancer cells, but also overexpression of PAR‐4 was detected in carcinogenic tissue, associated with increased proliferation and migration of cancer cells.…”