Procoagulant microparticles derived from cancer cells have determinant role in the hypercoagulable state associated with cancer

Abstract

Hypercoagulablity is a common alteration of blood coagulation in cancer patients. However, the procoagulant activity of cancer cells is not sufficient to induce hypercoagulability. The present study was aimed to identify the mechanism with which hypercoagulabilty is produced in the presence of cancer cells. We focused on the analysis of the procoagulant elements carried by cancer cell-derived microparticles (CaCe-dMP) and we evaluated the impact of microparticles associated with the cancer cells from which they stem on thrombin generation. CaCe-dMP from the cancer cells were isolated from the conditioned medium and analyzed for tissue factor (TF) and procoagulant phospholipid expression. Thrombin generation of normal plasma was assessed by the Thrombinoscope (CAT®) in the presence or absence of pancreas adeno-carcinoma cells (BXPC3) or breast cancer MCF7 cells supplemented with the respective CaCe-dMP. Both BXPC3 and MCF7 cells express abundant amounts of active TF. Phosphatidylserine was identified on the surface of CaCe-dMP, unlike the cancer cells themselves. The expression of TFa by the microparticles was significantly higher to that observed on the cancer cells. Culture of the cancer cells with their microparticles resulted in thrombin generation significantly higher as compared to the upper normal limit. In conclusion, cancer cells 'enrich' the microenvironment with procoagulant elements, especially procoagulant micro-particles which express TF and procoagulant phospholipids. The association of cancer cells with procoagulant microparticles is necessary for a state of hypercoagulability, at the level of the tumoral microenvironment. The intensity of the hypercoagulability depends on the histological type of the cancer cells.

Platelets and Metastasis: New Implications of an Old Interplay

“…Tumor cells have been found responsible for the production of these pro-coagulant MPs. MPs expressing TF, PSGL-1, and PS can be detected in the culture medium of tumor cells and in tumor-bearing mice, and mediate thrombin generation and thrombus growth ex vivo and in vivo ( 77 , 100 – 103 ). These MPs accumulate in the growing thrombi through a PSGL-1-mediated mechanism and accelerate thrombus growth ( 86 , 100 ).…”

Thrombin Generation and Cancer: Contributors and Consequences

“…Circulating cancer cells also release EVs, providing another surface that contributes directly to thrombin generation in cancer. EV-free plasma is not able to generate thrombin [36], and cancer cell-derived EVs directly support thrombin generation, shown by in vitro studies of EVs released from leukaemia cell lines [35,37], prostate cancer cell lines [38] and breast and pancreatic cancer cell lines [39]. Many in vitro studies have linked expression of TF on EVs with their procoagulant potential (as measured by various functional assays such as thrombin generation performed in EV-enriched samples) [35,37,39,40,41].…”

“…EV-free plasma is not able to generate thrombin [36], and cancer cell-derived EVs directly support thrombin generation, shown by in vitro studies of EVs released from leukaemia cell lines [35,37], prostate cancer cell lines [38] and breast and pancreatic cancer cell lines [39]. Many in vitro studies have linked expression of TF on EVs with their procoagulant potential (as measured by various functional assays such as thrombin generation performed in EV-enriched samples) [35,37,39,40,41]. Circulating TF-positive EVs (TF+EVs) have been seen in leukaemia [37], breast [39], pancreatic [39,42] and lung [42] cancer patients.…”

Extracellular vesicles and microvascular pathology: Decoding the active dialogue

“…Tumor apoptotic vesicles may enhance the risk of thrombotic events in cancer patients undergoing chemotherapy by mechanisms depending notably on phosphatidylserine, TF expression, Factor VII and the prothrombinase complex . EV at large play an important role in the hypercoagulable state of cancer patients, and they have the potential to become involved in complexes with neutrophil extracellular traps, which lead to enhanced thrombin generation …”