OC-03 - Modelisation of the procoagulant properties of cancer cells and their capacity to alter the antithrombotic efficiency of LMWHs and specific inhibitors of factor Xa

G T Gerotziafas; A Rousseau; P van Dreden; E Mbemba; V Gkalea; A Khaterchi; A Larsen; I Elalamy

doi:10.1016/S0049-3848(16)30120-7

OC-03 - Modelisation of the procoagulant properties of cancer cells and their capacity to alter the antithrombotic efficiency of LMWHs and specific inhibitors of factor Xa

Thromb Res. 2016 Apr:140 Suppl 1:S169. doi: 10.1016/S0049-3848(16)30120-7. Epub 2016 Apr 8.

Authors

G T Gerotziafas¹, A Rousseau², P van Dreden³, E Mbemba², V Gkalea⁴, A Khaterchi⁴, A Larsen², I Elalamy¹

Affiliations

¹ INSERM U938, Faculté de Médecine Pierre et Marie Curie, Université Paris VI, Paris; Service d'Hématologie Biologique Hôpital Tenon, Hôpitaux Universitaires Est Parisien, Assistance Publique Hôpitaux de Paris, Paris.
² INSERM U938, Faculté de Médecine Pierre et Marie Curie, Université Paris VI, Paris.
³ Research and Development, Diagnostica Stago, Gennevilliers; France.
⁴ Service d'Hématologie Biologique Hôpital Tenon, Hôpitaux Universitaires Est Parisien, Assistance Publique Hôpitaux de Paris, Paris.

PMID: 27161675
DOI: 10.1016/S0049-3848(16)30120-7

Abstract

Introduction: The risk of venous thromboembolism varies according to the histological type of cancer. The failure of antithrombotic treatment is more frequent in cancer patients as compared to non-cancer ones.

Aim: We aimed to elucidate the mechanism of activation of blood coagulation induced by cancer, the impact of chemo-resistance phenotype on the capacity of cancer cells to trigger thrombin generation and the alterations of the efficiency of LMWHs and the specific inhibitors of factor Xa (fondaparinux and apixaban) in the presence of cancer cells.

Materials and methods: Thrombin generation of human plasma was assessed in the presence of various cancer cell lines. The model of cancer-induced hypercoagulability was coupled to the research for the expression of procoagulant molecules by cancer cells.

Results: The pancreatic adenocarcinoma cells BXPC3 and the breast adenocarcinoma cells MCF7 were initially tested. The BXPC3 cells induce significantly higher thrombin generation as compared to the MCF7 cells. In the same line Marchetti et al. showed that malignant hematologic cells (NB4, HEL, and K562) and H69 small cell lung cells express different procoagulant potential on triggering thrombin generation of human plasma. The comparison of the procoagulant activity has been extended to cancer cell lines from various cancers (i.e. colon, ovarian and prostatic cancer) as well as to different cell lines of the same type of cancer. The differences of the cancer cell lines to trigger thrombin generation are mainly due to the expression of TF. The acquisition of chemoresistant phenotype by cancer cells is correlated with increased TF expression and enhancement of theit procoagulant activity. The ability of cancer cells to activate FXII is an alternative pathway of significant importance for some cancer cell lines (i.e. MCF7). Clinically relevant concentrations of LMWH and specific direct and indirect inhibitors of FXa (apixaban and fondaparinux) inhibit thrombin generation induced by cancer cells. The synergy between the anti-Xa and anti-IIa activities of LMWHs rather than the AT-dependent selective inhibition of FXa results in profound inhibition of thrombin generation induced by BXPC3 cells. This experimental model allowed the functional distinction between the two specific FXa inhibitors (apixaban and fondaparinux).

Conclusions: The cancer cell-based model of hypercoagulability is suitable for the identification of the prothrombotic fingerprint of various cancer types. This experimental model allows to perform pharmacological studies for the evaluation of the efficiency of the antithrombotic drugs in cancer-induced hypercoagulability. It is suitable for the study of the impact of anticancer drugs on the procoagulant properties of the cancer cells.