BMS-262084, a FXIa inhibitor, interferes with tumor cell-induced coagulation activation only in tumor cells with low tissue factor (TF) procoagulant activity (PCA)

Introduction Inhibition of coagulation factor XI (FXI) has become a promising new antithrombotic strategy with a presumably low bleeding risk [1]. While it is efficacious and safe in prevention of postoperative venous thromboembolism in orthopedic patients [2] [3] [4] [5], its role in treatment and prophylaxis of cancer-associated thrombosis (CAT) is less clear. Here, we provide mechanistic insights into FXI inhibition in tumor cell-induced coagulation activation.

Method FXIa amidolytic activity was assessed by in-house chromogenic assays. Coagulation activation by four distinct cancer cell lines (i.e., BxPC-3, MCF-7, THP-1, and HL‑60) was analyzed by single-stage clotting and modified thrombin generation assay in the presence or absence of the FXIa inhibitor, BMS-262084, and peak or trough concentrations of tinzaparin (0.85 and 0.2 IU/mL) and rivaroxaban (270 and 26 ng/mL). Coagulation initiation by recombinant human TF (rhTF) served as control. Further, tumor cell-induced platelet aggregation was recorded by light transmission aggregometry in a similar way.

Results While BMS-262084 potently inhibited FXIa, with concentrations > 0.5 µM showing complete neutralization of its amidolytic activity, it interfered with rhTF-induced fibrin formation only at low rhTF concentrations. Under these conditions, the effect of 10 µM BMS-262084 was comparable to that of FXa inhibition by peak levels of tinzaparin or rivaroxaban. Similarly, the ability of equal BMS‑262084 concentrations to mitigate tumor cell-induced fibrin formation, thrombin generation and platelet aggregation inversely correlated with the magnitude of cellular TF expression. Consistently, BMS–262084 had negligible effects on tumor cell-induced fibrin formation and platelet aggregation by highly procoagulant BxPC–3 cells, but potently prevented both thrombogenic effects in the presence of very low TF expressing HL-60 cells. Of note, the most prominent BMS-262084 anticoagulant effect was recorded in the modified thrombin generation assay, particularly on peak and total thrombin generation. In this assay, BMS-262084 even significantly reduced peak and total thrombin generation of highly procoagulant BxPC–3 cells suggesting that BMS–262084 predominantly interfered with the intrinsic amplification loop of coagulation.

Conclusion FXI inhibition predominantly interferes with the propagation phase of TF-triggered coagulation activation by tumor cells. Thus, the anticoagulant potency of FXI inhibitors may critically dependent on levels of TF expression by cancer cells, a finding with potential clinical implications for CAT prophylaxis and treatment.

Conflict of Interest

J.M., A.S., J.R., C.L. and L.B. declare no conflicts of interests relevant to the content of the submitted abstract. CC.R. has received travel support from Pfizer. M.V. declares personal fees for lectures from Bristol-Myers Squibb and travel support from Bayer, Bristol-Myers Squibb and LEO Pharma. C.B. has received personal fees for consultancy from Bayer, Bristol-Myers Squibb and Sanofi, and for travel expenses from Bristol-Myers Squibb, Pfizer and Sanofi. F.L. has received personal fees for lectures or consultancy and/or research support from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, LEO Pharma, Pfizer, Sanofi, and Viatris.; The submitted work was supported in part by an Early Career Research Grant from the GTH e.V. to L.B..

• References

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• 3 Weitz JI, Bauersachs R, Becker B. et al. Effect of Osocimab in Preventing Venous Thromboembolism Among Patients Undergoing Knee Arthroplasty: The FOXTROT Randomized Clinical Trial. JAMA 2020; 323 (02) 130-139
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Publication History

Article published online:
20 February 2023