PB0551 - Prevention of tumor cell-induced coagulation activation by the small-molecule FXIa inhibitor, BMS-262084, is dependent on tissue factor (TF) expression levels

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Jonathan Mäder

Medical student
UKE, Hamburg, Germany
Hamburg, Hamburg, Germany

Co-Author(s)

MV

Minna Voigtländer

Specialist Physician
II. Medizinische Klinik und Poliklinik, Zentrum für Onkologie, UKE, Hamburg, Germany
Hamburg, Hamburg, Germany
CR

Christina C. Rolling

Specialist physician
II. Medizinische Klinik und Poliklinik, Zentrum für Onkologie, UKE, Hamburg, Germany
Hamburg, Hamburg, Germany
AS

Anita Schulenkorf

Research technician
II. Medizinische Klinik und Poliklinik, Zentrum für Onkologie, UKE, Hamburg, Germany
Hamburg, Hamburg, Germany
CL

Carina Lehr

Research technician
II. Medizinische Klinik und Poliklinik, Zentrum für Onkologie, UKE, Hamburg, Germany
Hamburg, Hamburg, Germany
CB

Carsten Bokemeyer

Head of Department
II. Medizinische Klinik und Poliklinik, Zentrum für Onkologie, UKE, Hamburg, Germany
Hamburg, Hamburg, Germany
Lennart Beckmann

Physician
Zentrum für Onkologie, UKE, Hamburg, Germany
Hamburg, Hamburg, Germany
FL

Florian Langer

Medical Specialist in Internal Medicine
Universitätsklinikum Eppendorf, II. Medizinische Klinik und Poliklinik, Hubertus Wald Tumorzentrum, Universitäres Cancer Center Hamburg (UCCH), Hamburg, Germany
Hamburg, Hamburg, Germany

Background: Aberrant TF expression by tumor cells plays a critical role in the pathogenesis of cancer-associated thrombosis (CAT). While targeting FXI is highly efficacious in preventing postoperative venous thromboembolism, its role in CAT is less clear.

Aims: To investigate FXI inhibition in the context of tumor cell-induced coagulation activation.

Methods: A fibrin clot formation assay was used to measure the procoagulant activity (PCA) of recombinant human TF (rhTF) or tumor cells in the presence or absence of the small-molecule FXIa inhibitor, BMS-262084. Peak or trough concentrations of tinzaparin (0.85 and 0.2 IU/mL) and rivaroxaban (270 and 26 ng/mL) served as controls. Further, tumor cell-induced thrombin generation and platelet aggregation were analyzed. FXIa amidolytic activity was assessed by a chromogenic assay.

Results: BMS-262084 completely inhibited FXIa amidolytic activity at > 0.5 µM. In contrast to rivaroxaban and tinzaparin, 10 µM BMS-262084 mitigated the PCA of rhTF only at low rhTF concentrations. Under these conditions, the effect of BMS-262084 was comparable to that of peak tinzaparin and rivaroxaban levels. Similarly, the ability of BMS-262084 to inhibit tumor cell-induced fibrin formation, thrombin generation and platelet aggregation was inversely correlated with the magnitude of cellular TF expression. While in strongly TF-expressing pancreatic BxPC-3 cells FXI inhibition had negligible effects, it potently prevented tumor cell-induced fibrin formation, thrombin generation and platelet aggregation in leukemic HL-60 cells showing hardly any TF expression. Overall, the most prominent effects of BMS-262084 were observed on peak and total thrombin generation, suggesting that FXI inhibition predominantly interfered with the propagation phase of coagulation. Consistently, BMS-262084 already markedly reduced tumor cell-induced thrombin generation at moderately TF-expressing leukemic THP-1 and breast MCF-7 cells.

Conclusion(s): The efficacy of FXI inhibitors in preventing tumor cell-induced coagulation activation may depend on TF expression levels. These findings have potential clinical implications for CAT prophylaxis and treatment.