Effect of factor XI inhibition on tumor cell-induced coagulation activation
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Effect of factor XI inhibition on tumor cell-induced coagulation activation. / Mäder, Jonathan; Rolling, Christina C; Voigtländer, Minna; Schulenkorf, Anita; Lehr, Carina; Regenhardt, Judith; Bokemeyer, Carsten; Beckmann, Lennart; Langer, Florian.
In: J THROMB HAEMOST, Vol. 22, No. 1, 01.2024, p. 199-212.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Effect of factor XI inhibition on tumor cell-induced coagulation activation
AU - Mäder, Jonathan
AU - Rolling, Christina C
AU - Voigtländer, Minna
AU - Schulenkorf, Anita
AU - Lehr, Carina
AU - Regenhardt, Judith
AU - Bokemeyer, Carsten
AU - Beckmann, Lennart
AU - Langer, Florian
N1 - Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.
PY - 2024/1
Y1 - 2024/1
N2 - BACKGROUND: Cancer-associated thrombosis is a frequent complication in patients with malignancies. While factor XI (FXI)/FXIa inhibition is efficacious in preventing postoperative venous thromboembolism, its role in tumor cell-induced coagulation is less defined.OBJECTIVES: We thus aimed to provide mechanistic insights into FXI/FXIa inhibition in tumor cell-induced coagulation activation.METHODS: Procoagulant activity (PCA) of 4 different tissue factor (TF) expressing tumor cell lines was analyzed by single-stage clotting and thrombin generation assay in the presence of a FXIa inhibitor, BMS-262084 (BMS), an inhibitory FXI antibody (anti-FXI), or peak and trough concentrations of rivaroxaban or tinzaparin. Further, tumor cell-induced platelet aggregation was recorded. Recombinant human TF served as positive control.RESULTS: Although BMS and anti-FXI potently inhibited FXIa amidolytic activity, both inhibitors efficiently mitigated recombinant human TF- and tumor cell-induced fibrin clot formation and platelet aggregation only in the presence of low TF PCA. The anticoagulant effects showed an inverse correlation with the magnitude of cellular TF PCA expression. Similarly, BMS markedly interfered with tumor cell-induced thrombin generation, with the most prominent effects on peak and total thrombin. In addition, anticoagulant effects of FXIa inhibition by 10 μM BMS were in a similar range to those obtained by 600 nM rivaroxaban and 1.6 μM tinzaparin at low TF PCA levels. However, rivaroxaban and tinzaparin also exerted marked anticoagulant activity at high TF PCA levels.CONCLUSION: Our findings indicate that FXI/FXIa inhibition interferes with tumor cell-induced coagulation activation only at low TF PCA expression levels, a finding with potential implications for future in vivo studies.
AB - BACKGROUND: Cancer-associated thrombosis is a frequent complication in patients with malignancies. While factor XI (FXI)/FXIa inhibition is efficacious in preventing postoperative venous thromboembolism, its role in tumor cell-induced coagulation is less defined.OBJECTIVES: We thus aimed to provide mechanistic insights into FXI/FXIa inhibition in tumor cell-induced coagulation activation.METHODS: Procoagulant activity (PCA) of 4 different tissue factor (TF) expressing tumor cell lines was analyzed by single-stage clotting and thrombin generation assay in the presence of a FXIa inhibitor, BMS-262084 (BMS), an inhibitory FXI antibody (anti-FXI), or peak and trough concentrations of rivaroxaban or tinzaparin. Further, tumor cell-induced platelet aggregation was recorded. Recombinant human TF served as positive control.RESULTS: Although BMS and anti-FXI potently inhibited FXIa amidolytic activity, both inhibitors efficiently mitigated recombinant human TF- and tumor cell-induced fibrin clot formation and platelet aggregation only in the presence of low TF PCA. The anticoagulant effects showed an inverse correlation with the magnitude of cellular TF PCA expression. Similarly, BMS markedly interfered with tumor cell-induced thrombin generation, with the most prominent effects on peak and total thrombin. In addition, anticoagulant effects of FXIa inhibition by 10 μM BMS were in a similar range to those obtained by 600 nM rivaroxaban and 1.6 μM tinzaparin at low TF PCA levels. However, rivaroxaban and tinzaparin also exerted marked anticoagulant activity at high TF PCA levels.CONCLUSION: Our findings indicate that FXI/FXIa inhibition interferes with tumor cell-induced coagulation activation only at low TF PCA expression levels, a finding with potential implications for future in vivo studies.
U2 - 10.1016/j.jtha.2023.09.015
DO - 10.1016/j.jtha.2023.09.015
M3 - SCORING: Journal article
C2 - 37751848
VL - 22
SP - 199
EP - 212
JO - J THROMB HAEMOST
JF - J THROMB HAEMOST
SN - 1538-7933
IS - 1
ER -