Anti-TFPI for hemostasis induction in patients with rare bleeding disorders, an ex vivo thrombin generation (TG) guided pilot study

Assaf A. Barg; Tami Brutman-Barazani; Einat Avishai; Ivan Budnik; Omri Cohen; Rima Dardik; Sarina Levy-Mendelovich; Tami Livnat; Gili Kenet

doi:10.1016/j.bcmd.2022.102663

Anti-TFPI for hemostasis induction in patients with rare bleeding disorders, an ex vivo thrombin generation (TG) guided pilot study

Assaf A. Barg, Tami Brutman-Barazani, Einat Avishai, Ivan Budnik, Omri Cohen, Rima Dardik, Sarina Levy-Mendelovich, Tami Livnat, Gili Kenet

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Background: Rare bleeding disorders (RBD) are inherited coagulopathies, whose hemostatic control is based upon replacement therapy. Marstacimab (PF-06741086) is a human monoclonal IgG that targets the Kunitz2 domain of tissue factor pathway inhibitor [TFPI]. Marstacimab is currently in development for bleeding prophylaxis in patients with hemophilia. Objectives: To assess the potential impact of Marstacimab upon thrombin generation (TG) in RBD patients' plasma samples. Results: Our cohort included 18 RBD patients, with severe deficiencies: 5 Von Willebrand Disease (VWD) type 3, 4 FVII, 3 FXI, 2 FXIII deficiency and 1 patient with: FX, FV + FVIII, Fibrinogen, combined vitamin K dependent factors' deficiency. Citrated samples from RBD patients were collected and spiked with Marstacimab, TG was measured by calibrated automated thrombogram. Among all patients a reduced baseline TG was observed as compared to controls. Improvement of median (lag time, peak and ETP was observed in Marstacimab spiked samples from 8 min, 99 nM, 1116 nMx min to 5.5 min, 194 nM,1614 nMx min, respectively. None of the values measured among RBD patients exceeded normal controls. Conclusion: These in vitro data suggest that Marstacimab may serve as a promising approach for restoring the hemostatic balance in various RBD, though potential clinical implications should be further investigated.

Original language	English
Article number	102663
Journal	Blood Cells, Molecules, and Diseases
Volume	95
DOIs	https://doi.org/10.1016/j.bcmd.2022.102663
State	Published - Jul 2022
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2022

Funding

The authors declare no conflict of interest except Gili Kenet - receives grant and research support from Alnylam, Bayer, BPL, Opko Biologics, Pfizer, Shire and honoraria for consultancy/lectures from Alnylam, Bayer, CSL, Opko Biologics, Pfizer, Takeda and ROCHE. Assaf A. Barg receives honoraria for lectures from ROCHE. The study was supported by an investigator initiated study grant, yet Pfizer company was not involved in study design, data generation and interpretation.

Funders	Funder number
Alnylam
BPL
Pfizer
Bayer
Roche
Takeda Pharmaceutical Company
Shire
Commonwealth Serum Laboratories

Keywords

Marstacimab (PF-06741086)
Rare bleeding disorders
TFPI
Thrombin- generation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bcmd.2022.102663

Cite this

Barg, A. A., Brutman-Barazani, T., Avishai, E., Budnik, I., Cohen, O., Dardik, R., Levy-Mendelovich, S., Livnat, T., & Kenet, G. (2022). Anti-TFPI for hemostasis induction in patients with rare bleeding disorders, an ex vivo thrombin generation (TG) guided pilot study. Blood Cells, Molecules, and Diseases, 95, Article 102663. https://doi.org/10.1016/j.bcmd.2022.102663

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abstract = "Background: Rare bleeding disorders (RBD) are inherited coagulopathies, whose hemostatic control is based upon replacement therapy. Marstacimab (PF-06741086) is a human monoclonal IgG that targets the Kunitz2 domain of tissue factor pathway inhibitor [TFPI]. Marstacimab is currently in development for bleeding prophylaxis in patients with hemophilia. Objectives: To assess the potential impact of Marstacimab upon thrombin generation (TG) in RBD patients' plasma samples. Results: Our cohort included 18 RBD patients, with severe deficiencies: 5 Von Willebrand Disease (VWD) type 3, 4 FVII, 3 FXI, 2 FXIII deficiency and 1 patient with: FX, FV + FVIII, Fibrinogen, combined vitamin K dependent factors' deficiency. Citrated samples from RBD patients were collected and spiked with Marstacimab, TG was measured by calibrated automated thrombogram. Among all patients a reduced baseline TG was observed as compared to controls. Improvement of median (lag time, peak and ETP was observed in Marstacimab spiked samples from 8 min, 99 nM, 1116 nMx min to 5.5 min, 194 nM,1614 nMx min, respectively. None of the values measured among RBD patients exceeded normal controls. Conclusion: These in vitro data suggest that Marstacimab may serve as a promising approach for restoring the hemostatic balance in various RBD, though potential clinical implications should be further investigated.",

keywords = "Marstacimab (PF-06741086), Rare bleeding disorders, TFPI, Thrombin- generation",

author = "Barg, {Assaf A.} and Tami Brutman-Barazani and Einat Avishai and Ivan Budnik and Omri Cohen and Rima Dardik and Sarina Levy-Mendelovich and Tami Livnat and Gili Kenet",

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AU - Barg, Assaf A.

AU - Brutman-Barazani, Tami

AU - Avishai, Einat

AU - Budnik, Ivan

AU - Cohen, Omri

AU - Dardik, Rima

AU - Levy-Mendelovich, Sarina

AU - Livnat, Tami

AU - Kenet, Gili

PY - 2022/7

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N2 - Background: Rare bleeding disorders (RBD) are inherited coagulopathies, whose hemostatic control is based upon replacement therapy. Marstacimab (PF-06741086) is a human monoclonal IgG that targets the Kunitz2 domain of tissue factor pathway inhibitor [TFPI]. Marstacimab is currently in development for bleeding prophylaxis in patients with hemophilia. Objectives: To assess the potential impact of Marstacimab upon thrombin generation (TG) in RBD patients' plasma samples. Results: Our cohort included 18 RBD patients, with severe deficiencies: 5 Von Willebrand Disease (VWD) type 3, 4 FVII, 3 FXI, 2 FXIII deficiency and 1 patient with: FX, FV + FVIII, Fibrinogen, combined vitamin K dependent factors' deficiency. Citrated samples from RBD patients were collected and spiked with Marstacimab, TG was measured by calibrated automated thrombogram. Among all patients a reduced baseline TG was observed as compared to controls. Improvement of median (lag time, peak and ETP was observed in Marstacimab spiked samples from 8 min, 99 nM, 1116 nMx min to 5.5 min, 194 nM,1614 nMx min, respectively. None of the values measured among RBD patients exceeded normal controls. Conclusion: These in vitro data suggest that Marstacimab may serve as a promising approach for restoring the hemostatic balance in various RBD, though potential clinical implications should be further investigated.

AB - Background: Rare bleeding disorders (RBD) are inherited coagulopathies, whose hemostatic control is based upon replacement therapy. Marstacimab (PF-06741086) is a human monoclonal IgG that targets the Kunitz2 domain of tissue factor pathway inhibitor [TFPI]. Marstacimab is currently in development for bleeding prophylaxis in patients with hemophilia. Objectives: To assess the potential impact of Marstacimab upon thrombin generation (TG) in RBD patients' plasma samples. Results: Our cohort included 18 RBD patients, with severe deficiencies: 5 Von Willebrand Disease (VWD) type 3, 4 FVII, 3 FXI, 2 FXIII deficiency and 1 patient with: FX, FV + FVIII, Fibrinogen, combined vitamin K dependent factors' deficiency. Citrated samples from RBD patients were collected and spiked with Marstacimab, TG was measured by calibrated automated thrombogram. Among all patients a reduced baseline TG was observed as compared to controls. Improvement of median (lag time, peak and ETP was observed in Marstacimab spiked samples from 8 min, 99 nM, 1116 nMx min to 5.5 min, 194 nM,1614 nMx min, respectively. None of the values measured among RBD patients exceeded normal controls. Conclusion: These in vitro data suggest that Marstacimab may serve as a promising approach for restoring the hemostatic balance in various RBD, though potential clinical implications should be further investigated.

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Anti-TFPI for hemostasis induction in patients with rare bleeding disorders, an ex vivo thrombin generation (TG) guided pilot study

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

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