https://doi.org/10.4081/btvb.2023.89
Influence of emicizumab on protein C-mediated clotting regulation
Submitted: 20 July 2023
Accepted: 21 September 2023
Published: 25 October 2023
Accepted: 21 September 2023
Abstract Views: 1833
PDF: 186
Supplementary Material: 34
Supplementary Material: 34
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Emicizumab, a FVIII-mimetic bispecific antibody, is insensitive to degradation by activated protein C (APC) and may thus induce a procoagulant state. We investigated the effect of emicizumab on protein C-mediated inhibition of coagulation under in vitro conditions mimicking physiological and pathological clotting activation. Thrombin generation (TG) in tissue factor-triggered hemophilic plasma containing emicizumab (50 μg/mL) was inhibited by APC or thrombomodulin in a concentration-dependent manner, and to a similar extent as in plasma added with FVIII (Kovaltry, 1 IU/mL). However, when clotting was activated via the intrinsic pathway, emicizumab-plasma displayed resistance to APC, manifested by a barely detectable prolongation of the lag time of TG, and by the lack of inhibition of FXa generation. Moreover, in contact-activated plasma added with APC, the generation of a second wave of thrombin, following prothrombin replenishment, was much greater in emicizumab-plasma than in Kovaltry-plasma, suggesting that the insensitivity of emicizumab to APC may translate in greater thrombin formation. Considering the major role played by the contact system in the thrombotic process, hemophilia A patients under emicizumab treatment might be at increased thrombotic risk.
Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017;377:809-18.
DOI: https://doi.org/10.1056/NEJMoa1703068
Mahlangu JN, Oldenburg J, Paz-Priel I, et al. Emicizumab prophylaxis in patients who have hemophilia A without Inhibitors. N Engl J Med 2018;379:811-22.
DOI: https://doi.org/10.1056/NEJMoa1803550
Kitazawa T, Igawa T, Sampei Z, et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med 2012;18:1570-4.
DOI: https://doi.org/10.1038/nm.2942
Lenting PJ, Denis CV, Christophe OD. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII? Blood 2017;130:2463-68.
DOI: https://doi.org/10.1182/blood-2017-08-801662
Esmon CT. The protein C pathway. Chest 2003;124:26s-32s.
DOI: https://doi.org/10.1378/chest.124.3_suppl.26S
Bertina RM, Koeleman BP, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64-7.
DOI: https://doi.org/10.1038/369064a0
Nicolaes GA, Dahlbäck B. Factor V and thrombotic disease: description of a janus-faced protein. Arterioscler Thromb Vasc Biol 2002;22:530-8.
DOI: https://doi.org/10.1161/01.ATV.0000012665.51263.B7
Dahlbäck B, Villoutreix BO. Regulation of Blood Coagulation by the Protein C Anticoagulant Pathway. Arterioscler Thromb Vasc Biol 2005;25:1311-20.
DOI: https://doi.org/10.1161/01.ATV.0000168421.13467.82
Shen L, Dahlbäck B. Factor V and protein S as synergistic cofactors to activated protein C in degradation of factor VIIIa. J Biol Chem 1994;269:18735-8.
DOI: https://doi.org/10.1016/S0021-9258(17)32228-7
Wilhelm AR, Parsons NA, Samelson-Jones BJ, et al. Activated protein C has a regulatory role in factor VIII function. Blood 2021;137:2532-43.
DOI: https://doi.org/10.1182/blood.2020007562
de Visser MC, Rosendaal FR, Bertina RM. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood 1999;93:1271-6.
DOI: https://doi.org/10.1182/blood.V93.4.1271
Laffan MA, Manning R. The influence of factor VIII on measurement of activated protein C resistance. Blood Coagul Fibrinolysis 1996;7:761-5.
DOI: https://doi.org/10.1097/00001721-199611000-00003
Kyrle PA, Minar E, Hirschl M, et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000;343:457-62.
DOI: https://doi.org/10.1056/NEJM200008173430702
Yada K, Nogami K, Shinozawa K, et al. Emicizumab-mediated haemostatic function in patients with haemophilia A is down-regulated by activated protein C through inactivation of activated factor V. Br J Haematol 2018;183:257-66.
DOI: https://doi.org/10.1111/bjh.15525
Hemker HC, Al Dieri R, De Smedt E, Béguin S. Thrombin generation, a function test of the haemostatic-thrombotic system. Thromb Haemost 2006;96:553-61.
DOI: https://doi.org/10.1160/TH06-07-0408
Ammollo CT, Semeraro F, Incampo F, et al. Dabigatran enhances clot susceptibility to fibrinolysis by mechanisms dependent on and independent of thrombin-activatable fibrinolysis inhibitor. J Thromb Haemost 2010;8:790-8.
DOI: https://doi.org/10.1111/j.1538-7836.2010.03739.x
Muczynski V, Smith A, Sefiane T, et al. A FVIII-Mimetic Bispecific Antibody with an Embedded Self-Regulation Mechanism Reduces the Risk of Prothrombotic Events for the Treatment of Haemophilia A. Blood 2022;140:677-8.
DOI: https://doi.org/10.1182/blood-2022-169482
Grover SP, Mackman N. Intrinsic Pathway of Coagulation and Thrombosis. Arterioscler Thromb Vasc Biol 2019;39:331-8.
DOI: https://doi.org/10.1161/ATVBAHA.118.312130
Fredenburgh JC, Weitz JI. News at XI: moving beyond factor Xa inhibitors. J Thromb Haemost 2023;21:1692-702.
DOI: https://doi.org/10.1016/j.jtha.2023.04.021
How to Cite
Mancazzo, F., Vitulli, A., Dirienzo, L., Ammollo, C. T., Semeraro, F., & Colucci, M. (2023). Influence of emicizumab on protein C-mediated clotting regulation. Bleeding, Thrombosis and Vascular Biology, 2(4). https://doi.org/10.4081/btvb.2023.89
Copyright (c) 2023 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Similar Articles
- Maria Barca-Hernando, Victor Garcia-Garcia, Luis Jara-Palomares, Location of metastasis and complications in patients with venous thromboembolism and cancer: systematic review , Bleeding, Thrombosis and Vascular Biology: Vol. 3 No. s1 (2024): 12th ICTHIC
- Mehrie H. Patel, Alok A. Khorana, New drugs, old problems: immune checkpoint inhibitors and cancer-associated thrombosis , Bleeding, Thrombosis and Vascular Biology: Vol. 3 No. s1 (2024): 12th ICTHIC
- Paolo Prandoni, New perspectives for prevention of the post-thrombotic syndrome , Bleeding, Thrombosis and Vascular Biology: Vol. 1 No. 1 (2022)
- Rushad Patell, Jeffrey I. Zwicker, Rohan Singh, Simon Mantha, Machine learning in cancer-associated thrombosis: hype or hope in untangling the clot , Bleeding, Thrombosis and Vascular Biology: Vol. 3 No. s1 (2024): 12th ICTHIC
- Ottavia Borghese, Claudio Vincenzoni, Commentary on “Preventive percutaneous coronary intervention versus optimal medical therapy alone for the treatment of vulnerable atherosclerotic coronary plaques (PREVENT): a multicenter, open-label, randomized controlled trial” , Bleeding, Thrombosis and Vascular Biology: Vol. 3 No. 2 (2024)
- Gianfranco De Girolamo, Luca Sarti, Sonia Cecoli, Karin Bonora, Chiara Ajolfi, Francesco Bellelli, Valeria Coluccio, Gualtiero Palareti, Marco Marietta, Safety and efficacy of treatment with vitamin K antagonists in patients managed in a network of anticoagulation services or as routine general care , Bleeding, Thrombosis and Vascular Biology: Vol. 1 No. 1 (2022)
- Benedetta Izzi, Simona Costanzo, Alessandro Gialluisi, Amalia De Curtis, Sara Magnacca, Teresa Panzera, Augusto Di Castelnuovo, Maria Benedetta Donati, Chiara Cerletti, Marc F. Hoylaerts, Giovanni de Gaetano, Licia Iacoviello, *on behalf of the Moli-sani Study Investigators, Platelet distribution width is associated with cardiovascular mortality in an adult general population , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 3 (2023)
- Luca Barcella, Chiara Ambaglio, Paolo Gritti, Francesca Schieppati, Varusca Brusegan, Eleonora Sanga, Marina Marchetti, Luca Lorini, Anna Falanga, Long-term persistence of high anti-PF4 antibodies titer in a challenging case of AZD1222 vaccine-induced thrombotic thrombocytopenia , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 2 (2023)
- Marwa Eltemamy, Robert Namushi, Narayanamoorthi Saravanan, Importance of assessment of carotid plaques in the managementof acute ischemic stroke: floating intracarotid plaque , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 3 (2023)
- Daniela Poli, Walter Ageno, Emilia Antonucci, Salvatore Bradamante, Eugenio Bucherini, Paolo Chiarugi, Antonio Chistolini, Benilde Cosmi, Anna Falanga, Antonio Insana, Domenico Lione, Rosa Maria Lombardi, Giuseppe Malcangi, Rossella Marcucci, Giuliana Martini, Lucilla Masciocco, Carmelo Paparo, Daniele Pastori, Simona Pedrini, Vittorio Pengo, Pasquale Pignatelli, Andrea Toma, Sophie Testa, Gualtiero Palareti, Management of anticoagulation in atrial fibrillation patients in Italy: insight from the Atrial Fibrillation-Survey on Anticoagulated Patients Register (AF-START) , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 2 (2023)
You may also start an advanced similarity search for this article.
