Hemostatic efficacy of marstacimab alone or in combination with bypassing agents in hemophilia plasmas and a mouse bleeding model.
blood coagulation
hemophilia A
hemophilia B
lipoprotein‐associated coagulation inhibitor
tissue factor pathway inhibitor
Journal
Research and practice in thrombosis and haemostasis
ISSN: 2475-0379
Titre abrégé: Res Pract Thromb Haemost
Pays: United States
ID NLM: 101703775
Informations de publication
Date de publication:
Feb 2022
Feb 2022
Historique:
received:
21
12
2021
accepted:
07
01
2022
entrez:
23
3
2022
pubmed:
24
3
2022
medline:
24
3
2022
Statut:
epublish
Résumé
Patients with hemophilia have deficiencies in intrinsic coagulation factors and can develop inhibitors that limit the effectiveness of replacement coagulation factors. Marstacimab, a human monoclonal antibody, binds and inhibits the human tissue factor pathway inhibitor. Marstacimab is currently under development as a potential prophylactic treatment to prevent bleeding episodes in patients with hemophilia A and B. To assess the effects of marstacimab alone or in combination with the bypassing agent recombinant factor FVIIa (rFVIIa) or activated prothrombin complex concentrate (aPCC) on thrombin generation and bleeding. Marstacimab and/or rFVIIa or aPCC were added to hemophilic A or B plasma or nonhemophilic plasma in vitro. Hemostatic activity was measured using the thrombin generation assay. In vivo effects were assessed using a mouse acute bleeding model. Male hemophilia A mice were dosed with marstacimab plus aPCC before tail clip; blood loss was quantified by measuring hemoglobin. Marstacimab plus rFVIIa or aPCC slightly increased peak thrombin levels compared with either agent alone. This increase was within the reported range for nonhemophilic plasma and did not exceed levels observed in nonhemophilic plasma treated with marstacimab alone. Hemophilia A mice that received 200 U/kg aPCC had significantly reduced bleeding (62%) compared with vehicle-treated mice ( Marstacimab alone or with bypassing agents increased hemostasis in hemophilia plasma without generating excessive thrombin. The hemostatic activity of marstacimab plus aPCC was confirmed in hemophilia A mice.
Sections du résumé
Background
UNASSIGNED
Patients with hemophilia have deficiencies in intrinsic coagulation factors and can develop inhibitors that limit the effectiveness of replacement coagulation factors. Marstacimab, a human monoclonal antibody, binds and inhibits the human tissue factor pathway inhibitor. Marstacimab is currently under development as a potential prophylactic treatment to prevent bleeding episodes in patients with hemophilia A and B.
Objective
UNASSIGNED
To assess the effects of marstacimab alone or in combination with the bypassing agent recombinant factor FVIIa (rFVIIa) or activated prothrombin complex concentrate (aPCC) on thrombin generation and bleeding.
Methods
UNASSIGNED
Marstacimab and/or rFVIIa or aPCC were added to hemophilic A or B plasma or nonhemophilic plasma in vitro. Hemostatic activity was measured using the thrombin generation assay. In vivo effects were assessed using a mouse acute bleeding model. Male hemophilia A mice were dosed with marstacimab plus aPCC before tail clip; blood loss was quantified by measuring hemoglobin.
Results
UNASSIGNED
Marstacimab plus rFVIIa or aPCC slightly increased peak thrombin levels compared with either agent alone. This increase was within the reported range for nonhemophilic plasma and did not exceed levels observed in nonhemophilic plasma treated with marstacimab alone. Hemophilia A mice that received 200 U/kg aPCC had significantly reduced bleeding (62%) compared with vehicle-treated mice (
Conclusions
UNASSIGNED
Marstacimab alone or with bypassing agents increased hemostasis in hemophilia plasma without generating excessive thrombin. The hemostatic activity of marstacimab plus aPCC was confirmed in hemophilia A mice.
Identifiants
pubmed: 35316941
doi: 10.1002/rth2.12679
pii: S2475-0379(22)01170-0
pmc: PMC8925002
doi:
Types de publication
Journal Article
Langues
eng
Pagination
e12679Informations de copyright
© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.
Références
Haemophilia. 2013 Jan;19(1):e1-47
pubmed: 22776238
Blood Coagul Fibrinolysis. 2007 Oct;18(7):677-84
pubmed: 17890956
Thromb J. 2015 Jan 23;13(1):4
pubmed: 25635172
J Thromb Haemost. 2018 Nov;16(11):2246-2257
pubmed: 30194803
Haemophilia. 2016 Jul;22(4):615-24
pubmed: 26879158
Pathophysiol Haemost Thromb. 2003;33(1):4-15
pubmed: 12853707
J Thromb Haemost. 2009 Sep;7(9):1517-22
pubmed: 19566792
J Thromb Haemost. 2018 Sep;16(9):1722-1731
pubmed: 29908043
Nature. 1989 Apr 6;338(6215):518-20
pubmed: 2927510
Nat Biotechnol. 2011 Oct 23;29(11):1028-33
pubmed: 22020385
Haemophilia. 2019 Sep;25(5):797-806
pubmed: 31336410
Curr Opin Hematol. 2014 Sep;21(5):395-403
pubmed: 25054908
Haemophilia. 2004 Sep;10 Suppl 2:3-9
pubmed: 15385040
Blood Transfus. 2013 Apr;11(2):178-82
pubmed: 22790275
Blood. 1988 Dec;72(6):2020-5
pubmed: 3143429
J Thromb Haemost. 2018 Jun 11;:
pubmed: 29888855
N Engl J Med. 2017 Aug 31;377(9):809-818
pubmed: 28691557
J Biol Chem. 1998 Feb 20;273(8):4378-86
pubmed: 9468488
Front Med (Lausanne). 2021 May 05;8:670526
pubmed: 34026796
Blood. 2007 Mar 1;109(5):1931-7
pubmed: 17082321
J Pharm Sci. 2018 Jul;107(7):1995-2004
pubmed: 29571739
J Thromb Haemost. 2015 Jun;13 Suppl 1:S200-7
pubmed: 26149025
Thromb Res. 2016 May;141 Suppl 2:S28-30
pubmed: 27207418
N Engl J Med. 2013 Jan 17;368(3):231-9
pubmed: 23323899
Thromb Haemost. 2005 Mar;93(3):475-80
pubmed: 15735797
Front Biosci (Landmark Ed). 2012 Jan 01;17(1):262-80
pubmed: 22201743
Blood. 2012 Jun 14;119(24):5871-8
pubmed: 22563084