Hemostatic efficacy of marstacimab alone or in combination with bypassing agents in hemophilia plasmas and a mouse bleeding model

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 und...

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Bibliographic Details
Published in:Research and practice in thrombosis and haemostasis 2022-02, Vol.6 (2), p.e12679-n/a, Article e12679
Main Authors: Pittman, Debra D., Rakhe, Swapnil, Bowley, Sheryl R., Jasuja, Reema, Barakat, Amey, Murphy, John E.
Format: Article
Language:English
Subjects:
blood coagulation
Blood platelets
Chloride
Hemophilia
hemophilia A
hemophilia B
lipoprotein‐associated coagulation inhibitor
Monoclonal antibodies
Original
Plasma
Reagents
tissue factor pathway inhibitor
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Summary: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 (p 
ISSN:2475-0379
2475-0379
DOI:10.1002/rth2.12679