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Anti TFPI for Hemostasis Induction in Patients with Rare Bleeding Disorders, an ex vivo Thrombin Generation (TG) Guided Study

T. Brutman-Barazani1, E. Avishai1, I. Budnik2, A.A. Barg1, S. Levi-Mendelovich1, T. Livnat1, G. Kenet1

1Sheba Medical Center, Tel Hashomer, Israel, 2Sechenov University, Moscow, Russian Federation

Abstract Number: PB0135

Meeting: ISTH 2021 Congress

Theme: Coagulation and Natural Anticoagulants » Tissue Factor Pathway

Background: Rare bleeding disorders (RBD) are inherited coagulopathies with variable bleeding phenotype, whose hemostatic control is based upon replacement therapy. Marstacimab (PF-06741086) is a fully human monoclonal IgG that targets the Kunitz2 domain of tissue factor pathway inhibitor [TFPI].  PF-06741086 is currently in development for bleeding prophylaxis in patients with hemophilia.

Aims: To assess the potential impact of PF-06741086 upon thrombin generation (TG) in RBD patients’ plasma samples.

Methods: Citrated samples from RBD patients were collected and processed into platelet poor plasma (PPP) or platelet rich plasma (PRP). Samples were spiked with 150 µg/ ml of PF-06741086 and incubated for 30 minutes. TG was measured by calibrated automated thrombogram and compared to baseline samples and normal controls.

Results: Our study cohort included 20 RBD patients, with severe deficiencies: 5 VWD type 3, 4 FVII, 3 FXI, 2 FXIII deficiency and 1 patient with each of the following: FX, FV+FVIII, Fibrinogen, combined vitamin K dependent factors’ deficiency, Glanzman thrombasthenia and Bernard Soulier. Figure 1 shows representative TG curves before and after spiking with PF-06741086. Among all patients a significantly reduced baseline TG was observed as compared to controls. Improvement of TG (lag time, peak and ETP) was observed in PF-06741086 spiked samples from 8 min, 99nM, 1116 nM/min to 5.5 min, 194 nM,1614 nM/min, respectively- see Figure 2.  Notably, when PF-06741086 was added to normal controls’ PPP, no significant TG increase was noted.  None of the values measured among RBD patients exceeded normal controls.

Conclusions: These in vitro data suggest that PF-06741086 may serve as a promising approach for restoring the hemostatic balance and correction of TG in various RBD.

 
TG curves before and after spiking with PF-06741086.
 
 
PF-06741086 induced TG improvement in RBD patients’ plasma

To cite this abstract in AMA style:

Brutman-Barazani T, Avishai E, Budnik I, Barg AA, Levi-Mendelovich S, Livnat T, Kenet G. Anti TFPI for Hemostasis Induction in Patients with Rare Bleeding Disorders, an ex vivo Thrombin Generation (TG) Guided Study [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/anti-tfpi-for-hemostasis-induction-in-patients-with-rare-bleeding-disorders-an-ex-vivo-thrombin-generation-tg-guided-study/. Accessed August 19, 2022.

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