Abstract Number: PB1179
Meeting: ISTH 2020 Congress
Background: Restoring the hemostatic equilibrium by targeting the anticoagulant, TFPI shows tremendous promise for hemophilia. Because of the mechanism of action, it is plausible that this strategy could also fill the unmet need for treating other rare bleeding disorders. Our in vitro data indicate that modulating TFPI activity is potentially effective in restoring hemostatic activity in some human factor deficient plasmas.
Aims: To explore the in vivo therapeutic advantage of blocking TFPI function in the background of a specific clotting factor deficiency, e.g. coagulation factor VII (FVII).
Methods: To generate FVII-deficient mice, wild-type (wt) mice were treated with a single dose of a liver targeted antisense oligonucleotide (ASO) to knockdown plasma FVII (ASO-FVII; 40 mg/kg).
Results: The almost complete lack of plasma FVII (< 1% levels of baseline) substantially increased the clot time (n=5; p< 0.0001) and impaired thrombin generation vs. wt mice. Injection of a monoclonal TFPI antibody (ab) against kunitz-2 domain (1-5 mg/kg) in ASO-FVII mice
(n=3-5; p< 0.005) resulted in a dose-dependent reduction of the prolonged clot time. To assess efficacy, we used two bleeding models and monitored blood loss in ASO-FVII mice (n=3-5) injected with PBS or TFPI ab (0.5-5 mg/kg). We found that ASO-FVII mice exhibited a ~6-fold (p< 0.005) increase in blood loss vs. wt; however, administration of TFPI ab (p< 0.005) reduced the bleeding phenotype in ASO-FVII mice in a dose-dependent manner. Intravital microcopy studies showed that ASO-FVII mice (n=3) displayed considerably impaired thrombus formation following vascular injury. In contrast, infusion of TFPI ab (2.5 mg/kg) into ASO-FVII mice produced an increase in both platelet and fibrin accumulation after injury.
Conclusions: Our data indicate that modulating TFPI activity mitigates bleeding and restores clot formation in a mouse model of bleeding disorders. TFPI inhibition thus represents a potential alternative therapeutic strategy to enhance hemostasis in some rare bleeding disorders.
To cite this abstract in AMA style:Ivanciu L, Crosby JR, Revenko AS, Davidson RJ, Camire RM. Blocking Tissue Factor Pathway Inhibitor (TFPI) Function Has a Therapeutic Benefit in Murine Models of Factor Deficiencies [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/blocking-tissue-factor-pathway-inhibitor-tfpi-function-has-a-therapeutic-benefit-in-murine-models-of-factor-deficiencies/. Accessed May 18, 2021.
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