Abstract Number: PB1034
Meeting: ISTH 2022 Congress
Background: Vitamin K-dependent protein S is an anticoagulant protein functioning as a cofactor in both protein C and TFPI pathways. The Gla-domain of protein S mediates the interaction with negatively charged phospholipid, where it fulfills its anticoagulant activity. Inhibition of anticoagulant pathways is a means to rebalance the haemostatic system in bleeding disorders, offering therapeutic possibilities.
Aims: To investigate whether protein C and TFPI anticoagulant systems in plasma can be inhibited by an in-house monoclonal antibody (mab47) against the Gla-domain of protein S.
Methods: A calcium-dependent mab47 against the Gla-domain of protein S was added to human plasma and the anticoagulant activity of activated protein C (APC) or TFPI tested in a thrombin generation assay (TGA). The effects of the antibody on protein S anticoagulant activity were also tested in purified APC and TFPI systems.
Results: The mab47 was found to efficiently inhibit the anticoagulant activity of both APC and TFPI when included in the TGA. In TGA with added TFPI, the antibody dose-dependently inhibited the anticoagulant effect of TFPI, approximately an equimolar concentration of antibody to protein S was required to neutralise the effect of TFPI. In a FXa-inhibition assay using TFPI, protein S, FV-Short and negatively charged phospholipid, addition of mab47 neutralized the synergistic TFPI-cofactor activity of protein S and FV-Short. In the TGA with added APC (0-20 nM), addition of the mab47 inhibited the anticoagulant effect of APC.
Conclusion(s): We have identified a mab which efficiently inhibits the anticoagulant effect of protein S in both protein C and TFPI anticoagulant pathways. The antibody (mab47) is calcium-dependent and directed against the Gla-domain of protein S. Its mechanism of action is that it inhibits binding of protein S to the negatively charged phospholipid. The antibody has the potential to rebalance the haemostatic system in cases with bleeding disorders.
To cite this abstract in AMA style:Dahlback B. Calcium-dependent monoclonal antibody against Gla-domain of protein S efficiently inhibiting both protein C and TFPI anticoagulant pathways [abstract]. https://abstracts.isth.org/abstract/calcium-dependent-monoclonal-antibody-against-gla-domain-of-protein-s-efficiently-inhibiting-both-protein-c-and-tfpi-anticoagulant-pathways/. Accessed September 24, 2023.
« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/calcium-dependent-monoclonal-antibody-against-gla-domain-of-protein-s-efficiently-inhibiting-both-protein-c-and-tfpi-anticoagulant-pathways/