Mechanisms of thrombin inhibition by protein S and the TFPIα-fVshort-protein S complex
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| Format: | Preprint |
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2025
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| _version_ | 1866914197574516736 |
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| author | Ginsberg, Alexander G. Ahnström, Josefin Crawley, James T. B. Leiderman, Karin Monroe, Dougald M. Neeves, Keith B. Sindi, Suzanne F. Fogelson, Aaron L. |
| author_facet | Ginsberg, Alexander G. Ahnström, Josefin Crawley, James T. B. Leiderman, Karin Monroe, Dougald M. Neeves, Keith B. Sindi, Suzanne F. Fogelson, Aaron L. |
| contents | Protein S (PS) is a notable anticoagulant implicated in both bleeding and thrombotic disorders, making it a promising drug target. Importantly, PS enhances the anticoagulant function of TFPI$α$, likely circulating in the bloodstream together with TFPI$α$ and a truncated form of factor V (fVshort) in the trimolecular complex, TFPI$α$-fVshort-PS, which we call protein S complex (PSC). PSC has been proposed to strongly inhibit thrombin production by enhancing the ability of TFPI$α$ to inhibit clotting factor Xa up to 100-fold and by localizing to platelet membranes, limiting fXa activity shortly after coagulation starts.
Yet, exactly how PS functions with TFPI$α$ as an anticoagulant remains poorly understood. To investigate, we extend an experimentally validated mathematical model of blood coagulation to include PSC and free PS (not part of PSC) in the plasma, as well as free PS and TFPI$α$ in platelets. We find that shortly after coagulation initiation, PSC strongly inhibits thrombin production. We find that the (unknown) magnitude of the enhanced affinity of PSC binding to inhibit fXa critically regulates PSC's impact on thrombin production. We find that under flow, PSC can unexpectedly accumulate on platelets to concentrations ~50 times higher than in the plasma. We also find that PSC limits thrombin production by occupying fV-specific binding sites on platelets.
Our results show that changes in PSC can dramatically impact severity of pathological bleeding disorders. For the east Texas bleeding disorder, elevated PSC concentrations eliminate thrombin bursts, leading to bleeding. With fV deficiency, reducing PSC rescues thrombin production in severe fV deficiency and returns thrombin production due to mild fV deficiency to normal. Finally, thrombin production in severe hemophilia A can be substantially improved by blocking PSC's anticoagulant function. |
| format | Preprint |
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arxiv_https___arxiv_org_abs_2512_11495 |
| institution | arXiv |
| publishDate | 2025 |
| record_format | arxiv |
| spellingShingle | Mechanisms of thrombin inhibition by protein S and the TFPIα-fVshort-protein S complex Ginsberg, Alexander G. Ahnström, Josefin Crawley, James T. B. Leiderman, Karin Monroe, Dougald M. Neeves, Keith B. Sindi, Suzanne F. Fogelson, Aaron L. Molecular Networks Tissues and Organs 92-10 Protein S (PS) is a notable anticoagulant implicated in both bleeding and thrombotic disorders, making it a promising drug target. Importantly, PS enhances the anticoagulant function of TFPI$α$, likely circulating in the bloodstream together with TFPI$α$ and a truncated form of factor V (fVshort) in the trimolecular complex, TFPI$α$-fVshort-PS, which we call protein S complex (PSC). PSC has been proposed to strongly inhibit thrombin production by enhancing the ability of TFPI$α$ to inhibit clotting factor Xa up to 100-fold and by localizing to platelet membranes, limiting fXa activity shortly after coagulation starts. Yet, exactly how PS functions with TFPI$α$ as an anticoagulant remains poorly understood. To investigate, we extend an experimentally validated mathematical model of blood coagulation to include PSC and free PS (not part of PSC) in the plasma, as well as free PS and TFPI$α$ in platelets. We find that shortly after coagulation initiation, PSC strongly inhibits thrombin production. We find that the (unknown) magnitude of the enhanced affinity of PSC binding to inhibit fXa critically regulates PSC's impact on thrombin production. We find that under flow, PSC can unexpectedly accumulate on platelets to concentrations ~50 times higher than in the plasma. We also find that PSC limits thrombin production by occupying fV-specific binding sites on platelets. Our results show that changes in PSC can dramatically impact severity of pathological bleeding disorders. For the east Texas bleeding disorder, elevated PSC concentrations eliminate thrombin bursts, leading to bleeding. With fV deficiency, reducing PSC rescues thrombin production in severe fV deficiency and returns thrombin production due to mild fV deficiency to normal. Finally, thrombin production in severe hemophilia A can be substantially improved by blocking PSC's anticoagulant function. |
| title | Mechanisms of thrombin inhibition by protein S and the TFPIα-fVshort-protein S complex |
| topic | Molecular Networks Tissues and Organs 92-10 |
| url | https://arxiv.org/abs/2512.11495 |