Completed Heart, Stroke & Blood Cells, Biochemistry & Physiology

Protein S-TFPI anticoagulant pathway:- molecular mechanisms and therapeutic potential.

Funder BHF Charity-funded
Recipient organisation Imperial College London
Funding £1.4M
Period Oct 2018 — Oct 2023

In plain English

AI plain-English summary

Blood clots that form inside blood vessels can cause heart attacks and strokes, and the body’s own defence against this relies on a protein called TFPI, which needs a helper called protein S to work properly. Exactly how this pair stops clotting has remained unclear, partly because mice lacking either protein die before birth, making them impossible to study. This project will fill that gap by building new laboratory tools to watch TFPI and protein S in action under flowing blood, and by solving the atomic structure of key parts of protein S to see how it grips TFPI. The team will also create a genetically modified mouse line that survives with a subtly altered protein S, allowing them to test the pathway’s role in living animals for the first time. If successful, this fundamental science could reveal a new way to prevent dangerous clots without the bleeding risks of current drugs. The researchers will also test whether injecting antibodies that extend TFPI’s lifespan in the bloodstream can safely boost the body’s natural clot-stopping power—a potential future treatment for thrombosis.

View original technical description
The TFPI anticoagulant pathway inhibits the initiation of coagulation, and is essential for the regulation of haemostasis and prevention of thrombotic events. TFPI is highly dependent upon its cofactor, protein S. How this anticoagulant pathway functions physiologically has not been well studied due to the embryonic lethality of Tfpi-/- and Pros1-/- mice. In this programme grant, we shall develop new assays to characterise TFPI/protein S function under flow. We shall elucidate the crystal structure of the protein S LG1/LG2 domains in isolation and in complex with its binding partners, TFPI K3 and C4BP. We shall characterise functional conformational changes in protein S that occur following binding to phospholipids that determine its affinity for TFPI. Using novel mAbs and a novel knock-in mouse line, we shall characterise the anticoagulant actions of the TFPI/protein S pathway in vivo using murine thrombosis models. Finally, we shall explore the therapeutic efficacy of augmenting the TFPI anticoagulant pathway in vivo using non-inhibitory anti-TFPI mAbs that prolong endogenous TFPI plasma ½-life.

View the original record at the funder ↗

Researchers

James Crawley (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

FV-short as a major regulator of TFPI during the initiation of coagulation
Characterisation and function of novel profibrinolytic receptors on the platelet membrane
Characterisation and role of phospholipids in the initiation of coagulation through tissue factor
Artificial binding proteins for the targeted modulation of fibrin-related thrombosis risk (Miss Katherine Kearney)
Fibrin at the interface of platelet activation and thrombus stabilisation

Original classification

None

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.