Active Heart, Stroke & Blood Cells, Biochemistry & Physiology

Targeting the Fibrinogen αC-Region to Reduce Blood Clotting and Thromboembolism

Funder BHF Charity-funded
Recipient organisation University of Leeds
Funding £1.3M
Period Jan 2024 — Dec 2028

In plain English

AI plain-English summary

Blood clots that break loose and travel through the bloodstream kill thousands of people in the UK each year, and a team of researchers has identified a specific region of a key clotting protein that could be targeted to stop them. The problem is that current blood-thinning drugs can cause dangerous bleeding. The researchers have discovered that a part of the fibrinogen protein called the αC-region controls how stiff a clot becomes, how resistant it is to natural breakdown, and how many red blood cells get trapped inside it. This makes clots more likely to cause blockages. The team now plans to develop small binding proteins called Affimers that latch onto this αC-region and alter clot properties without disabling the entire clotting system. If successful, this work could produce a new class of treatments for venous thromboembolism—the condition where clots form in deep veins and travel to the lungs. Such a therapy might prevent dangerous clots while leaving normal clotting intact, reducing the risk of uncontrolled bleeding that limits current treatments. The researchers will test their best candidates using blood from patients undergoing clot-dissolving therapy for pulmonary embolism, moving toward a preclinical drug candidate.

View original technical description
Research funded by our previous BHF programme has: 1) helped establish fibrin clot structure as risk factor for thromboembolism, and 2) discovered key molecular and cellular mechanisms that regulate clot structure and stability. Our major discoveries show that the fibrinogen αC-region controls clot stability through resistance to fibrinolysis and increased clot stiffness. We further found that the αC-region regulates red blood cell retention in the clot, and that it dictates thrombus growth through interactions with platelet receptor GPVI. We thus hypothesise that the fibrinogen αC-region represents an excellent target for the treatment and prevention of thromboembolism. Affimers are high-affinity binding proteins that are an attractive alternative to antibodies. Our aim is to develop Affimers that bind the αC-region for treatment of venous thromboembolism. αC-targeting Affimers will be characterised for their impact on clot formation, structure and stability using in-vitro and in-vivo models of thromboembolism. Affimers with the most desirable properties will be tested for ex-vivo clot structure and stability using plasma from patients with pulmonary embolism undergoing ultrasound-mediated thrombolysis. Best performing Affimers will be investigated for pharmacokinetic properties and taken further for pharmaceutical development. Combined, these studies will deliver preclinical molecule(s) for the modulation of clot structure to alleviate thromboembolism.

View the original record at the funder ↗

Researchers

Robert Ariens (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Fibrinogen-targeted conformational proteins for identification of the mechanistic pathways controlling fibrin network stability
Conformational proteins to study molecular mechanisms underpinning GPVI-fibrin(ogen) interaction in blood clot propagation
Targeting the fibrinogel alphaC Region to Reduce Blood Clotting
Artificial binding proteins for the targeted modulation of fibrin-related thrombosis risk (Miss Katherine Kearney)
Affimers targeting multiple anti-fibrinolytic proteins for the management of the enhanced thrombotic environment in diabetes

Original classification

None

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