Active Heart, Stroke & Blood

S100A8/A9 as a novel regulator of fibrinolysis in thromboinflammation

Funder BHF Charity-funded
Recipient organisation University of Aberdeen
Funding £289K
Period Nov 2025 — Feb 2028

In plain English

AI plain-English summary

Blood clots in veins become dangerously hard to dissolve when the immune system’s alarm signal S100A8/A9 triggers platelets to release and hold onto a clot-stabilising protein called PAI-1. This matters because venous thrombosis—clotting in deep veins—is common in sepsis, obesity, diabetes, and cancer, and current treatments often fail when inflammation makes clots resistant to breakdown. Researchers know that high levels of PAI-1 and neutrophil NET formation correlate with organ damage, but the direct link between S100A8/A9 and PAI-1 release from platelets has not been tested. The team will use a custom “thrombolysis-on-a-chip” device with blood from healthy donors and patients with deep vein thrombosis to measure how S100A8/A9 alters clot dissolution. They will combine this with an animal model of DVT to test drugs that block PAI-1 or S100A8/A9. If successful, this fundamental science could reveal new drug targets for preventing clot-driven organ damage in inflammatory diseases. The work is mechanistic—it asks how immune cells and platelets talk to each other—but understanding that conversation could eventually lead to therapies that restore the body’s natural ability to clear clots, reducing the need for risky blood thinners.

View original technical description
Venous thrombosis is prevalent in many diseases, including sepsis, obesity, diabetes and cancer and is driven by inflammatory dysregulation of the haemostatic system. Levels of the fibrinolytic inhibitor, PAI-1, and markers of neutrophil NET formation (NETosis) correlate with thromboinflammation and organ damage. The alarmin S100A8/A9 is secreted during NETosis and promotes procoagulant platelet and fibrin formation. Platelets harbour the primary circulating pool of PAI-1, which is partially retained on the procoagulant membrane. We hypothesise that S100A8/A9 provokes PAI-1 release and retention on the platelet membrane, driving a hypofibrinolytic state. In this project we will assess the direct effect of S100A8/A9 on fibrinolysis and downstream effects on PAI-1 externalisation, release and functional activity. Using our novel ‘thrombolysis-on-a-chip’ model with blood from healthy donors and patients with deep vein thrombosis (DVT) we will analyse the functional consequences of the relationship between PAI-1 and S100A8/A9. This will be combined with a translational in vivo model of DVT to test the efficacy of pharmacological approaches to target PAI 1 and S100A8/A9. This project will unravel novel mechanisms by which innate immune cell activation modulate fibrinolysis, through the alarmin S100A8/A9. Importantly, we will identify novel points of interception to dampen these responses in thromboinflammatory conditions.

View the original record at the funder ↗

Researchers

Nicola Mutch (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Understanding the role of neutrophil extracellular traps-associated S100A12 in thrombo-inflammation during sepsis
Platelet Endothelial Aggregation Receptor 1
Affimers targeting multiple anti-fibrinolytic proteins for the management of the enhanced thrombotic environment in diabetes
Immunomodulatory role of platelets ITAM receptors in systemic inflammation and sepsis associated with cardiovascular diseases
Investigation of the functions of formyl peptide receptors in the regulation of thrombosis and haemostasis in pathophysiological conditions

Original classification

None

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