Title: Investigating the role of procoagulant enzymatically oxidized phospholipids in arterial thrombosis using in vivo models
Funder: The Academy of Medical Sciences

Abstract: Enzymatically oxidized phospholipids (eoxPL) generated by circulating blood cells support coagulation reactions. However, their role in arterial thrombosis, such as acute coronary syndrome (ACS), remains poorly understood. Here, I will investigate the role of procoagulant eoxPL, namely hydroxyeicosatetraenoic acid-containing eoxPL (HETE-PL), in mediating arterial thrombosis in genetically modified murine models. This proposal builds on studies from our group and my recently awarded PhD where a role for HETE-PL in enhancing thrombin generation on the surface of platelets and leukocytes was uncovered. Furthermore, lipidomic analysis of human arterial thrombi from patients with ACS and limb ischaemia demonstrated the presence of HETE-PL within clot architecture. Mice which lack the Alox15 gene, and are therefore unable to generate leukocyte 12- and 15-HETE-PL, were protected against arterial thrombosis in a ferric chloride carotid artery injury model. These findings suggest that eoxPL are critical for arterial thrombus formation. I intend to expand on these findings by attempting to rescue the Alox15-/- phenotype of defective thrombosis by injecting liposomes containing 12- and 15-HETE-PL to support my observation. In addition, since platelets are recognized to be the main drivers of arterial thrombosis and the main source of 12-HETE-PL in humans, I plan to investigate whether platelet-specific Alox12-/- mice exhibit a similar impaired thrombosis phenotype to the one I observed with Alox15-/-. Findings from this project may lead to the identification of eoxPL therapeutic targets for the prevention of pathological clotting which continues to be a significant burden of morbidity and mortality worldwide.

Lay abstract: Cardiovascular (heart) disease is the number one cause of death in the UK. Patients who experience a heart attack are at a higher risk of suffering another event, stroke or death. Heart attacks happen as a result of blockages in arteries. These blockages are caused by inflammation (a reaction to a damaging irritant) and lead to activation of blood cells such as white cells (responsible for wound healing) and platelets (responsible for blood clotting) which in turn lead to abnormal clotting and blockages in arteries. Blood clotting happens through interactions of blood proteins with particular fats (phospholipids) that are present on the surface of cells and are linked to inflammation. Their role in driving abnormal clotting events in heart attacks is unknown. If identified, it may serve as a potential new treatment. This is important since one in ten patients who experience a heart attack remain at risk of developing another event, a stroke, or dying despite current treatment. Here, I intend to use mouse models which are deficient in a specific type of phospholipids generated by blood cells, known as ‘enzymatically oxidized phospholipids’, to investigate how they impact clot formation in damaged arteries. This builds on work I carried out during my PhD which demonstrated the presence of these specialized phospholipids within arterial clots from patients with heart attacks. This research aims to identify the drivers of clotting in arteries which may help identify new treatment targets for this disease process.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD;CARDIOVASCULAR