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Characterising the role of inflammatory procoagulant phospholipids in arterial thrombosis

Protty, Majd 2021. Characterising the role of inflammatory procoagulant phospholipids in arterial thrombosis. PhD Thesis, Cardiff University.
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Abstract

Arterial thrombosis is an inflammatory response triggered by atherosclerotic plaque rupture causing acute coronary syndromes (ACS), strokes and death. Clotting reactions require interactions of coagulation proteins with aminophospholipids (aPL) and enzymatically oxidized phospholipids (eoxPL) on the surface of blood cells. This thesis investigates the role of aPL and eoxPL in arterial thrombosis. Using liquid chromatography with tandem mass spectrometry (LC-MS/MS), I quantified eoxPL generated in thrombin-activated platelets from a healthy cohort and demonstrated a large degree of inter- and intra-individual variation. Aspirin supplementation in-vivo reduced the amount of COX-1 derived eoxPL, but increased diacyl 12 hydroxyeicosatetraenoic acid (12-HETE) containing eoxPL (12-HETE-PL) generation without affecting the levels of free 12-HETE. This suggests that aspirin interferes with re-esterification pathways of 12-HETE to acyl lysophospholipids. Lipidomic analysis of arterial thrombi extracted from patients undergoing clot retrieval procedures demonstrated the presence of HETE-PL, with a predominance of platelet-derived 12-HETE-PL. Using a clinical cohort, I demonstrated elevated thrombin generation on the surface of isolated EV and leukocytes, but not platelets, from patients with ACS versus healthy controls (HC). Lipidomic analysis demonstrated no differences between groups in HETE-PL amounts from resting platelets, leukocytes and EV. Nevertheless, as seen with the healthy cohort, thrombin-activated platelets from patients supplemented with aspirin had higher diacyl 12-HETE-PL generation. Finally, there were no differences in the fraction (%) externalized phosphatidylethanolamine (%PE) on the surface of platelets and leukocytes across the groups. However, EV samples had lower %PE in ACS versus HC which, unlike platelets and leukocytes, correlated inversely with thrombin generation. In summary, eoxPL were detected within arterial thrombi and their synthesis is increased with aspirin. Thrombin generation is higher on the surface of EV from ACS patients, which may be explained by differences in the aPL lipidome between groups. Further studies examining therapeutic agents targeting procoagulant lipids are needed.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 21 June 2021
Last Modified: 21 Jun 2021 14:26
URI: http://orca.cardiff.ac.uk/id/eprint/142032

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