Date of Award
MD (Medical Doctor)
Professor Dermot Kenny
Professor Geraldine McCarthy
Abbvie Pharmaceuticals (Ireland)
Platelet Function, Inflammation, Cardiovascular Risk
Patients with inflammatory arthritis (IA) are at increased risk of adverse cardiovascular events. While traditional risk factors are important, recent evidence highlights the key role of inflammation in cardiovascular disease (CVD). Platelets play a key patho-physiological role in the complex chain of events leading to the occlusion of a coronary artery. To date, platelet function in the IA population has been poorly investigated.
We examined platelet function in patients with IA and assessed the influence of disease activity on platelet reactivity. Our data demonstrate an enhanced platelet response, unique to ADP stimulation, in patients with inflammatory arthritis whose disease is poorly controlled. Remarkably there was no difference in platelet reactivity noted in response to any of the other agonists tested (arachidonic acid, collagen, epinephrine, and TRAP).
Using both ex vivo measures of platelet function and in vitro assays we then investigated the amplifying effect of several pro-inflammatory cytokines (IL-1b, IL-6, anti-TNFaand IL17a) on the platelet ADP pathway and also found a decreased platelet ADP response in patients with previously refractory disease who were treated with the IL-6 inhibitor tocilizumab.
Following our observation of an, heretofore unknown, inhibitory effect of sulfasalazine therapy on platelet aggregation, we subsequently demonstrate that this is due to both the parent compound and its metabolites, and confined to the arachidonic acid pathway.
Finally, we prospectively assessed the impact of improved disease control with anti-TNFaagents on platelet function, insulin metabolism, and cholesterol levels in patients with IA. We found patients who respond to anti-TNFatherapy also achievea normalization of platelet function and decreased insulin resistance, with no change in lipid profile.
Taken together, these findings offer novel mechanistic insights into how inflammation and its treatment influences platelet function and CVD risk in this vulnerable patient population, for whom anti-platelet guidelines are currently lacking.
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MacMullan P. Platelet Function in Inflammatory Arthritis [MD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2018.