The Effect of Antiplatelet Medications on Innate Immune Activation

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Platelets are the main type of blood cell involved in the formation of blood clots that cause heart attacks. We give antiplatelet drugs (aspirin, for example) to reduce the risk of another clot forming and causing another heart attack. Platelets are also known to have a role in inflammation and infection. In a recent large clinical trial of patients with heart attacks, known as the PLATO study, it was shown that patients treated with a new antiplatelet medication (ticagrelor) developed fewer lung infections, as well as fewer heart attacks, compared to the previous standard treatment (clopidogrel). There was evidence that this might partly explain the reduced risk of death after a heart attack when ticagrelor is used instead of clopidogrel.I therefore hypothesise that ticagrelor and clopidogrel have different effects on the immune response, which is, in part, due to their differing effect on platelet receptors and, in part, due to mechanisms unrelated to platelet receptors. I therefore plan to study the effect of ticagrelor and other antiplatelet agents on the immune response. This may help us to further improve the treatment of patients after a heart attack with the prospect of developing new drugs that have a better effect on the immune response. To date, no studies have been published that directly investigate the effect of ticagrelor on the immune response.In the first study, I will take blood from healthy volunteers and examine the effects of antiplatelet agents on white blood cells in detail, as they are the main type of cell involved in the immune response. I will study whether adding these antiplatelet agents to the blood affects white blood cell surface markers of activation and their ability to localise towards areas of infection. I will also study whether antiplatelet agents affect the ability of white blood cells to consume and kill bacteria. I will assess whether or not the antiplatelet agents interfere with platelets interactions with white blood cells. I will determine whether ticagrelor affects white blood cells through its known mechanisms of action by comparing its effects to other agents that also affect the same pathways. By performing the experiments in the presence and absence of platelets, I will also determine whether ticagrelor's effects are due to its effects on platelets and their subsequent interaction with white blood cells or whether it acts directly on white blood cells.In the second study, I will investigate the effect of antiplatelet medications on the immune response of healthy volunteers. Thirty healthy volunteers will be randomised to take ticagrelor, clopidogrel or no antiplatelet medication for one week (ten participants in each group). They will then attend the Sheffield Clinical Research Facility where I will use the safe, well-established method of injection of a very low dose of endotoxin (a component of bacteria rather than actual bacteria) into the bloodstream to stimulate an immune response. I will study whether ticagrelor or clopidogrel affect this immune response by measuring their effect on inflammatory markers, white blood cell function and the interaction of platelets with white blood cells. I will use the findings from my first study to guide which aspects of white blood cell function to examine in detail.The third study will involve patients with coronary artery disease who are due to undergo a stenting procedure to treat their narrowed coronary arteries. These patients are often started on clopidogrel prior to the procedure. I will take blood before and one week after the initiation of clopidogrel. I will study whether initiating clopidogrel causes any changes in patients' immune response, particularly the function of white blood cells and their interactions with platelets. I will also explore effects on white blood cell function in detail, guided by the findings from my first study.