The Effect of Antiplatelet Medications on Innate Immune Activation

血小板是参与形成导致心脏病发作的血凝块的主要血细胞类型。我们给予抗血小板药物（例如阿司匹林），以降低另一个血栓形成和导致另一次心脏病发作的风险。血小板也已知在炎症和感染中起作用。在最近一项针对心脏病发作患者的大型临床试验（称为PLATO研究）中，与以前的标准治疗（氯吡格雷）相比，使用新的抗血小板药物（替格瑞洛）治疗的患者发生肺部感染较少，心脏病发作也较少。有证据表明，这可能部分地解释了当替格瑞洛代替氯吡格雷时心脏病发作后死亡风险降低的原因，因此我假设替格瑞洛和氯吡格雷对免疫反应有不同的影响，这部分是由于它们对血小板受体的不同影响，部分是由于与血小板受体无关的机制。因此，我计划研究替格瑞洛和其他抗血小板药物对免疫反应的影响。这可能有助于我们进一步改善心脏病发作后患者的治疗，并有前景开发对免疫反应有更好效果的新药。迄今为止，还没有发表过直接研究替格瑞洛对免疫反应影响的研究。在第一项研究中，我将从健康志愿者中抽取血液，详细检查抗血小板药物对白色血细胞的影响，因为它们是参与免疫反应的主要细胞类型。我将研究在血液中加入这些抗血小板药物是否会影响白色血细胞表面活化标志物及其对感染区域的定位能力。我还将研究抗血小板药物是否影响白色血细胞消耗和杀死细菌的能力。我将评估抗血小板药物是否会干扰血小板与白色血细胞的相互作用。我将通过比较替格瑞洛与其他影响相同途径的药物的作用，确定替格瑞洛是否通过其已知的作用机制影响白色血细胞。通过在有血小板和无血小板的情况下进行实验，我还将确定替格瑞洛的作用是否是由于其对血小板的影响及其随后与白色血细胞的相互作用，或者它是否直接作用于白色血细胞。在第二项研究中，我将调查抗血小板药物对健康志愿者免疫反应的影响。30名健康志愿者将随机接受替格瑞洛、氯吡格雷或不接受抗血小板药物治疗一周（每组10名参与者）。然后，他们将参加谢菲尔德临床研究机构，在那里我将使用安全、完善的方法，将非常低剂量的内毒素（细菌的一种成分，而不是真正的细菌）注射到血液中，以刺激免疫反应。我将通过测量替格瑞洛或氯吡格雷对炎症标志物、白色血细胞功能以及血小板与白色血细胞相互作用的影响来研究它们是否影响这种免疫反应。我将利用第一项研究的发现来指导对白色血细胞功能的哪些方面进行详细检查。第三项研究将涉及即将接受支架植入术治疗狭窄冠状动脉的冠状动脉疾病患者。这些患者通常在手术前开始使用氯吡格雷。我将在开始使用氯吡格雷之前和之后一周采集血液。我将研究开始使用氯吡格雷是否会引起患者免疫反应的任何变化，特别是白色血细胞的功能及其与血小板的相互作用。我还将详细探讨对白色血细胞功能的影响，以我第一项研究的结果为指导。

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.