血小板功能检测在经皮冠状动脉介入术后抗血小板治疗中的应用进展

阿司匹林联合P2Y12受体拮抗剂双联抗血小板治疗是经皮冠状动脉介入(PCI)术后药物治疗的基石。但抗血小板药物的作用受多种因素的影响,不同个体在接受标准抗血小板治疗方案后的反应性差异与血栓、出血等不良事件显著相关。因此,针对高危血栓或出血患者可行血小板功能学检测,指导个体化抗血小板治疗。但血小板功能检测尚处于探索阶段,存在争议且未得到指南的强烈推荐,其标准化是提高检测结果的准确性和临床应用的指导价值的关键。本文将根据近年循证资料、指南共识和临床经验,对血小板功能检测在PCI术后抗血小板治疗中的应用作一概述。     

血小板功能检测及其临床应用

随着人们生活水平的提高及人口老龄化的出现,心脑血管疾病已成为危害人类健康的第一杀手,其病理基础是动脉硬化及其继发的血栓形成和栓塞,血小板在血栓形成过程中发挥了重要作用。因此,抗血小板治疗是该类疾病一级和二级预防的重要措施。然而不同患者对同等剂量抗血小板药物治疗的反应性存在差异,在规范用药基础上,仍有患者出现心血管不良事件,即抗血小板药物抵抗现象。因此,对抗血小板药物的效应进行个体化预测具有重要意义。临床上已有多种手段可以监测血小板功能,那么血小板功能实验预测心血管病人血栓与出血风险的能力如何?能否依据血小板功能实验来调整药物剂量或更换抗血小板药物?本文简要概述血小板功能及检测方法,并结合最新研究进展重点关注血小板功能检测在临床中的应用,为临床合理使用抗血小板药物进行个体化治疗提供一定的参考。     

血小板功能检测指导下个体化抗血小板治疗的研究进展

阿司匹林和P2 Y12受体拮抗剂的双联抗血小板治疗是经皮冠状动脉介入治疗（ PCI）和急性冠脉综合征（ acute coronary syn-drome,ACS）患者治疗的基石,CAPRIE、CURE、CREDO 等［1-3］多项临床试验已证实其有效性和安全性。然而,同一种抗血小板药物可产生不同的抗血小板效应,即血小板反应多样性,低反应性者血栓事件可能增加,高反应性者出血事件风险增加。血小板功能检测显示：表现为血小板高反应性的部分患者对药物反应不良,易发生复发心肌梗死、支架内血栓和死亡等缺血事件;另一部分患者对药物过度反应,易发生胃肠道出血,卒中和死亡等出血事件［4-5］。导致抗血小板药物,尤其是经典P2 Y12受体拮抗剂氯吡格雷反应多样性的现象已经受到了国内外学者的高度关注,并开展了各种临床研究和药物代谢机制的探讨［6］。新型P2 Y12受体拮抗剂普拉格雷,其强效抗血小板作用在克服血小板高反应性的同时,也显著增加了出血的风险［7］。因此,通过血小板功能检测以预测患者不良心血管事件的风险有着重要的临床意义,而如何在血小板功能检测的指导下推进个体化抗血小板治疗也逐渐成为临床关注的热点问题。     

抗血小板药物“治疗无反应”的研究进展

近年来新型抗血小板药物陆续出现,阿司匹林与氯吡格雷双联抗血小板仍是目前预防支架内血栓形成及不良心血管事件发生最常用药物。接受标准双联抗血小板药物治疗有部分患者仍再次发生临床缺血事件,出现抗血小板药物"治疗无反应"现象引起了人们极大关注。关于这一现象研究很多,这些研究都有一定局限性,如不同实验室检测体外血小板功能方法不同、不同患者对抗血小板药物反应存在广泛个体差异以及其他疾病对抗血小板药物疗效影响等。文章主要从体外检测血小板功能方法、药物代谢基因多态性及影响抗血小板药物代谢相关临床疾病等方面总结目前可能得到的证据,来阐述影响残余血小板活性原因及其与血栓形成事件之间关系。     

血小板相关活性肽的研究进展

血小板活化、聚集是诱导血管内血栓形成的重要因素,因此,抗血小板治疗在心脑血管疾病的防治中至关重要。然而,现有抗血小板药物虽能降低血栓事件发生,但由于存在抵抗或低应答,不良缺血事件仍有发生;且这些药物产生的消化道大出血、脑出血等并发症严重影响治疗及预后。因此,血小板功能研究及新型抗血小板药物研发仍尤为重要。目前研究发现,多种生物活性肽存在抗血小板活化、聚集等作用。本综述旨在探讨血小板相关活性肽的研究进展。     

脑梗死患者抗血小板药物的精准策略选择

抗血小板治疗是脑梗死全程管理的重要手段之一，然而临床上抗血小板药物存在个体反应差异且与预后密切相关，因此精准选择抗血小板药物具有重要意义。血小板功能检测及药物基因检测是抗血小板药物精准治疗的核心环节。对于高危缺血风险或预后较差、高出血风险的患者，可考虑行基因检测和（或）血小板功能检测。阿司匹林和氯吡格雷仍是目前最经典的抗血小板药物，其他抗血小板药物的有效性及安全性有待进一步验证。对于阿司匹林抵抗人群，不推荐增加阿司匹林剂量，可考虑换用其他抗血小板药物。基于CYP2C19基因型进行氯吡格雷剂量调整的策略仍有待研究，携带CYP2C19失功能等位基因的患者，建议换用其他抗血小板药物。     

反复发作的缺血性卒中

部分患者对抗血小板药物表现为低反应性或无反应, 接受抗血小板规范治疗后仍发生心脑血管事件。本例患者为63岁女性, 长期服用阿司匹林和氯吡格雷, 多次出现肢体乏力, 行头颅磁共振扫描均提示急性脑梗死。后经血小板聚集试验、闭合试验及基因检测证实, 该患者存在阿司匹林和氯吡格雷低反应性。改服西洛他唑, 随访1年余, 未再发生心脑血管事件。     

血栓弹力图对老年患者抗血小板药物治疗的反应性评价

正随着中国社会逐渐老龄化,老年心脑血管疾病患者显著增加,而血小板在动脉粥样硬化的进展和血管不良事件中起着关键性作用,抗血小板药物对于心脑血管疾病的治疗效用已经得到证实[1]。阿司匹林与氯吡格雷是近年来临床上最常用的抗血小板药物。临床实践中,由于个体化差异,部分老年患者不能达到对血小板的良好抑制,还是会发生血栓栓塞事件,称为阿司匹林或氯吡格雷抵抗;同时,若抗血小板药物使用后发生出血相关不良反应,也会显     

冠心病介入术后行非心脏外科手术的抗栓策略研究

目的 明确药物涂层支架植入患者行非心脏手术围手术期应用Ⅱb/Ⅲa受体拮抗剂替代口服双联抗血小板药物是否发挥预防支架内血栓的作用,同时不增加外科手术的出血.方法 入选入院前1年内曾因冠心病植入药物涂层支架服用双联抗血小板药物(阿司匹林和氯吡格雷)而后无缺血性胸痛症状,心功能纽约分级为2级,年龄60 ～75岁,因外科疾病保守治疗无效需手术治疗的6例患者,手术前5d停用口服双联抗血小板药物,应用Ⅱb/Ⅲa受体拮抗剂替罗非班0.1 μg/( kg· min)持续静脉微量泵泵入,外科手术前2h停用替罗非班,手术结束后在重症监护室中应用替罗非班0.1 μg(kg· min)持续静脉微量泵泵入,术后根据外科情况允许,停用替罗非班,尽早恢复口服双联抗血小板药物使用.分析围手术期新发心血管事件,特别是支架内血栓事件,以及严重出血事件,替罗非班的药物不良反应事件.结果6例患者围手术期均未发生缺血性室性恶性心律失常、心绞痛、心肌梗死、心源性猝死,未发生大量出血而导致输血或需二次手术止血等出血事件,并且未发生替罗非班的药物不良反应.结论药物涂层支架植入术后患者行非心脏手术Ⅱb/Ⅲa受体拮抗剂替代口服双联抗血小板药物预防围手术期支架内血栓的治疗措施可能是可行的和安全的,但需要大样本随机对照试验以进一步证实.     

房颤合并冠状动脉粥样硬化性心脏病的抗栓治疗策略

房颤和冠状动脉粥样硬化性心脏病均为常见疾病。缺血性卒中和系统性血栓栓塞是房颤患者的主要不良预后,抗栓治疗可显著减少血栓栓塞事件风险;另一方面,抗血小板治疗又是冠状动脉粥样硬化性心脏病治疗的关键。当房颤患者合并冠状动脉粥样硬化性心脏病时,需要通过抗凝联合抗血小板治疗以减少卒中及缺血性心脏事件的发生。然而,联合抗栓策略会增加出血并发症的风险。如何平衡出血和血栓风险,以及如何在不同口服抗凝药物和抗血小板药物中进行选择,制定最优的抗栓方案是临床工作面临的挑战。     

Assessing post-treatment platelet reactivity: a focus on patient selection and setting

Dual antiplatelet therapy is critical to inhibit platelet reactivity in order to prevent ischemic reccurences in stented patients. However, studies have observed a variable blockade of the P2Y12 adenosine diphosphate receptor between patients following clopidogrel intake. This interindividual variability in the biological response is not uncommon with clopidogrel (about 50%) and even prasugrel (20%). High on-treatment platelet reactivity (HTPR) is correlated with thrombotic events following percutaneous coronary intervention. Several studies suggested that tailoring of antiplatelet therapy based on platelet reactivity (PR) monitoring could safely reduce the rate of major adverse cardiovascular events in HTPR patients. In addition, low on-treatment PR was recently associated with bleeding events both in patients treated with prasugrel and clopidogrel. Of importance, bleedings are associated with a poor prognosis in stented patients. Overall, the potential of PR monitoring to individualize antiplatelet therapy might benefit stented patients by reducing both ischemic and bleeding risks. However, such strategies remain to be evaluated in adequately designed large-scale randomized clinical trials.     

The future of platelet function testing to guide therapy in clopidogrel low and enhanced responders

Dual oral antiplatelet therapy with aspirin and clopidogrel is the therapy of choice in patients with acute coronary syndromes and in patients undergoing coronary stent placement to lower the risk of thrombotic events. Responsiveness to aspirin and especially to clopidogrel is not uniform and is subject to considerable interindividual variability. Furthermore, there is a broad consensus that clopidogrel low response or so-called high on-treatment platelet reactivity is linked to the occurrence of ischemic events. On the other hand, evidence is accumulating that enhanced clopidogrel responders are at increased risk of bleeding. Newer antiplatelet drugs, such as prasugrel and ticagrelor, are more potent and produce more consistent inhibition of platelet aggregation via the P2Y(12) ADP platelet receptor. A variety of methods of platelet function testing are available for evaluating platelet inhibition in percutaneous coronary intervention-treated patients in order to help determine the individual risk for ischemic and bleeding complications. Although not yet routinely undertaken, platelet function testing offers the potential to tailor antiplatelet therapy for individual patients. Whether alteration of therapy based on platelet function testing improves patients' outcomes remains unclear and is currently under investigation. This article reviews the impact of antiplatelet drug responsiveness on clinical outcomes with a focus on P2Y(12) receptor inhibition as well as on current and future concepts for personalized antiplatelet strategies.     

Monitoring of antiplatelet therapy. Current limitations, challenges, and perspectives

Screening of platelet function can be performed by point-of-care testing followed by platelet aggregometry in response to agonists such as collagen, adenosine diphosphate, epinephrine, and arachidonic acid. Despite in use for decades, this technique is not well standardized. Monitoring of antiplatelet therapy is increasingly applied in patients at high risk for re-thrombosis or bleeding. To assess pharmacological inhibition of platelet function, agonist-induced platelet aggregation, thromboxane B2 (TxB2) and vasodilator-stimulated protein phosphorylation (VASP) are being measured. While serum TxB2 levels of < 2 ng/ml reflect aspirin-induced inhibition of cyclo-oxygenase-1 activity with high sensitivity, VASP exhibits a wide variability upon treatment with clopidogrel or prasugrel. Multiple studies reveal an association between high residual platelet reactivity and adverse cardiovascular events in patients on antiplatelet therapy. However, despite the plethora of platelet function assays currently under investigation, their use in daily practice cannot be recommended. This is due to several reasons: (i) there is no consensus on the method and a respective cut-off value associated with clinical adverse outcome, and (ii) data demonstrating any benefit of tailored antiplatelet therapy and its monitoring (based on assessment of platelet functions) are still limited. Thus, appropriate identification of 'resistant' or 'poor responders' to antiplatelet agents remains challenging in clinical practice.     

Clopidogrel resistance in diabetic patient with acute myocardial infarction due to stent thrombosis

Stent thrombosis is a morbid complication after percutaneous coronary intervention. Dual antiplatelet therapy significantly reduces stent thrombosis risk and forms currently the basis in acute ST elevation myocardial infarction pharmacologic treatment. The introduction of clopidogrel has made a major advance in the acute coronary syndrome treatment. However, there is growing evidence about failure in antiplatelet response after clopidogrel, which may lead to subsequent risk of future thrombotic events. The antiplatelet inhibitory effect of clopidogrel varies widely among individuals. High on-treatment platelet reactivity has been repeatedly associated with a hazard for cardiovascular events, including stent thrombosis. Laboratory monitoring of antiplatelet therapy efficacy may help identify patients with insufficient antiplatelet response. Prasugrel therapy was repeatedly described as an effective method to overcome clopidogrel resistance. We report a case of diabetic patient in whom myocardial reinfarction due to stent thrombosis developed. Clopidogrel resistance was detected in this patient using light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation assessment. After prasugrel administration, no other ischemic event occurred, and patient was released to outpatient care in good general condition.     

Platelet reactivity tests for assessing antiplatelet drug response: what the clinician needs to know

Antiplatelet therapy is a cornerstone in the treatment of cardiovascular disease to prevent ischemic events. Various tests have become clinically available to measure platelet function after antiplatelet treatment. A wide interpatient variability in the magnitude of platelet inhibition has been demonstrated in numerous studies, especially in response to clopidogrel. Several reasons including clinical, pharmacological and genetic factors have been identified. High on-clopidogrel platelet reactivity has been linked to adverse clinical outcome, in particular to stent thrombosis after percutaneous coronary interventions. New antiplatelet drugs including prasugrel and ticagrelor have been advocated to overcome the limitations of clopidogrel. Several studies addressed the concept of tailored antiplatelet treatment according to the results of platelet function testing. Within this review, we summarize the current status of personalized antiplatelet therapy for cardiovascular disease.     

Elinogrel, an orally and intravenously available ADP-receptor antagonist. How does elinogrel affect a personalized antiplatelet therapy?

The antiplatelet therapy with aspirin and the ADP-receptor blocker clopidogrel is currently the standard medication after coronary intervention or after acute coronary syndrome to prevent recurrent ischemic events and reduce mortality. However, high interindividual response variability to antiplatelet treatment is described in up to 44% of treated patients. A poor response to clopidogrel is caused by multifactorial mechanisms. Individual risk assessment including platelet function testing (PFT) can help to identify high risk patients, although recent randomized trials to investigate effects of PFT-guided therapy have failed to detect an impact on prognostic outcome. Poor response to standard antiplatelet agents can be overcome by switching to alternate substances. Elinogrel is a novel competitive, reversible ADP-receptor antagonist available in oral and intravenous formulation. Additional treatment with elinogrel showed advantages over clopidogrel, including more rapid, less variable, and more complete inhibition of platelet function without significantly increased bleeding complications. This review gives an overview over the investigational drug elinogrel for use in a personalized antiplatelet approach.     

Role of Platelet Transfusion in the Reversal of Anti-Platelet Therapy

Antiplatelet therapy is extensively used in the primary and secondary prophylaxis of arterial thrombotic disorders. Aspirin, the most commonly used antiplatelet agent, is a cyclooxygenase−1 inhibitor and considered a mild to moderate inhibitor of platelet function. Therefore, often a second antiplatelet agent is necessary in certain clinical conditions requiring greater inhibition of platelet function. An adenosine diphosphate (ADP) receptor, P2Y12, is an important target for this purpose; several agents inhibit this receptor providing potent antiplatelet effect. One of the side effects of these agents is bleeding, which in some patients may require reversal of antiplatelet effect. Similarly, patients undergoing emergent surgeries may benefit from reversal of antiplatelet effect to avoid excessive surgical bleeding. This article reviews current literature on this topic.     

Modern antiplatelet agents in coronary artery disease

Dual antiplatelet therapy is well recognized in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions. Despite clinical benefits of aspirin and clopidogrel therapy, a number of limitations curtail their efficacy: slow onset of action, variability in platelet inhibitory response and potential drug–drug interactions. Furthermore, the single platelet-activation pathway targeted by these agents allows continued platelet activation via other pathways, ensuring incomplete protection against ischemic events, thus, underscoring the need for alternate antiplatelet treatment strategies. A number of novel antiplatelet agents are currently in advance development and many have established superior effects on platelet inhibition, clinical outcomes and safety profile than clopidogrel in high-risk patients. The aim of this review is to provide an overview of the current status of P2Y12 receptor inhibition and PAR-1 antagonists in determining a future strategy for individualized antiplatelet therapy.     

Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection

Summary.  The definition 'resistance to antiplatelet drugs' should be limited to situations in which failure of the drug to hit its pharmacological target has been documented by specific laboratory tests. Aspirin resistance, as determined by specific tests (e.g. serum thromboxane B₂), appears to be rare (1–2%) and, in most instances, is caused by poor compliance. In contrast to aspirin, studies that used specific tests to measure the pharmacological effect of thienopyridines [e.g. vasodilator-stimulated phosphoprotein (VASP)] showed a wide variability of responses to these drugs, with significant proportions of subjects (15–30%) who are very poor responders. Inter-individual differences in the extent of metabolism of thienopyridines to their active metabolites is the most plausible mechanism for the observed inter-individual variability in platelet inhibition. The demonstration that some patients may be 'resistant' or 'poor responders' to the pharmacological effect of antiplatelet drugs, has prompted the need of laboratory monitoring of antiplatelet therapy. However, many published studies have been performed using unspecific tests of platelet function, which identify patients on antiplatelet treatment with high residual platelet reactivity, which is not necessarily because of resistance to antiplatelet drugs. Despite this drawback, identification of patients with high residual platelet reactivity may be useful to predict their risk of atherothrombotic events. However, many studies still need to be carried out to identify the ideal laboratory test and to answer basic questions on its clinical utility and cost-effectiveness, before monitoring antiplatelet therapy can be recommended in the clinical practise. Until then, monitoring of antiplatelet therapy should be considered for investigational purposes only.     

New Antiplatelet Agents and the Role of Platelet Function Testing in Acute Coronary Syndromes

Background

Dual antiplatelet therapy is a guideline mandated for patients with acute coronary syndromes (ACS). Despite its use, thrombotic events continue to occur both early and late. Platelet function testing has been used to define the in vitro effects of new antiplatelet agents, and it has been suggested that it be used to choose therapy. The role of platelet function testing, particularly with newer antiplatelet agents, remains unclear.

Objective

We review the rationale for platelet function testing and its application in monitoring patients on antiplatelet therapy. We also review recent clinical trials of newer antiplatelet agents. On the basis of this review, we reach conclusions on the current role of antiplatelet function testing in monitoring modern antiplatelet therapy and the role of the new antiplatelet agents in the treatment of ACS.

Methods

We reviewed recent publications on platelet function testing and clinical trials of newer antiplatelet therapies compared with clopidogrel.

Results

Platelet function testing is complex, but there is now a bedside test, VerifyNow. High platelet reactivity has been associated with worse cardiovascular outcomes in patients undergoing percutaneous coronary intervention. Recent clinical trials have not found any advantage in outcomes in patients who have their therapy adjusted by monitoring their platelet function. Newer agents, prasugrel, ticagrelor, and cangrelor, produce more rapid, complete, less variable effects on platelet function than clopidogrel. Prasugrel was found to improve outcomes compared with clopidogrel in patients with ACS undergoing percutaneous intervention. Ticagrelor is beneficial in all patients with ACS and reduces cardiovascular mortality compared with clopidogrel. Cangrelor improves outcomes in patients undergoing stenting. Recent studies to assess the role of platelet function monitoring of the effects of clopidogrel and modifying treatments have not been successful.

Conclusion

Recent clinical trials have indicated that newer antiplatelet agents have advantages over clopidogrel in the treatment of ACS. Platelet function testing gives us a guide to the timing, efficacy, and variability of therapy and can correlate with poor patient outcomes; however, the use of antiplatelet function testing to tailor therapy does not seem appropriate.