心血管疾病患者发生阿司匹林抵抗的相关因素分析

目的探讨心血管疾病患者发生阿司匹林抵抗（AR）的相关因素。方法110例冠心病患者服用阿司匹林14d，用二磷酸腺苷和花生四烯酸作诱导荆测定血小板聚集功能。结果110例患者中无一例AR，其中，阿司匹林半抵抗（ASR）9例，阿司匹林敏感（AS）101例，2组女性比例和高血压发生率差异有统计学意义（P〈0．05或0．01）。结论女性与合并高血压可能为心血管疾病患者发生AR的相关因素。     

阿司匹林抵抗的相关临床研究

目的:探讨我国患病人群中阿司匹林抵抗(aspirin resistance,AR)现象,比较不同AR实验检测法对阿司匹林疗效的判断及其临床应用价值。方法:对264例口服阿司匹林的患者(高血压、糖尿病等)分别进行光学法血小板聚集率(platelet aggregation test,PagT)、血栓弹力图(thrombelastography,TEG)、血和尿11-脱氢-血栓素B2(11-dehydro thromboxane B2,11-DH-TXB2)及P-选择蛋白表达检测,并对比分析患者的AR发生率、相关危险因素及AR与临床终点事件间的相关性。结果:口服阿司匹林患者采用各种方法检测到的AR发生率基本一致(P>0.05)。糖尿病患者AR和阿司匹林半抵抗(aspirin semi-resistance,ASR)的检出率有高于其他疾病组的趋势。低密度脂蛋白和空腹血糖的升高是AR的危险因素。几种检测方法的结果间有一定相关性(r为0.408～0.709,P<0.01)。以P-选择蛋白阳性为标准,TEG较其他检测方法有更高的灵敏度(89.29%)和特异度(92.31%),且与P-选择蛋白阳性间的一致性更高(K值为0.904,P<0.001)。结论:低密度脂蛋白升高和空腹血糖升高是AR发生的危险因素,TEG血小板图对AR检出的灵敏度较高,与P-选择蛋白检测结果间的一致性较高。     

阿司匹林抵抗

1 阿司匹林抵抗问题的提出 临床试验表明阿司匹林是心脑血管疾病患者一二级预防有效的抗血小板药物。但是，仍有患者每天服用阿司匹林出现心血管事件。于是提出了阿司匹林抵抗（Aspirin Resistance．AR）这个概念。血小板形成血栓过程包括血小板黏附，活化和聚集。阿司匹林抗血栓作用主要通过抗血小板聚集完成。血小板聚集主要由血小板聚集仪测定，用聚集度表示。Mehta等人的研究表明冠状动脉疾病患者服用阿司匹林后的血小板聚集度有很大差异，部分患者聚集度无明显降低，     

服用小剂量阿司匹林患者的阿司匹林抵抗

目的 探讨服用小剂量阿司匹林患者的阿司匹林抵抗（AR）现象及其影响因素.方法 入选328例病情稳定的心脑血管病、糖尿病等患者,每日服用阿司匹林100 mg,连服14 d后,分别用花生四烯酸（AA）、二磷酸腺苷（ADP）作诱导剂检测血小板聚集率.满足AA诱导的血小板平均聚集率≥20%、ADP诱导的血小板平均聚集率≥70%两项者为AR;仅满足其中一项为阿司匹林半抵抗（ASR）;均不满足者为阿司匹林敏感（AS）.用统计学方法分析各组间各项临床特征差异及影响AR与ASR的独立危险因素.结果 328例患者中AR发生率为4.9%,ASR发生率为27.4%.与AS相比,AR＋ASR中以女性、高龄、糖尿病及高血压病患者较多,吸烟者较少.Logistic回归分析表明,糖尿病[相对比值比（OR）=0.953,95%可信区间（CI）0.323～0.876,P=0.013]和高血压病（OR=0.610,95%CI 0.376～0.991,P=0.045）是发生AR与ASR的独立危险因素.不吸烟者发生AR与ASR的危险性升高（OR=2.231,95%CI 1.182～4.210,P=0.013）.结论 服用小剂量阿司匹林的患者中AR发生率为4.9%;发生AR与ASR可能与糖尿病、高血压等因素有关,不吸烟者发生AR与ASR的危险性升高.     

服用小剂量阿司匹林对于冠心病患者的阿司匹林抵抗

目的探讨服用小剂量阿司匹林冠心病患者的阿司匹林抵抗（AR）现象及其相关因素。方法经冠脉造影确诊为冠心病患者137例，服用阿司匹林100mg／d≥1周后，分别用花生四烯酸（AA）、二磷酸腺苷（ADP）作诱导剂检测血小板聚集率。满足AA诱导的血小板平均聚集率≥20％、ADP诱导的血小板平均聚集率≥70％两项者为AR；仅满足其中一项为阿司匹林半抵抗（ASR）；均不满足者为阿司匹林敏感（脶）。结果137例患者中AR发生率为22．63％（31例），ASR发生率为17．52％（24例），AR＋ASR发生率为40．16％（55例）．AS发生率为59．85％（82例）。AR＋ASR组中的糖尿病、不稳定型心绞痛患者均较As组多（P〈0．05）；AR＋ASR组患者血浆总胆固醇浓度显著高于AS组（P〈0．05），血浆低密度脂蛋白-胆固醇浓度有高于AS组倾向（P〉0．053）。结论服用小剂量阿司匹林的冠心病患者AR＋ASR发生率为40．16％；AR或ASR者血浆胆固醇浓度较高；精尿病、不稳定型心绞痛患者AR或ASR发生率较高。     

老年心脑血管病患者阿司匹林抵抗及相关因素分析

目的了解老年心脑血管病患者阿司匹林抵抗（AR）的发生率,分析相关危险因素。方法选取老年缺血性心脑血管病患者150例,测定其血小板聚集率。将患者分为阿司匹林敏感（AS）组和非AS组。分别测定患者年龄、性别、红细胞计数、糖化血红蛋白等指标并比较组间差异。结果AR发生率为3．3％;阿司匹林半抵抗发生率为32．7％。非AS组吸烟百分比、红细胞计数及糖化血红蛋白水平明显高于AS组,差异有统计学意义（P〈0．05）。结论吸烟、红细胞计数及糖化血红蛋白水平升高是AR发生的危险因素。     

阿司匹林抵抗机制的研究进展及临床处理策略

20世纪70年代,Vane[1]提出并论证了阿司匹林(aspirin)可通过抑制前列腺素(PG)生成来抑制血小板聚集。现在人们已逐渐达成共识,已有百年历史的阿司匹林除具镇痛、抗     

阿司匹林抵抗与尿11-脱氢-血栓素B2的检测及相关性研究

目的 探讨心脑血管病患者发生阿司匹林抵抗（aspirinresistance，AR）的影响因素以及AR与尿11-脱氢-血栓素B2（11-dehydro-Thromboxane，11-d-TXB2）的相关性。方法 220例心脑血管病患者服用阿司匹林（100mg／d）至少7d以上，用二磷酸腺苷和花生四烯酸作诱导剂测定血小板聚集功能，找出AR患者，测定11-d-TXB：的含量。结果 女性易发生AR，高血压患者发生AR几率高，AR者的11-d-TXB2含量同阿司匹林敏感者相比差异有统计学意义（P〈0．01）。结论 正确认识阿司匹林抵抗现象，对AR患者，可加大阿司匹林用量或换用其他抗血小板药物。     

冠心病患者阿司匹林抵抗临床特征

目的:探讨冠心痛患者阿司匹林抵抗(AR)及阿司匹林半抵抗(ASR)的临床相关因素.方法:186例冠心病患者,光学法检测分别由二磷酸腺苷和花生四烯酸诱导的血小板聚集率.将患者分为AR或ASR组及阿司匹林敏感(AS)组.Logistic回归方法分析各临床因素与AR或ASR的相关性.结果:AR+ASR组与AS组中女性患者例数分别为28/58和39/128,糖尿病患者例数分别为23/58和26/128.低密度脂蛋白胆固醇(LDL-C)分别为(3.01 4±0.72)mmol/L和(2.7±0.65)mmol/L,均存在统计学差异(均P<0.05);AR+ASR组与AS组中高血压病怠者例数分别为23/58和34/128,吸烟患者例数分别为17/58和25/128,差异均无统计学意义(均P>0.05);总胆固醇、甘油三酯、高密度脂蛋白胆固醇、血小板计数及血红蛋白两组间比较差异无统计学意义(均P>0.05).Logistic回归分析显示高LDL-C血症及糖尿病是AR或ASR的易患因素.结论:AR或ASR在女性冠心病患者及合并糖尿病或高LDL-C的冠心病患者中易于发生,其中高LDL-C血症及糖尿病与AR或ASR相关性最强.     

阿司匹林抵抗研究进展

阿司匹林在心肌梗死、缺血性脑血管病的预防中是一种有效的抗血小板药物。但在长期随访中发现，应用阿司匹林治疗的冠心痛患者仍有可能发生血栓栓塞事件，这称为阿司匹林抵抗。导致这种现象的确切原因还不明确，可能与药物问的相互作用、剂量不足等有关。但到目前为止，仍无法用同一机制解释所有的阿司匹林抵抗，并且很多研究所得出的结果是矛盾的。因此，认为在具有阿司匹林抵抗的人群中可能存在一定的群体特征性，也正因如此导致了阿司匹林抵抗的复杂性。期望用同一机制解释所有的阿司匹林抵抗现象是不可行的，应当针对不同群体做更多的研究工作。按照传统中医理论，结合心血管疾病多病程较长，且在存在阿司匹林抵抗的人群中多反复发作等特点，应将其归属于络病的范畴。联合应用具有扶正化浊，活血解毒通络功效的中药，发挥中医中药辨证论治和整体调节的优势，也许可以解决具有不同群体特征性的阿司匹林抵抗的问题，从而更有效地预防心血管疾病的发生。     

Platelets interact with tissue factor immobilized on surfaces: effects of shear rate

Background While procoagulant activities of Tissue Factor (TF) have been widely investigated, its possible pro‐adhesive properties towards platelets have not been studied in detail. Material and methods We explored the interaction of platelets with human Tissue Factor (hTF) firmly adsorbed on a synthetic surface of polyvinilidene difluoride (PVDF) using different shear rates. For studies at 250 and 600 s^?1, TF firmly adsorbed was exposed to flowing anticoagulated blood in flat perfusion devices. Deposition of platelets and fibrin were evaluated by morphometric, immunocytochemical and ultrastructural methods. Prothrombin fragment 1 + 2 (F1 + 2) levels were also measured. Experiments at 5000 s^?1, were performed on the Platelet Function Analyzer (PFA‐100?) with experimental cartridges with collagen (COL) or collagen‐hTF (COL + TF). Haemostatic effect of recombinant activated FVIIa (rFVIIa) was assessed in the same experimental settings. Results Platelet deposition on hTF reached 19·8 ± 1·3% and 26·1 ± 3·4% of the total surface, at 250 and 600 s^?1, respectively. Fibrin formation was significantly higher at 250 s^?1 than at 600 s^?1 (P < 0·05). The addition of rFVIIa did not influence platelet deposition but raised fibrin formation and thrombin generation at both shear rates (P < 0·05). At 5000 s^?1, closure times (CT) in the PFA‐100 were significantly shortened in the presence of hTF (154·09 ± 14·69 s vs. 191·45 ± 16·09 s COL alone; P < 0·05). Addition of rFVIIa did not cause a further reduction of CT. Conclusions Our studies demonstrate that hTF is an adhesive substrate for platelets and suggest that the von Willebrand factor could mediate these interactions. At low and intermediate shear rates, rFVIIa enhanced the procoagulant action of hTF, but this effect was not observed at very high shear rates.     

Usefulness of PFA-100® testing in the diagnostic screening of patients with suspected abnormalities of hemostasis: comparison with the bleeding time

BACKGROUND: Global tests of hemostasis that are used to screen patients with clinical suspicion of bleeding disorders should help the physician to identify the phase of the hemostatic system that is abnormal and guide further diagnostic workup. PATIENTS AND METHODS: We compared the performance of Platelet Function Analyzer-100 (PFA-100) closure time (CT) with bleeding time (BT), both of which are screening tests for primary hemostasis, in the diagnostic workup of 128 consecutive patients who were screened for bleeding disorders. The sensitivities of BT and PFA-100 CT for known defects of hemostasis were evaluated; in addition, we calculated their correlation with the levels of severity of the bleeding symptoms, which were recorded using a standardized questionnaire. RESULTS: The sensitivity of PFA-100 testing was 71% for von Willebrand disease (VWD) [with both collagen-adenosine diphosphate (C-ADP) and collagen-epinephrine (C-EPI) cartridges]; 58% (C-EPI) and 8% (C-ADP) for platelet function disorders (PFDs); and the sensitivity of BT was 29% (VWD) and 33% (PFD). C-EPI CT was also prolonged in about 20% of patients with abnormalities of coagulation or fibrinolysis. Only the C-EPI CT was significantly associated with the levels of severity of the patients' bleeding scores. CONCLUSIONS: BT and C-EPI are insufficiently sensitive to be recommended as hemostasis screening tests. The C-ADP cartridge, which is sensitive to VWD only, might prove useful in further diagnostic workup of defects of primary hemostasis. The association of C-EPI CT with the severity of bleeding symptoms as a useful predictor of risk of bleeding in clinical practise should be tested in properly designed studies.     

Use of the PFA-100™ closure time to predict cardiovascular events in aspirin-treated cardiovascular patients: a systematic review and meta-analysis

Summary. Background: PFA‐100? is a point‐of‐care assay that evaluates platelet reactivity in high‐shear‐stress conditions by measuring the closure time (CT) of a membrane aperture. When determined with a collagen/epinephrine cartridge (CEPI), the CT is usually prolonged by aspirin. Studies of the predictive value of a short PFA‐100?CT_CEPI for ischemic events in aspirin‐treated patients have given variable results. Objectives: To conduct a systematic review and meta‐analysis of studies on the clinical predictive value of a short PFA‐100?CT_CEPI in aspirin‐treated cardiovascular patients. Patients and methods: Relevant studies were identified by scanning electronic databases. Studies were selected if they included aspirin‐treated patients with symptomatic atherosclerosis, measured the PFA‐100?CT_CEPI, used a CT cut‐off value to define aspirin ‘responders’ and ‘non‐responders’, and reported ischemic events. Results: We selected seven non‐prospective studies (1466 patients) and eight prospective studies (1227 patients). In non‐prospective studies, the PFA‐100?CT_CEPI was performed after the ischemic clinical endpoint, and a publication bias was identified. In prospective studies, the global odds ratio (OR) for the recurrence of an ischemic event in ‘aspirin non‐responders’ relative to ‘aspirin responders’ was 2.1 [95% confidence interval (CI) 1.4–3.4, P < 0.001]. Pooled analysis with a random effect model revealed no heterogeneity (Q Cochran P = 0.36 and I² = 9.4%). Conclusions: A short PFA‐100?CT_CEPI is associated with increased recurrence of ischemic events in aspirin‐treated cardiovascular patients. This finding needs to be confirmed in stable ischemic patients, and the PFA‐100?CT_CEPI cut‐off needs to be refined in these patients.     

A contemporary viewpoint on ‘aspirin resistance’

Abstract

Aspirin is an irreversible inhibitor of platelet prostaglandin synthase activity, and is the most widely prescribed drug for the secondary prevention of cardiovascular disease. In recent years, clinical and laboratory evidence has shown significant individual variability in the response to aspirin and its link to clinical outcome. The term ‘aspirin resistance’ has been introduced to describe situations when clinical or ex-vivo effects of aspirin are less than expected. The accumulating evidence of increased risk of major adverse clinical events (MACE) associated with ‘aspirin resistance’ in the settings of acute coronary syndrome (ACS), stroke, and peripheral arterial disease has stimulated the search for ways of overcoming aspirin resistance. Existence of the link between high on-treatment platelet reactivity and atherothrombotic events suggests the common mechanisms for atherosclerosis progression and thrombotic complications with the platelets, being a key cellular interface between coagulation and inflammation.

This review article provides a contemporary view on ‘aspirin resistance’ and discusses its definition, clinical importance, and possible mechanisms in light of recent data on the role of platelets in atherothrombosis.     

The genetics of aspirin resistance

Aspirin is widely used for the prophylaxis of cardiovascular events in patients with cardiovascular risk factors or established atherosclerotic disease. However, despite aspirin treatment, a substantial number of patients experience recurrent events. Such 'aspirin resistance' is generally defined as failure of aspirin to produce an expected biological response, for example inhibition of platelet aggregation or of thromboxane A2 synthesis. Whilst its aetiology is multifactorial, genetic factors are also likely to play their part. Here we review the evidence for and against such a genetic contribution, as well as the data suggesting the involvement of specific genes.     

Clinical implications of aspirin resistance

Aspirin (acetylsalicylic acid) is one of the main therapeutic medications used in the prevention of thromboembolic vascular events. Aspirin exhibits its antiplatelet action by irreversibly inhibiting platelet cyclooxygenase-1 enzyme, thus preventing the production of thromboxane A2 (TXA2). Aspirin resistance, as measured in vitro, is the inability of aspirin to reduce platelet activation and aggregation by failure to suppress the platelet production of TXA2. Laboratory tests of platelet TXA2 production or platelet function dependent on TXA2 can detect aspirin resistance in vitro. The clinical implication of this laboratory definition has not yet been elucidated via prospective trials that have controlled for confounders, such as hypertension, diabetes and dyslipidemia. Large meta-analyses have found low-dose aspirin to be as effective as high-dose aspirin in preventing vascular events, making a dose-dependent improvement in laboratory response clinically irrelevant. Possible causes of aspirin resistance include poor compliance, inadequate dose, drug interactions, genetic polymorphisms of cyclooxygenase-1, increased platelet turnover and upregulation of non-platelet pathways of thromboxane production. However, there is currently no standardized approach to the diagnosis and no proven effective treatment for aspirin resistance. Further research exploring the mechanisms of aspirin resistance is needed in order to better define aspirin resistance, as well as to develop a standardized laboratory test that is specific and reliable, and can correlate with the clinical risk of vascular events. The intent of this paper is to review the literature discussing possible mechanisms, diagnostic testing and clinical trials of aspirin resistance and to discuss its clinical relevance as it pertains to cerebrovascular and cardiovascular disease.     

Clinical implications of aspirin resistance

Aspirin (acetylsalicylic acid) is one of the main therapeutic medications used in the prevention of thromboembolic vascular events. Aspirin exhibits its antiplatelet action by irreversibly inhibiting platelet cyclooxygenase-1 enzyme, thus preventing the production of thromboxane A₂ (TXA₂). Aspirin resistance, as measured in vitro, is the inability of aspirin to reduce platelet activation and aggregation by failure to suppress the platelet production of TXA₂. Laboratory tests of platelet TXA₂ production or platelet function dependent on TXA₂can detect aspirin resistance in vitro. The clinical implication of this laboratory definition has not yet been elucidated via prospective trials that have controlled for confounders, such as hypertension, diabetes and dyslipidemia. Large meta-analyses have found low-dose aspirin to be as effective as high-dose aspirin in preventing vascular events, making a dose-dependent improvement in laboratory response clinically irrelevant. Possible causes of aspirin resistance include poor compliance, inadequate dose, drug interactions, genetic polymorphisms of cyclooxygenase-1, increased platelet turnover and upregulation of nonplatelet pathways of thromboxane production. However, there is currently no standardized approach to the diagnosis and no proven effective treatment for aspirin resistance. Further research exploring the mechanisms of aspirin resistance is needed in order to better define aspirin resistance, as well as to develop a standardized laboratory test that is specific and reliable, and can correlate with the clinical risk of vascular events. The intent of this paper is to review the literature discussing possible mechanisms, diagnostic testing and clinical trials of aspirin resistance and to discuss its clinical relevance as it pertains to cerebrovascular and cardiovascular disease.     

Indices of platelet activation and the stability of coronary artery disease

AIM: To determine whether indices of platelet activation are associated with the stability of coronary artery disease (CAD). METHODS: Platelet function was examined in 677 consecutive aspirin-treated patients presenting for cardiac catheterization. Patients were grouped into recent myocardial infarction (MI), no MI but angiographically documented CAD (non-MI CAD) and no angiographically detectible CAD (no CAD), as well as additional subgroups. RESULTS: Compared with non-MI CAD or no CAD patients, more patients with recent MI had a shortened platelet function analyzer (PFA)-100 collagen-epinephrine closure time (CT) and increased circulating monocyte-platelet aggregates, neutrophil-platelet aggregates, activated platelet surface GPIIb-IIIa and plasma soluble CD40 ligand (sCD40L). More patients with non-MI CAD had shortened PFA-100 CTs and increased monocyte-platelet aggregates compared with patients with no CAD. Platelet surface P-selectin did not differ among the groups. Subgroup analysis revealed that decreasing PFA-100 CT correlated with the stability of CAD. CONCLUSIONS: Indices of platelet activation, especially the PFA-100 CT, are associated with the stability of CAD, and may reflect plaque instability, an ongoing thrombotic state and/or reduced responsiveness to aspirin.     

Higher aspirin resistance in diabetes

The major advances in cardiovascular care can be linked to the combined growth of advanced imaging modalities and the variety of treatment options available for patients with complex structural, acquired and congenital, valvular, myocardial and aortic diseases. Paralleling this growth are the number and spectrum of complications – such as device failures and infections – that these patients will inevitably encounter. The keys to successful implementation of advanced cardiac therapy are the real-time images, 3D reconstructions, and the hemodynamic and tissue profiles that can be obtained to evaluate these patients and their devices. We will review the roles of echocardiography, multidetector computed tomography and MRI in the evaluation of normal and abnormal cardiac device function.