張仕娟，宋玉寧，李乃坤，孫錫波，李炳選

(濰坊醫(yī)學(xué)院附屬益都中心醫(yī)院，山東青州 262500)

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急性腦梗死患者發(fā)生阿司匹林抵抗的危險(xiǎn)因素

張仕娟，宋玉寧，李乃坤，孫錫波，李炳選

(濰坊醫(yī)學(xué)院附屬益都中心醫(yī)院，山東青州 262500)

目的探討急性腦梗死患者發(fā)生阿司匹林抵抗(AR)的危險(xiǎn)因素。方法162例急性腦梗死患者于入院當(dāng)日開始口服阿司匹林腸溶片100 mg/d，服用阿司匹林10 d后，根據(jù)血小板聚集實(shí)驗(yàn)結(jié)果將患者分為阿司匹林抵抗(AR)者(AR組，49例)和非AR者(非AR組，113例)，收集患者一般臨床資料，采用實(shí)時(shí)熒光定量PCR檢測(cè)血小板中微小RNA-19a(miR-19a)，利用多因素Logistic回歸分析法分析影響AR發(fā)生的影響因素，利用受試者工作特征曲線(ROC曲線)評(píng)估血小板miR-19a表達(dá)量預(yù)測(cè)AR的價(jià)值。結(jié)果AR組血小板miR-19a表達(dá)量為0.78±0.09、2型糖尿病26例(53.1%)，非AR組血小板miR-19a表達(dá)量為0.59±0.11、2型糖尿病34例(30.1%)，兩組比較，P均<0.05。多因素Logistic回歸分析顯示，血小板miR-19a表達(dá)量升高是影響急性腦梗死患者發(fā)生AR的獨(dú)立危險(xiǎn)因素(OR=4.82，95%CI：1.374～15.835)。ROC曲線分析顯示，當(dāng)miR-19a截?cái)嘀禐?.69時(shí)，ROC曲線下面積為0.927(95%CI：0.888～0.966)，診斷急性腦梗死的靈敏度為93.9%、特異度為82.3%。結(jié)論急性腦梗死AR患者血小板miR-19a表達(dá)升高，是AR發(fā)生的獨(dú)立危險(xiǎn)因素，可作為預(yù)測(cè)急性腦梗死發(fā)生AR的指標(biāo)。

急性腦梗死；阿司匹林抵抗；微小RNA-19a

急性腦梗死是臨床常見的危急癥，具有較高的致死、致殘率，嚴(yán)重影響患者生存質(zhì)量。研究[1]表明，血小板活化、黏附和聚集在血栓形成中發(fā)揮關(guān)鍵性作用，是腦梗死的重要病理基礎(chǔ)。抗血小板治療是急性腦梗死的常規(guī)治療方法之一，其中阿司匹林是常用的藥物[2]，然而患者會(huì)經(jīng)常出現(xiàn)阿司匹林抵抗(AR)現(xiàn)象[3,4]。研究[5]表明，血小板活化涉及多種微小RNA(miRNA)表達(dá)變化，miRNA表達(dá)變化會(huì)影響血小板活性。微小RNA-19a(miR-19a)可通過影響內(nèi)皮細(xì)胞黏附、增殖而影響血管新生，與血小板聚集關(guān)系密切[6]。本研究對(duì)49例急性腦梗死患者發(fā)生AR者的臨床資料作回顧性分析，并總結(jié)其危險(xiǎn)因素。

1　資料與方法

1.1臨床資料2013年2月～2015年8月濰坊醫(yī)學(xué)院附屬益都中心醫(yī)院收治的急性腦梗死患者162例，男94例，女68例；年齡39～77(61.4±10.5)歲。均符合第四屆全國腦血管病會(huì)議修訂的診斷標(biāo)準(zhǔn)，并經(jīng)影像學(xué)檢查確診，均為首次發(fā)病，發(fā)病時(shí)間4～72 h。排除標(biāo)準(zhǔn)：①具有出血傾向者；②血小板計(jì)數(shù)>450×109/L或<100×109/L；③合并有重要臟器功能障礙、腫瘤、造血系統(tǒng)疾病者；④近30 d行外科手術(shù)治療者，使用非甾體類抗炎藥、華法林、低分子肝素等可能影響血小板功能的藥物者；⑤對(duì)口服阿司匹林過敏者，或有其他禁忌證者。所有患者于入院當(dāng)日開始口服阿司匹林腸溶片100 mg/d，服用阿司匹林10 d后，根據(jù)血小板聚集實(shí)驗(yàn)結(jié)果將患者分為阿司匹林抵抗(AR)者(AR組，49例)和非AR者(非AR組，113例)。

2　結(jié)果

AR組血小板miR-19a表達(dá)量為0.78±0.09、2型糖尿病26例(53.1%)，非AR組血小板miR-19a表達(dá)量為0.59±0.11、2型糖尿病34例(30.1%)，兩組比較，P均<0.05。AR組男30例(61.2%)、女19例(38.8%)、高血壓32例(65.3%)、吸煙16例(32.7%)，對(duì)照組男64例(56.6%)、女49例(43.4%)、高血壓63例(55.8%)、吸煙31例(27.4%)，兩組比較，P均>0.05。兩組年齡、白細(xì)胞計(jì)數(shù)、紅細(xì)胞計(jì)數(shù)、血小板計(jì)數(shù)、纖維蛋白原、LDL-C、C反應(yīng)蛋白、白蛋白、糖化血紅蛋白比較見表1，由表1可知，兩組各指標(biāo)比較，P均>0.05。將血小板miR-19a表達(dá)量、2型糖尿病進(jìn)行多因素Logistic回歸分析，顯示血小板miR-19a表達(dá)量升高是影響急性腦梗死患者發(fā)生AR的獨(dú)立危險(xiǎn)因素(OR=4.82，95%CI：1.374～15.835)。ROC曲線分析顯示，當(dāng)miR-19a截?cái)嘀禐?.69時(shí)，ROC曲線下面積為0.927(95%CI：0.888～0.966)，診斷急性腦梗死的靈敏度為93.9%、特異度為82.3%。

表1　兩組年齡、白細(xì)胞計(jì)數(shù)、紅細(xì)胞計(jì)數(shù)、血小板計(jì)數(shù)、纖維蛋白原、LDL-C、C反應(yīng)蛋白、白蛋白、糖化血紅蛋白比較±s)

3　討論

近年來，隨著人們生活方式的轉(zhuǎn)變及老齡化的加劇，急性腦梗死發(fā)病率呈逐年上升趨勢(shì)[7]，嚴(yán)重威脅人類生存健康。研究[8]證實(shí)，抑制血小板活化是有效預(yù)防腦梗死發(fā)生及復(fù)發(fā)的手段。阿司匹林是目前臨床上最為常用且療效確定的抗血小板藥物，可抑制血小板聚集[9]。然而文獻(xiàn)[10]報(bào)道，服用阿司匹林藥物者中有5.5%～65.0%發(fā)生AR。AR可增加急性腦梗死患者復(fù)發(fā)缺血性血管事件的風(fēng)險(xiǎn)，是缺血性血管事件復(fù)發(fā)的獨(dú)立危險(xiǎn)因素[11]。本研究采用血小板聚集實(shí)驗(yàn)判斷AR，結(jié)果顯示162例患者中發(fā)生AR者49例。

目前，AR發(fā)生機(jī)制尚未研究清楚，可能與服藥依從性、劑量及炎癥、疾病嚴(yán)重程度、血小板更新速度等有關(guān)[12]。本研究對(duì)AR與非AR患者一般臨床指標(biāo)進(jìn)行比較時(shí)，發(fā)現(xiàn)AR患者中2型糖尿病比例高于非AR患者，提示2型糖尿病可能是影響AR發(fā)生的危險(xiǎn)因素。miRNA作為一種高度保守的單鏈非編碼RNA，研究[13]表明血小板活化過程中可出現(xiàn)多種miRNA表達(dá)變化。miR-19a作為miR-17-92基因簇編碼成員，參與調(diào)控血管內(nèi)皮細(xì)胞黏附及增殖過程，與血管新生密切相關(guān)[14]。有研究[15]指出，miR-19a高表達(dá)可通過抑制凝血酶敏感蛋白1表達(dá)而抑制腫瘤組織血管新生。本研究顯示，AR者血小板miR-19a表達(dá)量顯著高于非AR者，說明急性腦梗死患者血小板miR-19a表達(dá)升高可能參與了AR發(fā)生。進(jìn)一步對(duì)影響AR發(fā)生的因素進(jìn)行分析，發(fā)現(xiàn)血小板miR-19a表達(dá)量是影響急性腦梗死患者發(fā)生AR的獨(dú)立危險(xiǎn)因素；ROC曲線分析顯示，當(dāng)miR-19a截?cái)嘀禐?.69時(shí)，ROC曲線下面積為0.927(95%CI：0.888～0.966)，診斷急性腦梗死的靈敏度為93.9%、特異度為82.3%。說明急性腦梗死患者血小板miR-19a表達(dá)量可作為預(yù)測(cè)AR發(fā)生的生物學(xué)指標(biāo)。

總之，急性腦梗死AR患者血小板miR-19a表達(dá)量升高，是AR發(fā)生的獨(dú)立危險(xiǎn)因素，可作為預(yù)測(cè)急性腦梗死發(fā)生AR的指標(biāo)。

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Risk factors for aspirin resistance in patients with acute cerebral infarction

ZHANG Shijuan, SONG Yuning, LI Naikun, SUN Xipo, LI Bingxuan

(Yidu Center Hospital Affiliated to Weifang Medical University, Qingzhou 262500, China)

ObjectiveTo investigate the risk factors for aspirin resistance (AR) in patients with acute cerebral infarction. MethodsTotally 162 cases of patients with acute cerebral infarction received aspirin enteric-coated tablets 100 mg/d at the beginning of the day of admission. After taking aspirin 10 d, all patients were divided into the AR group (49 cases) and non-AR group (113 cases) according to the results of platelet aggregation test. The clinical data of patients were collected. The expression of microRNA-19a (miR-19a) in the platelets was detected by real-time fluorescence quantitative PCR. The influencing factors for the occurrence of AR were analyzed by Logistic regression analysis. The predictive value of expression of miR-19a in platelet for AR was analyzed by using receiver operating characteristic curve (ROC curve). ResultsThe expression level of miR-19a in the AR group was 0.78±0.09, the type 2 diabetes were found in 26 cases (53.1%), while in the non-AR group, the expression level of miR-19a was 0.59±0.11, the type 2 diabetes were found in 34 cases (30.1%), and significant difference was found between the two groups, all P<0.05. Multivariate Logistic regression analysis showed that the increased expression of miR-19a in platelet was an independent risk factor for AR in patients with acute cerebral infarction (OR=4.82, 95% CI:1.374-15.835). ROC curve analysis showed that, when miR-19a cutoff value was 0.69, the area under the ROC curve was 0.927 (95% CI:0.888-0.966), the sensitivity was 93.9% and the specificity was 82.3%. ConclusionThe expression of miR-19a in platelet of AR in patients with acute cerebral infarction is increased, which is an independent risk factor for the occurrence of AR and may be used as an indicator to predict the occurrence of AR in acute cerebral infarction.

acute cerebral infarction; aspirin resistance; micro RNA-19a

濰坊市科技局科研課題資助項(xiàng)目(2015ws109)。

10.3969/j.issn.1002-266X.2016.15.022

R741.02

B

1002-266X(2016)15-0062-03

2016-02-17)