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1 원저 허혈성뇌졸중환자에서신속혈소판기능검사를이용한클로피도그렐의혈소판응집억제반응측정 을지대학교의과대학을지대학병원신경과 김재국김형일신혜은이보람전종은이수주 Monitoring Platelet Inhibition by Clopidogrel Using Rapid Platelet Function Assay in Patients With Ischemic Stroke Jae Guk Kim, MD, Hyung-Il Kim, MD, Hye-Eun Shin, MD, Bo Ram Lee, MD, Jong-Un Chun, MD, Soo Joo Lee, MD Department of Neurology, Eulji University Hospital, Eulji University School of Medicine Background: Clopidogrel inhibits platelet P2Y12 adenosine diphosphate (ADP) receptors and has been widely used in patients with ischemic stroke. However, a considerable number of patients suffer from cerebrovascular events despite the use of clopidogrel. The rapid platelet function assay (RPFA) has been used for monitoring the antiplatelet effects on the P2Y12 ADP receptor. This study was performed to measure the platelet response to clopidogrel using RPFA in patients with ischemic stroke, and to identify the clinical factor related with clopidogrel resistance. Methods: A total of 86 patients taking clopidogrel (75 mg/day) were enrolled. Demographic data, vascular risk factors, the presence of obesity and metabolic syndrome, drug history, hemoglobin, platelet counts, and stroke subtypes were recorded. RPFA presented the results as P2Y12 Reaction Units (PRU), base PRU (BASE), and Inhibition (%). Inhibition was calculated as (1-PRU/BASE) 100. The patients showing ineffective aggregationinhibition (percentage of Inhibition < 20) on RPFA were defined as non-responders to clopidogrel. Results: The response of platelet aggregation-inhibition to clopidogrel showed a variable distribution with mean and standard deviation of 32.2±22.3%. Twenty four (27.9%) patients showed the inhibition below 20%. There was no difference between responders and non-responders regarding the clinical factors above. We found no influence of co-medication with the statins on platelet response to clopidogrel. Conclusions: There is a patient variability in response to clopidogrel and a considerable portion of stroke patients have clopidogrel resistance on the platelet function test. The clinical usefulness of routine platelet function test requires further validation. J Korean Neurol Assoc 26(4): , 2008 Key Words: Clopidogrel, Platelet aggregation, Platelet function test, Stroke 서론 Received March 31, 2008 Revised September 12, 2008 Accepted June 11, 2008 *Soo Joo Lee, MD Department of Neurology, Eulji University Hospital, Eulji University School of Medicine, 1306 Dunsan2-dong, Seo-gu, Daejeon, , Korea Tel: Fax: sjoolee@eulji.ac.kr * This work was supported by BumSuk Academic Research Fund of 혈소판의활성화와혈소판응집력의변화는죽경화성변화에의한혈관의급성폐색에서중요한병태생리이다. 1 혈소판은위험인자에의해형성된죽경화판에혈전및색전을일으켜급성허혈합병증을유발하는중요한역할을하고있는것으로알려져있다. 2 항혈소판제는이러한혈소판의역할을차단하여뇌경색및다른혈전성질환의발생빈도를낮추어주기때문에예방혹은재발을막기위한목적으로널리사용되고있다. J Korean Neurol Assoc Volume 26 No. 4,

2 김재국김형일신혜은이보람전종은이수주 클로피도그렐 (clopidogrel) 은 thienopyridine 의화학적유도체로서혈소판의 P2Y12 ADP (adenosine diphosphate) 수용체를비가역적으로변화시켜혈소판응집에중요한피브리노겐 (fibrinogen) 과혈소판의결합을선택적으로억제한다. 3 현재까지알려진연구결과에따르면클로피도그렐은아스피린을복용하는경우에비해심근경색, 뇌졸중및사망률을 8.7% 정도줄인다고알려져있다. 4 그러나혈소판기능검사에서나타나는클로피도그렐의혈소판억제효과가모든환자들에서일정하게관찰되지않고, 임상에서예방목적으로클로피도그렐을복용함에도불구하고혈관질환들이재발하는경우가있어이를임상적인클로피도그렐저항성 (clinical clopidogrel resistance) 이라고부른다. 5 관상동맥질환환자를대상으로시행된연구에서혈소판기능검사상불충분한혈소판응집억제반응을보인클로피도그렐저항성 (laboratory clopidogrel resistance) 은 5-44% 정도로다양하게보고되었다. 6 뇌졸중환자에서클로피도그렐저항성에대한연구는급성기환자들을대상으로시행된것과 2차적인예방을위해복용하는항혈소판제의불충분한응집억제반응을평가한연구들이있지만관상동맥질환환자들에대한연구에비해드물다. 7-9 본연구에서저자들은클로피도그렐을복용하는만성기허혈성뇌졸중환자를대상으로신속혈소판기능검사 VerifyNow R - P2Y12 assay (Accumetrics, San Diego, CA) 를이용하여클로피도그렐의혈소판응집억제반응을평가하고이와관련된임상인자들을알아보고자하였다. 대상과방법 1. 대상 저자들은 2006년 3월부터 2007년 2월까지을지대학병원에서허혈성뇌졸중으로진단받은뒤최소 1개월이상외래추적관찰하에있으면서 2차예방목적으로클로피도그렐 (75 mg/day) 을복용중인환자를대상으로하였다. 허혈성뇌졸중의진단은 CT나 MRI 에서증상에합당한뇌경색병변이확인되었거나병력에서일과성허혈발작 (transient ischemic attack, TIA) 이확인된경우로하였다. 클로피도그렐의효과가 4-7 일째에항정상태를유지한다는사실에따라최소 2주이상클로피도그렐을규칙적으로복용하고있는환자를대상으로혈액검사를하였다. 10 환자는연속적으로등록하였다. 1주이내다른항혈소판제또는혈소판응집에영향을미칠수있는보조약제를복용한경우, 항응고제를복용한경우, 24시간이상항혈소 판제복용을중단한경우, 24시간이내헤파린을투약받은경우, 출혈성질환의가족력및과거력이있는경우, 혈소판수치가 150,000/μl 이하또는 /μl 이상인경우, 헤모글로빈이 8.0 g/dl 이하인경우, 혈소판기능검사상오류가발생한경우등은연구분석대상에서제외하였다. 2. 방법 1) 임상자료의수집해당환자들에게연구에필요한정보를미리제공하고혈소판기능검사전에키, 몸무게, 허리둘레등을측정하였다. 또한각대상환자의나이, 성별, 고혈압, 당뇨, 고지혈증등의유무, 기본혈액검사결과, 클로피도그렐복용기간, 병용투약기록등의자료들을병력청취와의무기록을통해수집기록하였다. 고혈압은기존에고혈압을진단받고치료중이거나 2회이상혈압을측정하여수축기혈압이 140 mmhg, 이완기혈압이 90 mmhg 이상인경우로, 당뇨병은기존에당뇨를진단받았거나공복시혈당이 126 mg/dl 이상인경우로, 고지혈증은이전에고지혈증을진단받아치료받고있는환자들과총콜레스테롤이 220 mg/dl 이상인경우로정의하였다. 비만유무는체질량지수 (BMI, body mass index) 25 이상을기준으로구별하였으며, 대사증후군은미국의 NECP (National Cholesterol Education Program) 의 ATP (Adult Treatment Panel) III 정의에의해다음중 3개이상의기준을만족시키는경우에진단하였다. 1 허리둘레남자 90 cm, 여자 85 cm, 2 중성지방 (serum triglycerides) 150 mg/dl, 3 고밀도지질단백콜레스테롤 (HDL cholesterol) 남자 < 40 mg/dl, 여자 < 50 mg/dl, 4 공복혈당 (fasting blood glucose) 110 mg/dl 또는당뇨병치료중, 5 혈압 (systemic arterial blood pressure) 130/85 mmhg. 뇌혈관영상에서의미있는협착또는폐색병변은 50% 이상의협착을보이거나폐색된경우로정의하였으며, 뇌졸중의아형은 Trial of Org in Acute Ischemic Stroke Treatment (TOAST) 분류를기준으로 large artery disease (LAD), small vessel disease (SVD), cardioembolism (CE), other determined (OD), undetermined (UD) 로나누었다. 11 2) 혈액검사연구대상으로선정된환자에게 22게이지 (gauge) 의바늘을사용하여정맥혈 3 ml 를 3.2% sodium citrate 가주입된진공튜브에채혈하였다. 튜브를부드럽게 4-5 회기울여 citrate 와혈액이잘섞이게한다음실온에서채혈후 분사이에 302 대한신경과학회지제 26 권제 4 호, 2008

3 허혈성뇌졸중환자에서신속혈소판기능검사를이용한클로피도그렐의혈소판응집억제반응측정 3 ml 의 citrated 혈액을피브리노겐이도포된구슬, 혈소판촉진제인트롬빈수용체활성화펩티드 (thrombin receptor activating peptide, TRAP) 및 ADP 가포함된카트리지 (cartridge) 에넣고 VerifyNow R -P2Y12 assay 를통해클로피도그렐에의한혈소판응집억제반응을측정하였다. VerifyNow R -P2Y12 assay 에는 ADP 외에도프로스타글란딘 (prostaglandin E1, PGE1) 이포함되어있는데 PGE1 은세포내칼슘의농도를억제하여 P2Y1 수용체에결합하는 ADP 에의해혈소판응집이활성화되는것을억제한다. 즉 P2Y1 수용체에의한혈소판응집반응을제외하고클로피도그렐이작용하는 P2Y12 수용체에의한혈소판응집반응만을측정하여 P2Y12 반응도 (PRU, P2Y12 Reaction Unit) 로표시한다. 또한신속혈소판기능검사카트리지의분리된채널에있는 TRAP 은혈소판의 PAR (protease-activated receptor)-1과 PAR-4 에의한혈소판응집반응을통해기저값 (BASE, base PRU) 을나타내주는작용제 (agonist) 로이용된다. 즉클로피도그렐을복용하기전에혈소판의응집반응을직접측정하는것이아니라클로피도그렐이작용하는 ADP 가아닌 TRAP 에의해유도된 혈소판의응집반응을이용해기저혈소판기능을추정하여 BASE 로표시하게된다. 12 이와같이측정된 BASE, PRU 를이용하여혈소판응집저해백분율 (Inhibition, %=(1-PRU/BASE) 100) 이계산되어나타나며, Inhibition 이 20% 미만이면불충분한혈소판응집억제반응으로판정하였다. 3) 통계분석불충분한혈소판응집억제반응을보인군과그렇지않은군으로나누고비모수적검정법을이용하여두군을비교하였다. 이때비연속성변수들은 Fisher s exact test 를, 연속성변수의비교는 Mann-Whitney U test 와 Kruskal-Wallis H test를이용해분석하였다. 모든통계는양측검정을하였으며유의수준은 p-value 가 0.05 미만인경우로하고통계적분석은 SPSS for window version 12.0 을사용하였다. 결과 총 92 명의환자가연구에참가하였으나다른항혈소판제 Table 1. Comparison between the clopidogrel responders and non-responders Responders (Inhibition 20%) n=62 (72.1) Non-responders (Inhibition<20%) n=24 (27.9) p value Age, year, mean±sd 62.6± ± Sex, male, n (%) 28 (45.2) 13 (54.2) Hypertension, n (%) 48 (77.4) 18 (75.0) Diabetes, n (%) 16 (25.8) 10 (41.7) Hyperlipidemia, n (%) 31 (50.0) 9 (37.5) Hemoglobin, g/dl, mean±sd 13.6± ± Platelet, 10 3 /μl, mean±sd 270.4± ± Duration of treatment <30 days, n (%) 7 (11.3) 2 (8.3) 30 days ~ 1 year, n (%) 31 (50.0) 13 (54.2) >1 year, n (%) 24 (38.7) 9 (37.5) Obesity (BMI 25.0 Kg/m 2 ) 21/43 (48.8) 8/18 (44.4) Metabolic syndrome 20/43 (46.5) 10/21 (47.6) Coadministration of statins, n (%) Lipophilic statins, n=18 (%) 13/20 (65.0) 5/18 (27.9) Hydrophilic statins, n=18 (%) 16/18 (88.9) 2/18 (11.1) Transient Ischemic Attack 5 (8.1) 5 (20.8) TOAST classification, stroke subtypes Large artery disease 21/59 (35.6) 4/17 (23.5) Small vessel disease 18/59 (30.5) 9/17 (52.9) Undetermined 20/59 (33.9) 4/17 (23.5) Cervical ICA steno-occlusion 13/57 (22.8) 4/23 (17.4) BMI; body mass index, ICA; internal carotid artery, n; number of patients, numbers in parentheses are percentages, SD; standard deviation, TOAST; Trail of Org in Acute Stroke Treatment. Lipophilic statins include simvastatin and atorvastatin, and hydrophilic statins contain pravastatin and rosuvastatin. J Korean Neurol Assoc Volume 26 No. 4,

4 김재국김형일신혜은이보람전종은이수주 A B Figure 1. Distribution of BASE (base P2Y12 reaction unit) and PRU (P2Y12 reaction unit). These graphs show the range of BASE using TRAP (thrombin receptor activating peptide) (A), and PRU using ADP (adenosine diphosphate) on the rapid platelet function assay (B). There are inter-individual variability in BASE and PRU. 또는혈소판응집에영향을줄수있는약제를복용한 3명과혈소판기능검사에서오류를보인 3명을제외한 86명을최종분석했다. 환자들의평균연령은 62.8±11.4 세 ( 범위 :36 83세) 였으며남자는 41명 (47.7%) 이었다. 뇌졸중의위험인자중고혈압은 66명 (76.7%), 당뇨는 26명 (30.2%), 고지혈증은 40명 (46.5%) 에서관찰되었다. 환자들의헤모글로빈은 13.6±1.5 (g/dl), 혈소판수치는 267.1±50.3( 10 3 /μl) 이었다. 클로피도그렐복용기간을기준으로나눠보면 1개월미만이 9명 (10.5%), 1개월이상 1년미만이 44명 (51.2%), 1년이상이 33명 (38.4%) 이었다. 뇌졸중은 TOAST 분류기준으로 LAD 25명 Figure 2. Response variability to clopidogrel. This histogram shows the range of inhibition on the rapid platelet function assay. Ineffective aggregation-inhibition or resistance is defined as inhibition < 20%. Ineffective aggregation-inhibition is present in those patients below the solid arrow. Table 2. Results of VerifyNow R -P2Y12 assay Responders (Inhibition 20%) Non-responders (Inhibition < 20%) BASE 292.8± ±43.3 PRU 170.3± ±39.0 Inhibition (%) 41.2± ±11.1 BASE; base P2Y12 reaction unit, PRU; P2Y12 reaction unit. (29.1%), SVD 27명 (31.4%), CE 0명 (0%), OD 0명 (0%), UD 24명 (25.6%) 이었고 TIA 는 10명 (11.6%) 이었으며, 경부내경동맥의협착및폐색은 17명 (21.3%) 에서관찰되었다 (Table 1). TRAP 을작용제로사용하여측정한 BASE 는 134 에서 495 사이에분포하는데비해 ADP 를작용제로사용하여측정한 PRU 는 15에서 461 사이에분포하였다 (Fig. 1). 이는클로피도그렐의혈소판응집억제효과가광투과도의저하로나타난것이다. 일부환자에서는 BASE 보다 PRU 가커서 BASE-PRU 값이음수로나타난경우도있었다. 혈소판응집저해백분율 (Inhibition) 20% 미만으로불충분한응집억제반응을보인환자는 24 명 (27.9%), 20-40% 인환자는 36 명, 41-60% 인환자는 15명, 60-80% 인환자는 8명, 80% 이상인환자는 3명으로나타났다 (Fig. 2). VerifyNow R -P2Y12 assay 검사결과 Inhibition (%) 20을기준으로나눈두군에서 BASE 는차이가없었으나 PRU 는차이를보였다 (Table 2). 불충분한응집억제반응을보인군과그렇지않은군사이에인구학적자료 ( 나이, 성별 ), 위험인자 ( 고혈압, 당뇨, 고지혈증, 비만, 대사증후군유무 ), 혈액검사자료 ( 헤모글로빈, 혈소판수치 ), 클로피도그렐복용기간및병용하는 statin 종류, 뇌졸중의아형및경부내경동맥의협착및폐색유무에따른차이는없었다 (Table 1). 불충분한응집억제반응을보인환자군에서당뇨병발병비율이높고 statin 계약물의병용비율이낮았으며, 지방친화성 statin 복용비율 (27.9%) 이친수성 statin 복용비율 (11.1%) 보다높게나타났지만통계적유의성은없었다 (p=0.192, p=0.153, p=0.402). 고찰 혈소판기능검사들가운데가장널리쓰이는것은고전적인응집측정기 (conventional aggregometry - Born s method) 304 대한신경과학회지제 26 권제 4 호, 2008

5 허혈성뇌졸중환자에서신속혈소판기능검사를이용한클로피도그렐의혈소판응집억제반응측정 를이용한방법이다. 이것의원리는시간에따라혈소판응집이일어나면서빛의투과도가변화하는정도를백분율로표시하여혈소판응집정도를평가하는것이다. 이검사법은다른검사법과비교하여많은양의혈액, 긴검사시간및많은비용이필요하며, 검사자가혈액을여러단계를거쳐조작해야하고반복검사간에검사의재현성이낮다는단점들이있어임상에직접적용하기에한계가있다. 13 최근개발된 VerifyNow R -P2Y12 assay 는고전적인응집측정기법과같이혈소판응집반응에의한광투과도변화를측정하는혼탁도측정법 (turbidometry) 을원리로한다. 하지만이검사법은고전적인응집측정기법에비해검사에필요한혈액량이적고채혈된혈액 ( 전혈 ) 을그대로사용할수있으며, 검사방법이간단하고검사시간이짧아비전문가에의해서도현장검사 (point of care) 가가능하다는장점이있다. 13 또한고전적인응집측정기및다른혈소판기능검사들을이용하여클로피도그렐의혈소판응집억제효과를측정한비교연구에서다른검사들에비해 VerifyNow R -P2Y12 assay의혈소판응집억제효과측정이고전적인응집측정기법과의일치도가높다고보고되었다 본연구결과에서보듯이동일한용량의클로피도그렐을복용하였음에도환자마다넓은범위의 BASE, PRU, Inhibition 값을보였다 (Fig. 1). 이는혈소판응집억제반응이사람마다다양하게나타난다는이전연구결과와일치한다 본연구에서 2차예방목적으로클로피도그렐 (75 mg/day) 을복용하는 86명의뇌졸중환자들중 24명 (27.9%) 이신속혈소판기능검사 (VerifyNow R -P2Y12 assay) 에서불충분한혈소판응집억제반응을보였다. 급성기뇌경색환자를대상으로전혈에서저항을측정하는방법을이용한국내연구에서클로피도그렐의저항성은 18.6% 로보고되었으며, 7 67명의뇌경색환자를대상으로고전적인응집측정기를이용한국외연구에서클로피도그렐의불충분한응집억제는 18% 에서나타났다. 9 이런빈도의차이는불충분한응집억제반응에대한판단기준, 검사방법, 채혈시점및대상환자등의차이에기인한다. 혈액검사를통해환자의증상재발전에클로피도그렐의저항성을예측하는연구는앞에서도언급한것과같이고전적인검사방법의문제점과일정한판정기준이없는이유로드물었다. 이전연구들은고전적인응집측정기를이용한것이대부분이며관상동맥질환환자들에제한되어있는상태이다. 따라서본연구는만성기허혈성뇌졸중환자에서클로피도그렐에의한혈소판응집억제반응이환자마다다양하며적지않은비율의환자들 (27.9%) 에게불충분한응집억제반응이나타난것을확인한점에의미가있다. 관상동맥질환을가진환자를대상으로시행된연구에서클로피도그렐저항성은 5-44% 정도로다양하게보고되었다. 6 관상동맥중재시술을할때클로피도그렐 300 mg 을부하용량으로사용한환자를대상으로시행된이전연구들의결과 (24-44%) 와비교해볼때본연구에서저항성을보인환자의비율은약간낮았다. 6 그이유는관상동맥질환과허혈성뇌졸중이라는질환의차이외에도혈소판기능검사의시점 ( 급성기대만성기 ) 및방법의차이때문일수있다. 관상동맥질환환자들의경우중재시술시클로피도그렐 300 mg 을복용한뒤 1일이내에클로피도그렐의혈소판응집억제효과를측정한반면에본연구에서는최소 2주이상클로피도그렐 (75 mg/day) 을복용한환자들을대상으로혈소판기능검사를시행하였다. 환자의기저상태에영향을줄수있는중재시술직후에혈소판기능검사를시행할경우혈소판응집반응이더욱잘일어나게된다. 20 따라서급성기에혈소판기능검사를하게되면만성기에비해클로피도그렐저항성을보이는환자의비율이높게나타날수있다. 또한기존연구들의검사방법인광투과도를이용한응집측정기법은 ADP 만을작용제로사용하여혈소판의응집정도를측정하므로 P2Y12 ADP 수용체가아닌 P2Y1 ADP 수용체에의한혈소판응집효과를제거하지못한다. 따라서기존의방법으로는클로피도그렐에의한혈소판응집억제효과를정확하게평가할수없어검사방법에따라저항성을보이는비율에차이가날수있다. 환자의낮은순응도, 부족한용량, cytochrome P450 3A (CYP3A) 활성도의차이, P2Y12 수용체및 CYP3A system 의다형성 (polymorphism), 약물상호작용등이클로피도그렐저항성의기전으로제시되었지만아직까지명확하게밝혀진것은없다. 5,6 클로피도그렐복용용량과관련된연구에서 300 mg 의클로피도그렐을복용한뒤유지용량 (75 mg/day) 을사용한환자군에비해 600 mg 을복용한뒤유지용량을사용한환자군에서클로피도그렐저항성의발생빈도가상대적으로낮은것을확인할수있었다. 21 즉복용용량을증가시킴으로써클로피도그렐저항성을줄일수있음을보여주는연구결과이다. 하지만본연구에서는일정한용량 (75 mg/day) 의클로피도그렐을복용하는환자들을대상으로하였기에용량과저항성사이의연관성은확인할수없었다. 심혈관질환환자들을대상으로한연구에서당뇨병환자들은혈소판활성화및작용제에대한반응이높아서클로피도그렐저항성빈도가높은것으로알려져있다. 22 본연구에서는클로피도그렐저항성을보인환자군에서당뇨의빈도가높게 J Korean Neurol Assoc Volume 26 No. 4,

6 김재국김형일신혜은이보람전종은이수주 나타났으나통계적으로의미는없었다 (25.8% vs. 41.7%, p=0.192). 이연구는외래에직접방문한환자들만을대상으로시행되었다. 즉뇌졸중이나당뇨의합병증으로인해심한장애가남은환자들의경우외래에직접내원할수없기때문에비교적경한장애가남은환자들만이연구에참가하였다. 따라서당뇨가클로피도그렐저항성에미친영향을있는그대로평가하지못하고일부당뇨환자들만이연구대상으로선정되는선택오차 (selection bias) 가발생했을수있다. 클로피도그렐은비활성화상태로복용되는약물로 CYP3A 를통해활성화되면 P2Y12 수용체에비가역적으로결합하여 glycoprotein Ⅱb/Ⅲa 의활성화를억제함으로써혈소판의응집억제효과를나타낸다. 그런데 simvastatin, atorvastatin 과같은지방친화성 (lipophilic) statin 은 CYP3A 를통해대사된다. 따라서이런종류의 statin 중에일부는클로피도그렐과함께복용하게되면 CYP3A 에경쟁적억제제로작용하여클로피도그렐의항혈소판작용을방해하는것으로알려져있다. 23 하지만본연구에서지방친화성 statin 병용과불충분한혈소판응집반응사이에연관성은없었다. 이것은대상환자의숫자가적어연관관계를밝혀내지못했을가능성도있지만 CYP3A 의유전적다형성때문일수있다. 유전자형 (genotype) 이 non-expressor genotype인사람들은클로피도그렐과 CYP3A 억제제사이의약물간상호작용에취약하다는보고가있다. 24 따라서본연구대상환자들의유전자형이 non-expressor genotype 이아닌 expressor genotype 이어서지방친화성 statin 의영향을받지않아연관성이없는것으로나타났을수있다. 지방친화성 statin 과클로피도그렐의혈소판응집억제반응사이의관계는추후대상환자를보충하여 CYP3A 유전자형을함께조사함으로써확인해볼수있을것이다. 뇌졸중아형중 LAD 의병태생리는죽상경화증으로설명하고있으므로 LAD 환자들은 non-lad 환자들에비해불충분한응집억제반응을보일것으로유추해볼수있다. 하지만본연구에서 LAD 유무와불충분한응집억제반응사이에연관성은없었으며다른뇌졸중아형에서도다르지않았다. 또한경부내경동맥협착및폐색의유무에따른혈소판응집억제효과의차이는없었다. 이것은대상환자들이적어통계적연관성을확인하지못한것으로생각된다. 혈액검사를통해나타난저항성과임상에서보이는치료실패즉혈관질환의재발이일치하는것은아니다. 5,6 하지만혈액검사에서나타난저항성을통해임상적인혈관질환재발가능성을유추해볼수있는연구들이있다. 아스피린의경우혈소판기능검사에서저항성을보인환자가그렇지않은환자 보다추후혈관질환이재발하는상대적인위험도가약 4배정도높다는보고가있으며, 25 안정형협심증, 심근경색환자들을대상으로시행된연구에서혈액검사로클로피도그렐저항성이확인된환자들이혈전성질환의발병위험이높은것으로나타났다. 26,27 따라서더많은환자들을등록하고저항성을보인환자들을추적관찰하여임상적인재발여부를확인함으로써혈소판기능검사를통해나타난클로피도그렐저항성의임상적의의를찾을수있을것이다. 본연구는다음과같은제한점이있다. 우선대상환자의수가비교적적어통계적인차이점을구할때생길수있는제 2종오류 (type 2 error) 의가능성이있으며, 단일병원에방문한허혈성뇌졸중환자만을대상으로해서대표성이떨어지는약점이있다. 또한한환자에있어서도클로피도그렐복용시기에따라혈소판기능검사상클로피도그렐의혈소판응집억제반응이다르게보고되는바본연구와같이한번의혈소판기능검사로판정하는것보다는반복검사를통해결과를해석하는것이좋을것이다. 마지막으로불충분한혈소판응집억제반응의기준으로 Inhibition(%)<20 을임의로사용하였으나여러연구기관에서많은환자들을대상으로검사하고추적관찰을통해임상적재발을보이는환자들을분석함으로써적절한판정기준을정할수있을것이다. 결론적으로만성기뇌경색환자들의클로피도그렐에의한혈소판응집억제반응은다양하게나타났으며, 불충분한혈소판응집억제반응이적지않은환자들 (27.9%) 에게서관찰되었다. 이런혈소판기능검사의결과가혈전성질환의재발및예후판정에이용할수있을지에대해서는추가연구가필요할것으로생각된다. REFERENCES 1. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med 1999; 340: Zeller JA, Tschoepe D, Kessler C. Circulating platelets shows increased activation in patients with acute cerebral ischemia. Thromb Haemost 1999;81: Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation 1999;100: CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk ischemic events (CAPRIE). Lancet 1996:348: Wiviott SD, Antman EM. Clopidogrel resistance: a new chapter in a fast-moving story. Circulation 2004;109: Gurbel PA, Tantry US. Clopidogrel resistance? Thromb Res 2007; 120: Jeon SM, Cha JK, Kim SH, Kim JW. Clopidogrel resistance in acute ischemic stroke. J Korean Neurol Assoc 2006;24: 대한신경과학회지제 26 권제 4 호, 2008

7 허혈성뇌졸중환자에서신속혈소판기능검사를이용한클로피도그렐의혈소판응집억제반응측정 8. Cheon SM, Yun GU, Park KW, Kim SH, Kim JW, Shin HC, et al. The difference of platelet aggregability in patients with cerebral infarction according to type of anti-platelet agents. J Korean Neurol Assoc 2004;22: Pongrácz E. Measurement of platelet aggregation during antiplatelet therapy in ischemic stroke. Clin Hemorheol Microcirc 2004;30: Caplain H, Kieffer G, Thiercelin JF, Thebault JJ. Tolerance and clinical pharmacology of repeated administration of clopidogrel (SR25990C) a new antiplatelet agent, at three dose levels in normal healthy volunteers. Thromb Haemost 1989;62: Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org in Acute Stroke Treatment. Stroke 1993;24: Malinin A, Pokov A, Swaim L, Kotob M, Serebruany V. Validation of a VerifyNow R -P2Y12 cartridge for monitoring platelet inhibition with clopidogrel. Methods Find Exp Clin Pharmacol 2006;28: Michelson AD. Platelet function testing in cardiovascular diseases. Circulation 2004;110: Martin A, Pokov A, Spergling M, Defranco A, Schwartz K, Schwartz D, et al. Monitoring platelet inhibition after clopidogrel with the VerifyNow-P2Y12 R rapid analyzer: the VERIfy Thrombosis risk ASsessment (VERITAS) study. Thromb Res 2007;119: Paniccia R, Antonucci E, Gori AM, Marcucci R, Giglioli C, Antoniucci D, et al. Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary artery disease patients. J Thromb Haemost 2007;5: von Beckerath N, Pogatsa-Murray G, Wieczorek A, Sibbing D, Schömig A, Kastrati A. Correlation of a new point-of-care test with conventional optical aggregometry for the assessment of clopidogrel responsiveness. Thromb Haemost 2006;95: Järemo P, Lindahl TL, Fransson SG, Richter A. Individual variations of platelet inhibition after loading doses of clopidogrel. J Intern Med 2002;252: Angiolillo DJ, Fernández-Ortiz A, Bernardo E, Ramírez C, Sabaté M, Bañuelos C, et al. High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability. Eur Heart J 2004;25: Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005;45: Gurbel PA, Cummings CC, Bell CR, Alford AB, Meister AF, Serebruany VL. Onset and extent of platelet inhibition by clopidogrel loading in patients undergoing elective coronary stenting: the Plavix Reduction Of New Thrombus Occurrence (PRONTO) trial. Am Heart J 2003;145: Gurbel PA, Bliden KP, Hayers KM, Yoho JA, Herzog WR, Tantry US. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005;45: Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramírez C, Sabaté M, Jimenez-Quevedo P, et al. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 2005;54: Mach F, Senouf D, Fontana P, Boehlen F, Reber G, Daali Y, et al. Not all statins interfere with clopidogrel during antiplatelet therapy. Eur J Clin Invest 2005;35: Suh JW, Koo BK, Zhang SY, Park KW, Cho JY, Jang IJ, et al. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. CMAJ 2006;174: Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Huisman MV. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. Arch Intern Med 2007;167: Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109: Lev EI, Patel RT, Maresh KJ, Guthikonda S, Granada J, DeLao T, et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol 2006;47: J Korean Neurol Assoc Volume 26 No. 4,

(이수주-김재국) hwp

(이수주-김재국) hwp 원저접수번호 :09-029(2 차 -0710) 을지대학교을지대학병원신경과 김재국이상준조성래김진옥김효정윤동주고영채오건세이수주 Platelet Function Assay for Clopidogrel and Ticlopidine in Patients with Ischemic Stroke Jae Guk Kim, MD, Sang Jun Lee, MD, Sung Rae