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1 원저 Korean Circulation J 2003;33(10): 급성심근경색환자에서평균혈소판용적의예후예측능 경북대학교의과대학경북대학교병원순환기내과학교실 이주환 김형섭 권용섭 이현상 박만기 허정호양동헌 박헌식 조용근 채성철 전재은 박의현 The Prognostic Value of Mean Platelet Volume in Acute Myocardial Infarction Ju Hwan Lee, MD, Hyung Seop Kim, MD, Yong Seop Kwon, MD, Hyun Sang Lee, MD, Man Gee Park, MD, Jung Ho Heo, MD, Dong Heon Yang, MD, Hun Sik Park, MD, Yong Keun Cho, MD, Shung Chull Chae, MD, Jae Eun Jun, MD and Wee Hyun Park, MD Department of Internal Medicine, Kyungpook National University College of Medicine, Daegu, Korea ABSTRACT Background and Objectives:An increased platelet volume is associated with increased platelet reactivity, and may influence the outcome following a myocardial infarction. Subjects and Methods:One hundred patients with acute myocardial infarction, who visited Kyungpook National University Hospital between 2001 January and 2001 December, were included in this study. To determine the mean platelet volume (MPV), blood samples, taken at the time of arrival, were analyzed in an automated haematology analysis system (CELL-DYN3000, ABBOTT, USA). EDTA in the blood bottles was used as an anticoagulant. All samples were processed within 30 minutes of venipuncture, to avoid bias due to platelet swelling. The patients were followed for one year for readmission due to acute coronary syndrome, congestive heart failure or death. To stratify the prognostic value of the MPV, the patients were divided into 4 equal groups according to the percentiles of the platelet volume. Results:Eight patients died, and 20 were readmitted due to acute coronary syndrome or congestive heart failure. The MPV is not a significant predictor of death. However, in the prediction of MACE, death and readmission, the MPV and age were significant factors (p<0.001 and p=0.046, respectively). The highest quartile group(mpv> 8.8fL) had a 7 times greater risk of MACE than the lowest quartile group (MPV<7.4 fl). Conclusion:The MPV measured in the emergency room is a significant predictor of MACE with an acute myocardial infarction. Therefore, patients with a large MPV might require more intensive, closely controlled treatment strategies for secondary prevention. (Korean Circulation J 2003;33 (10): ) KEY WORDS:Blood platelets;myocardial infarction;prognosis. 878 서 급성심근경색은현대사회에서중요한사인의하나이며, 우리나라에서는최근그빈도가증가되고있다. 론 급성심근경색의가장중요한원인은동맥경화증이며, 동맥경화증의주요위험인자로서는흡연, 고지혈증, 당뇨병, 고혈압이잘알려져있고 1) 호모시스타인, 섬유소원 (fibrinogen), hs-crp 등의새로운위험인자들을 논문접수일 :2003 년 4 월 30 일수정논문접수일 :2003 년 6 월 19 일심사완료일 :2003 년 7 월 28 일교신저자 : 채성철 대구중구삼덕 2 가 50 번지경북대학교의과대학경북대학교병원순환기내과학교실전화 :(053) 전송 :(053) scchae@knu.ac.kr

2 발견하려는노력이진행중이다. 혈소판이동맥경화증의생성과정에서중요한역할을하는것은잘알려져있다. 혈소판은비정상적인내피세포에부착하여사이토카인 (cytokine) 과성장인자 (growth factor) 를포함하고있는과립 (granule) 을방출하여평활근세포 (smooth muscle cell) 와대식세포 (macrophage) 의이동과증식을유도하고포말세포 (foam cell) 를형성하여죽상반 (atheroma) 을이루게된다. 2) 그리고죽상반이파열되는경우혈소판이응집하고이에따른혈전생성은관상동맥의폐색을유발하여급성심근경색을일으키게된다. 3)4) 따라서혈소판의활성도는관상동맥질환에중요한역할을할것이다. 혈소판의활성도를측정하기위한시도로는혈소판의모양, 혈소판의응집정도, 혈소판활성화물질의정량적인측정등이있고, 근래에는혈소판용적을혈소판활성도의지표로사용하려는시도가있다. Corash 등 5) 은응집검출계 (aggregometer) 로측정시용적이큰혈소판이작은혈소판보다더활동적임을보고하였고, Karpatkin 등 6) 은혈소판의용적이크면혈소판의혈전생성능력이증가됨을보고하였다. 평균혈소판용적과급성심근경색및관상동맥증후군과의관계에대해서도연구들이있었다. 7-10) Martin 등 9) 은심근경색으로내원한 1716 명을대상으로심근경색후 6개월뒤의평균혈소판용적을측정하여 2년뒤사망과허혈성심질환의재발을측정하여허혈성심질환을일으킨군에서평균혈소판용적이더큼을보고하였다. 그리고 Halbmayer 등 10) 은관상동맥우회술대기중인허혈성심질환환자 426명과대조군 125 명의평균혈소판용적을비교하여두군간에평균혈소판용적의차이가없음을보고하였다. 그러나증가된혈소판용적의생리학적의미나급성심근경색에서의예후예측능에대해서는아직논란이있으며급성심근경색의급성기에측정한평균혈소판용적의예후예측능에대한연구는찾기가어려웠다. 이에저자는급성심근경색으로내원한환자들에서의평균혈소판용적의예후예측능에대해검토하였다 년 1월부터 2001년 11월까지경북대학교병원에내원한급성심근경색증환자를대상으로하였다. 급성심근경색은 ESC/ACC(European Society of Cardiology/American College of Cardiology) 진단기준에따라서 CK-MB 나 troponin의상승과허혈성흉통의동반이나심전도상병적인 Q파나허혈을시사하는소견이있는경우로하였다. 11) 상기기간에내원한급성심근경색환자 126 명중신생물 1명, 심근경색증의과거력이있던환자 4명, 만성신부전 1명, 급성감염 ( 폐렴 ) 1명, 통풍 1명, 추적관찰소실되었던 18 명을제외한총 100 명을대상으로하였다. 응급실내원직후일반혈액검사, 심근효소검사를시행하였으며공복후지질검사를시행하였고내원후면담을통해흡연력, 가족력, 기존의질환등을조사하였다. 구혈율은심초음파심첨부 4상에서 modified Simpson s method 를이용하여계산하였다. 고지혈증은총콜레스테롤 200 이상이거나저밀도지단백콜레스테롤 (LDL-cholesterol) 130 mg/dl 이상또는중성지방 150 mg/dl 이상으로정의하였다. 관상동맥조영술은총 71명에서시행하였으며 50% 이상의협착을유의한협착으로정의하였다. 추적관찰은 1년간시행하였다. 주요심장사건 (Major adverse cardiac event:mace) 으로는사망과, 심부전이나관상동맥증후군으로인한재입원으로정의하였다. 평균혈소판용적의측정은응급실내원시채혈후 30 분이내에측정하는것을원칙으로하였으며항응고제로는 EDTA를사용하여 CELL-DYN3000(ABBOTT, USA) 으로측정하였다. 본원의정도관리자료에따라 interassay variation coefficient 는 4% 로측정되었다. 두군간의평균혈소판용적의차이는 Student s t- test 를시행하여분석하였고, 교란변수를제거하고백분위수에의한 4군간의차이를알아보기위해 multivariate logistic regression analysis 를사용하였다. 통계처리를위해 Statistical Package for the Social Science(SPSS) version 10.0(SPSS, Illinois, USA) 을사용하였다. 결과 대상및방법 대상환자 100 명가운데남자가 70명이였으며평균연령은 61(±10) 세였다. 30명이고혈압으로치료받고있었으며 21명이당뇨병으로경구용혈당강하제또는인슐린을사용하고있었다. 6명에서허혈성심질환의가족력이있었으며 65명에서흡연력이있었고고지혈증 879

3 은 54명에서있었다 (Table 1). 84명이 ST절상승심근경색이였으며나머지 16명은 ST절비상승심근경색이였다. 이중 37명에서일차적경피적관상동맥중재술을시행하였고, 39명에서는 urokinase 를사용한혈전용해요법을시행하였으며이중 25명은입원기간내구조 (rescue) 경피적관상동맥중재술을시행하였다. 나머지 24명은보존적치료를하였으며이중 9명이입원기간내선택적인 (elective) 경피적관상동맥중재술을시행하였다. 관상동맥조영술을시행한 71명중 42명이일혈관질환을가져빈도가가장높았고 20명이이혈관질환, 9명이삼혈관질환을가지고있었다. 평균혈소판용적은 8.25 fl±1.22 fl이였다. 100 명의환자들중 8명이추적관찰기간중사망하였으며 20 명이재입원하였다. 각각의재입원의이유를살펴보면심근경색의재발이 2명, 불안정협심증이 12명, 심부전이 6명이였다. 사망한군과생존한군과의혈소판용적은사망군에서 8.74 fl±1.08 fl로생존군의 8.2 fl±1.23 fl와비교시유의한차이는없었다. 단변량분석에서사망의예측인자로서성별, 나이와구혈율이유의하게나타났으나 (Table 2) 다변량분석에서유의한인자는없었다. 두군간의관상동맥조영술소견도유의한차이는없었다. 주요심장사건의예측인자로서는나이와평균혈소판 Table 1. Demographic and clinical characteristics of the study population Characteristics Number of patients Gender, male/female 70/30 Risk factor Smoking 65 Hypertension 30 Hyperlipidemia 54 Diabetes mellitus 21 Family history 06 Diagnosis STEMI 84 NSTEMI 16 In-hospital therapy Primary PCI 37 Thrombolytics 14 Thrombolytics+rescue PCI 25 Conservative 15 Conservative+elective PCI 09 Coronary angiographic finding 1 vessel 42 2 vessel 20 3 vessel 09 Major adverse cardiac event Death 08 Reinfarction 02 Unstable angina 12 Heart failure 06 PCI:percutaneous coronary intervention, STEMI:STsegment elevation myocardial infarction, NSTEMI:non- ST segment elevation myocardial infarcition Table 2. Comparison of clinical and laboratory findings between survival and death cases in univariate analysis Survival (n=92) Death (n=8) p Male 67 (72.8%) 3 (37.5%) Age (yr).0060± ± Diabetes mellitus 19 (20.6%) 2 (25%) Hypertension 29 (31.5%) 1 (12.5%) Family history 05 (05.4%) 1 (12.5%) Smoking 61 (66.3%) 4 (50%) LDL (mg/dl).0123± ± PeakCKMB (ng/ml) 143.7± ± LVEF (%) 53.78± ± Platelet (number) k±64.3 k 214 k±86.5 k MPV (fl) 008.2± ± CAG 1 vessel 60% 40% vessel 27% 40% 3 vessel 12% 20% LVEF : left ventricular ejection fraction, MPV : mean platelet volume, CAG : coronary angiogram 880 Korean Circulation J 2003;33(10):

4 용적이단변량분석에서유의하였는데사고가일어난군에서평균혈소판용적이 8.9 fl±1.51 fl로사고가일어나지않은군의 7.9 fl±0.98 fl에비해의미있게증가되어있었다 (p<0.001)(table 3). 나이, 저밀도지단백콜레스테롤 (LDL-cholesterol), 당뇨병, 고혈압, 가족력, 흡연력, 구혈률을포함시켜시행한다변량분석에서도평균혈소판용적은유의한주요심장사건의예측인자였다 (p<0.05)(table 4). 평균혈소판용적의증가에따른위험도의증가를알 Table 4. Prognostic value of clinical and laboratory findings for prediction of MACE in logistic regression analysis Odds ratio 95% confidence interval Lower Upper Age LDL Diabetes mellitus Hypertension Family history Smoking LVEF MPV LVEF:left ventricular ejection fraction, MPV:mean platelet volume, MACE:major adverse cardiac event, LDL:low density lipoprotein p 아보기위해환자들을평균혈소판용적의백분위수에따라 4군으로구분했을때는 (Table 5) 평균혈소판용적이증가할수록주요심장사건의발생빈도가유의하게증가하였다 (p<0.05)(fig. 1). 이를다변량분석을시행하였을때평균혈소판용적의 4군은 1군보다 7배정도비차비 (odd s ratio) 가높았다 (p<0.05)(table 6). Table 5. Distribution of MPV and number of cases in each quartile of the study population Quartile MPV(fL) Number of patients 1 st nd rd th MPV:mean platelet volume % n=3 *:p=0.025 vs 1st quartile n=3 n=9 Fig. 1. Rate of MACE among MPV quartiles. * n=13 1st 2 nd 3 rd 4th MPV quartile Table 3. Comparison of clinical and laboratory findings between cases without and with MACE in univariate analysis No MACE group (n=72) MACE group (n=28) Male Age (yr) 00.60± ± Diabetes mellitus 13 (18%) 08 (28%) Hypertension 20 (27.8%) 10 (35.7%) Family history 05 (06.9%) 01 (03.6%) Smoking 48 (66.7%) 17 (60.7%) LDL (mg/dl) 0.120± ± Peak CKMB (ng/ml) 0.151± ± LVEF (%) 54.34± ± Platelet (number) 230 k±66 k 228 k±68 k MPV (fl) 007.9± ± CAG vessel 59% 58% 2 vessel 27% 29% 3 vessel 13% 11% LVEF : left ventricular ejection fraction, MPV : mean platelet volume, MACE : major adverse cardiac event, LDL:low density lipoprotein p 881

5 Table 6. Prognostic value of clinical and laboratory findings for prediction of MACE including MPV as dummy variable (quartile) in logistic regression analysis 882 Odds ratio 고 95% confidence interval Lower 혈소판의활성화는동맥경화증, 관상동맥질환, 뇌혈관질환등의발생에중요한역할을한다 ) 이러한혈소판의활성화는당뇨병, 16) 흡연, 17) 고혈압, 경구피임약의복용 18) 등과연관되어있다고알려져있다. 그리고혈소판의활성화에는혈소판의모양의변화, 혈소판의응집, 혈소판과립의방출등이관여하며, 혈소판의모양, 응집정도, 혈소판활성화물질의정량적인측정으로혈소판의활성화정도를알수있다. 혈소판의모양은 flow cytometry 나전자현미경 (electron microscopy) 으로측정할수있으나 19) 채혈후다른물질과의접촉이나온도의변화에따라모양의변화가발생할수있어혈소판활성화의척도로사용하기에는어려움이있다. 20) 혈소판의응집정도는혈소판응집검출계 (aggregometer) 에 ADP, collagen, epinephrine, thrombin 등의강도가다른작용제 (agonist) 를투입하였을때의반응으로측정할수있다. 그러나혈소판응집의측정은측정방법의번거러움과많은시간이필요하여실제임상에서많은수의환자를대상으로시행하기에는제약이있다. 또한생체외에서의응집이실제생체내에서의응집을반영하는지는알려지지않았다. 혈소판의활성도를측정하는다른방법으로혈소판세포막에있는항원을측정하는방법이있는데, 이는단일 찰 Upper Age LDL Diabetes Mellitus Hypertension Family history Smoking LVEF MPV 1 (1st:2nd) MPV 2 (1st:3rd) MPV 3 (1st:4th) LVEF:left ventricular ejection fraction, MACE:major adverse cardiac event,, LDL:low density lipoprotein p 클론성항체 (monoclonal antibody) 를사용하여활성화된혈소판세포막의 P-selectin 이나 GP Ⅱb-Ⅲa 등의항원을 flow cytometry 로측정하여혈소판의활성여부를측정한다. 이는매우높은예민도를가지고있으며항혈소판치료시행시치료효과를측정할수있다. 21) 본연구에서는혈소판의용적을측정하였는데, 용적이증가된혈소판의생리학적의미는여전히논란이많다. 혈소판용적의증가기전은확실히밝혀져있지않지만혈소판의형태및생리는혈소판의전구세포인거대핵세포 (megakaryocyte) 의분할시또는분할전에결정되어진다고알려져있다. 22) 거대핵세포의배수성 (megakaryocyte ploidy) 은혈소판용적과밀접하게연관되어있으며그기전은아직확실히알려져있지않다. 23) 만성적인저산소증이나, 항혈소판혈청에의한혈소판의생성과파괴가동시에증가되었을때는평균혈소판용적은증가되며, 24) 당뇨병이나흡연시에도평균혈소판용적의증가를관찰할수있다고보고되어있다. 이는빠른혈소판의교체때문일것으로생각되며이들은사이토카인 (cytokine) 에의해조절되며중요한역할을하는사이토카인으로생각되는 interleukin-3, thrombopoietin, interleukin-6 등이거대핵세포의배수성 (megakaryocyte ploidy) 에영향을주어더활동적이고용적이큰혈소판을만든다는보고가있다. EDTA 를항응고제로사용시혈소판용적은시간에비례하여팽창하여한시간이지나면 20%, 8시간이지나면 22% 가팽창하며, sodium citrate 를항응고제로사용시에는시간에따른혈소판용적은시간에영향을받지않는다고보고되고있다. 25) 그러므로 EDTA 항응고제를사용시에는채혈후측정시간까지의시간에따라값의차이가있을수있다. Martin 등 9) 은 EDTA 항응고제에의한혈소판용적변화영향을피하기위해채혈후용적의팽창의영향이없어진 24시간뒤에혈소판용적을측정하였으며, Halbmayer 등 10) 은채혈후 8시간이내로혈소판용적측정을하였다. 이러한측정시간의차이가, 앞서언급한대로두연구의상이한결과를초래하였을수있다. 저자들은항응고제로 EDTA 를사용했으나시간에따른오차를최소화하기위해응급실방문시채혈후 30 분이내에평균혈소판용적을측정하였다. 본연구에서증가된평균혈소판의용적은심근경색으로내원한환자에서관상동맥증후군의재발에중요한예측인자이었으며평균혈소판용적이 8.8 Korean Circulation J 2003;33(10):

6 fl 이상인환자군들은다른위험인자들과독립적으로심장사건의발생의위험성이높았다. 다른연구에서흡연, 당뇨, 고혈압이평균혈소판용적에미치는영향에대해언급하였으나본연구에서는이들과독립적으로평균혈소판용적이심근경색이후의관상동맥증후군발생의중요한위험인자임을알수있었다. 이연구에서는약제의사용에따른평균혈소판부피의변화는측정하지않았으므로향후항혈소판약제의사용에따른혈소판부피의변화를고려한연구가필요할것으로생각된다. 결론적으로심근경색으로내원한환자들에서증가된평균혈소판용적은사망과재입원의의미있는예측인자이며평균혈소판용적이큰군에서는적극적인심혈관질환의치료와예방을필요로할것으로생각한다. 연구의제한점본연구의제한점으로는첫째, 예후인자로써관상동맥중재술은포함되지않았다는점이며, 향후약물도포스텐트등관상동맥중재술의역할을포함하여연구가진행되어야할것이다. 둘째는기존에심근경색의중요한예후인자로알려져있는구혈율이주요심장사건의발생예측인자로는나타나지않았는데이는구혈율측정시심초음파를이용한 modified Simpson s method 가국소운동장애가있는심근경색환자에서부정확하였을수있고대상환자수가많지않았으므로앞으로더많은환자들을대상으로연구해보아야하겠다. 중심단어 : 혈소판 ; 심근경색 ; 예후. REFERENCES 1) McKarns SC, Smith CJ, Payne VM, Doolittle DJ. Blood parameters associated with atherogenic and thrombogenic risk in smokers and nonsmokers with similar lifestyles. Mod Pathol 1995;8: ) Bombeli T, Schwartz BR. Harlan JM. Adhesion of activated platelets to endothelial cells: evidence for a GPIIbIIIa-dependent bridging mechanism and novel roles for endothelial intercellular adhesion molecule 1 (ICAM-1), alphavbeta3 integrin, and GPIbalpha. J Exp Med 1998;187: ) Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362: ) Davies MJ. A macro and micro view of coronary vascular insult in ischemic heart disease. Circulation 1990;82:II ) Corash L, Tan H, Gralnick HR. Heterogeneity of human whole blood platelet subpopulations: I. relationship between buoyant density, cell volume, and ultrastructure. Blood 1977;49: ) Karpatkin S. Biochemical and clinical aspects of megathrombocytes. Ann N Y Acad Sci 1972;201: ) Martin J, Trowbridge T, Slater D. Mean platelet volume in myocardial infarction. Br Med J 1983;287: ) Pizzulli L, Yang A, Martin JF, Luderitz B. Changes in platelet size and count in unstable angina compared to stable angina or non-cardiac chest pain. Eur Heart J 1998;19: ) Martin JF, Bath PM, Burr ML. Influence of platelet size on outcome after myocardial infarction. Lancet 1991;338: ) Halbmayer WM, Haushofer A, Radek J, Schon R, Deutsch M, Fischer M. Platelet size, fibrinogen and lipoprotein(a) in coronary heart disease. Coron Artery Dis 1995;6: ) The Joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined. Eur Heart J 2000; 21: ) Mustard JF, Packham MA, Rowsell HC, Jorgensen L. The role of thrombogenic factors in atherosclerosis. Ann N Y Acad Sci 1968;149: ) Mustard JF, Packham MA. The role of blood and platelets in atherosclerosis and the complications of atherosclerosis. Thromb Diath Haemorrh 1975;33: ) Cahill MR, Newland AC. Platelet activation in coronary artery disease. Br J Biomed Sci 1993;50: ) Grau AJ, Ruf A, Vogt A, Lichy C, Buggle F, Patscheke H, Hacke W. Increased fraction of circulating activated platelets in acute and previous cerebrovascular ischemia. Thromb Haemost 1998;80: ) Tschoepe D, Roesen P, Esser J, Schwippert B, Nieuwenhuis HK, Kehrel B, Gries FA. Large platelets circulate in an activated state in diabetes mellitus. Semin Thromb Hemost 1991;17: ) Maly J, Pecka M, Vodickova L, Pidrman V, Mala H, Blaha M, Jebavy L. Changes in the activity of thrombocytes by smoking. Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove 1990;33: ) Bonnar J. Coagulation effects of oral contraception. Am J Obstet Gynecol 1987;157: ) Holmsen H. Significance of testing platelet functions in vitro. Eur J Clin Invest 1994;24(Suppl 1): ) Watts SE, Tunbridge LJ, Smith K, Lloyd JV. Storage of platelets for tests of platelet function: effects of temperature on platelet aggregation, platelet morphology and liberation of beta-thromboglobulin. Thromb Res 1986;44: ) Schmitz G, Rothe G, Ruf A, Barlage S, Tschope D, Clemetson KJ, Goodall AH, Michelson AD, Nurden AT, Shankey TV. European Working Group on Clinical Cell Analysis: Consensus protocol for the flow cytometric characterisation of platelet function. Thromb Haemost 1998;79: ) Thompson CB, Love DG, Quinn PG, Valeri CR. Platelet size does not correlate with platelet age. Blood 1983;62: ) Hoffman R, Long MW. Control of thrombocytopoiesis: current state of the art. Cancer Treat Res 1995;80: ) Gladwin AM, Martin JF. The control of megakaryocyte ploidy and platelet production: biology and pathology. Int J Cell Cloning 1990;8: ) Bath PM. The routine measurement of platelet size using sodium citrate alone as the anticoagulant. Thromb Haemost 1993;70:

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