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1 대한진단검사의학회지제 28 권제 6 호 2008 Korean J Lab Med 2008;28: DOI /kjlm Original Article Diagnostic Hematology 폐색전증진단을위한 D-dimer 검사의유용성 : 단일기관연구 박노진 1 서영익 1 윤순규 1 최태윤 1 신정원 1 어수택 2 김양기 2 순천향대학교병원진단검사의학과 1, 내과 2 Utility of D-dimer Assay for Diagnosing Pulmonary Embolism: Single Institute Study Rojin Park, M.D. 1, Young Ik Seo, M.D. 1, Soon Gyu Yoon, M.T. 1, Tae Youn Choi, M.D. 1, Jeong Won Shin, M.D. 1, Soo-Taek Uh, M.D. 2, and Yang-Ki Kim, M.D. 2 Departments of Laboratory Medicine 1 and Internal Medicine 2, Soonchunhyang University Hospital, Seoul, Korea Background : Pulmonary embolism (PE) presents with diverse non-specific signs and symptoms and its diagnosis mainly depends on diagnostic imaging tests which are laborious and not costeffective, and only a small proportion of patients with suspected PE actually have the disease. The aim of this study was to analyze the utility of D-dimer test for diagnosing PE by categorizing patients into PE likely and PE unlikely groups using Wells score for clinical probability. Methods : One hundred forty consecutive patients with clinically suspected PE, in whom D-dimer and imaging tests were performed were enrolled. Dignosis of PE was made when the imaging tests were positive. Wells scores were retrospectively assigned and the dignostic utility of D-dimer test was analyzed. Results : Of the 140 patients studied, D-dimer test was positive in 97 and diagnostic imaging tests revealed PE, deep vein thrombosis (DVT), and PE+DVT in 24, 3, and 7 patients, respectively. For the diagnosis of PE, D-dimer test with cutoff value of 230 ng/ml showed sensitivity, specificity, and negative predictive value of 96.8%, 39.6%, and 97.7%, respectively. These values were 96.3%, 37.9%, and 91.7% in PE likely group (n=56), and 100%, 38.8%, and 100% in PE unlikely group (n=84). Among 43 patients with D-dimer values of <230 ng/ml, only one patient was diagnosed with PE, who belonged to the PE likely group. Conclusions : D-dimer test cannot be used as a stand-alone test to diagnose PE, but it can be helpful for exclusion of PE especially in PE unlikely group according to Wells score. (Korean J Lab Med 2008;28:419-24) Key Words : Pulmonary embolism, D-dimer, Clinical probability, Negative predictive value 서 론 정맥혈전색전증 (venous thromboembolism, VTE) 은임상 Received : June 23, 2008 Manuscript No : KJLM2144 Revision received : September 22, 2008 Accepted : October 7, 2008 Corresponding author : Rojin Park, M.D. Department of Laboratory Medicine, Soonchunhyang University Hospital, 22 Daesagwan-gil, Yongsan-gu, Seoul , Korea Tel : , Fax : rpark@hosp.sch.ac.kr 적으로하지의부종과통증을동반하는심부정맥혈전증 (deep vein thrombosis, DVT) 과갑작스런호흡곤란을주증상으로하는폐색전증 (pulmonary embolism, PE) 으로나타나지만, 다양한비특이적양상으로도많이나타나기때문에진단에어려움을주고있다 [1, 2]. 특히적절한치료를하지않으면폐색전증은사망률이 30% 에이르기때문에빠른진단과치료가필요하다 [3]. VTE의진단은주로도플러초음파와전산화단층촬영과같은영상검사들에의존하고있다 [4, 5]. 영상검사들은비교적시간이걸리고고가의비용을필요로하는반면, VTE로 419

2 420 박노진 서영익 윤순규외 4 인 의심된환자들중실제진단되는비율은낮다 [6, 7]. D-dimer는교차결합되어있던섬유소가플라스민에의해잘린후생성되는생성물로서급성 VTE에서특징적으로증가하지만 [8, 9] 수술, 출혈, 외상, 암, 패혈증, 노령, 임신등과관련해서도증가할수있기때문에 VTE에대한특이도는떨어진다. 그렇지만 D-dimer는민감도와함께음성예측도가높기때문에 VTE를배제하는검사로주로사용되고있다 [10]. D-dimer 검사는임상적가능성 (clinical probability) 에따라서음성예측도에차이가나기때문에폐색전증진단을위한프론트라인 (frontline) 검사로사용하기위해서는임상적가능성에대한평가가적절히이루어져야한다 [11-14]. 이러한임상적가능성에대한평가는주로 Geneva 점수와 Wells 점수체계를사용하고있다 [15, 16]. 이연구에서는단일기관에서일정기간동안폐색전증이의심되어진단과정을거친환자들을대상으로하여임상적가능성을 Wells 점수 (Wells score) 에적용시켜서 D-dimer 검사의유용성을분석해보았다. 대상및방법 1. 대상 2006년 3월부터 2007년 10 월까지갑자기발생하거나심해진호흡곤란, 흉통, 빈맥등으로폐색전증이의심되어 D-dimer 검사와함께영상검사를한 140명의외래및입원환자들을대상으로하였다. 2. D-dimer 검사 (fibrinogen equivalent units) 의약 1/2의값을가진다. 3. 폐색전증진단임상적인소견을통해서설명되지않는호흡곤란또는흉통이있는경우에의심을하였고, 최근 4주동안 2일이상부동의소견이나수술을시행한경우, 객혈, 악성종양이동반된경우등의위험인자의유무를기준으로경험적으로판단하여진단하였다. 폐색전증이의심된모든경우에대해 D-dimer 검사와영상검사를시행하였다. 흉부및하지의전산화단층촬영, 폐관류및폐환기검사를시행하였고진단이불분명한경우폐동맥조영술을시행하였고 DVT가의심되는경우하지도플러초음파검사를시행하였다. 양성인경우에폐색전증으로진단하였다. 이렇게해서폐색전증으로진단되거나배제된모든환자들에대해후향적으로환자의의무기록을참조하여 Wells 점수 (Table 1) 를부여하였고 D-dimer 검사및영상검사결과와비교, 분석하였다 [17]. 점수가 4.0을초과한경우, PE likely 군으로분류하고, 4.0 이하인경우를 PE unlikely 군으로분류하였다. D- dimer 검사결과는 230 ng/ml 미만인경우음성으로판단하였다. 폐색전증이의심되는경우외래와입원환자를모두포함하였다. 외래환자인경우입원하고 2일이내에영상검사를통해서진단되었다. 4. 통계분석 D-dimer 검사의진단적유용성을판단하기위해서민감도, 특이도, 음성예측도등을구하고분석하였다. 3.2% (0.109 M) 구연산나트륨항응고제가포함되어있는튜브 (Becton Dickinson, Rutherford, NJ, USA) 에혈액을채취하여 2,000 g에서 15 분간원침하고혈소판결핍혈장을얻어서 -20 에보관하였다가검사시 37 에서녹인후 D-dimer 검사를시행하였다. 모든검사는검체채취후 24 시간이내에시행되었다. 검사는 D-dimer 시약 (HemosIL D-Dimer, Instrumental Laboratory, Lexington, MA, USA) 을사용하여자동혈액응고분석기 (ACL-9000, Instrumental Laboratory) 에서시행하였다. 이장비의 D-dimer 측정은 D-dimer에대한단클론성항인항체 8D3로입힌라텍스입자를이용한정량적면역비탁법 (quantitative immunoturbidimetry) 으로서 405 nm 의파장을이용하였다. 이시약은농도의단위를 DDU (d-dimer unit) 로제공하고있으며, 1 DDU는보통흔히사용되는 FEU 결과임상적으로폐색전증이의심된환자 140명에서 D-dimer 검사를실시하였다. 남자 76명 ( 나이, 23-96), 여자 64명 ( 나이, 18-96), 외래 93명, 입원 47 명이었으며, 대상군의주된특성과여러가지임상적위험요인들은 Table 2에서보여지는것과같다. 전체환자군을 PE likely 군 (Wells 점수 >4.0) 과 PE unlikely 군 (Wells 점수 4.0) 으로나눈결과각각 56명, 84 명이었고, 전자에서는민감도가 96.3%, 특이도가 37.9%, 음성예측도가 91.7% 이었다. 후자에서는민감도가 100%, 특이도가 38.8%, 음성예측도가 100% 이었다 (Table 3). 전체 140명중에서 D-dimer 검사양성은 97명이었고, 영상검사를통해서 PE 24명, DVT 3 명, PE+DVT 7명으로진단되었다 (Table 4). D-dimer 검사의

3 Utility of D-dimer for Diagnosing PE 421 Table 1. Wells score for pulmonary embolism* Variables Source: Wells et al. [17]. *>4, probability of PE is likely ; 4, probability for PE is unlikely. Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism. 경계값을 230 ng/ml으로정하였을때의민감도는 96.8%, 특이도는 39.6%, 음성예측도는 97.7% 이었다 (Table 4). 폐색전증이의심된전체 140명의환자중에서, D-dimer 수치가 230 ng/ml 이하인 43명중 1명만이폐색전증으로진단받았다. 이환자는 PE likely 군에속하였다. 외래환자 93명중에서 D- dimer 양성인 54명 (58.1%) 중 VTE는 20명 (37.0%), 입원환자 47명중에서는 D-dimer 양성인 43명 (91.5%) 중 VTE는 14 명 (32.6%) 이었다. 고 현재 D-dimer 검사는대부분정량적측정을하고있으며, 기존의 ELISA법, 전혈응집법, 면역비탁법, 미세입자효소면역법등의방법외에도최근에는류마토이드인자에의한위양성율을줄여준고감도의 D-dimer 검사법과민감도가더욱높아진화학발광법 (chemiluminescence) 을이용한검사시약도나오고있다 [18]. 이러한 D-dimer 검사는 VTE에서특징적으로증가함으로써이질환의진단에있어서중요한역할을하고있다. 이연구에서는일반적으로폐색전증진단을위해임상적가 찰 Points Clinical signs and symptoms of DVT 3.0 (minimum of leg swelling and pain with palpation of the deep veins) PE more likely than an alternative diagnosis 3.0 Heart rate >100/min 1.5 Immobilization or surgery in the previous 4 weeks 1.5 Previous DVT/PE 1.5 Hemoptysis 1.0 Malignancy (receiving treatment, treated in 1.0 the last 6 months or palliative) Table 3. Diagnostic utility of D-dimer test in PE-likely and -unlikely groups by Wells criteria Clinical probability of PE (N=140) Sensitivity Specificity Negative predictive value *DVT only 3 included; PE incidence, total: 31/140=22%. Abbreviations: See Table 1. Incidence of PE, N (%) Likely (56) 26/27 11/29* 11/12 27 (96.3%) (37.9%) (91.7%) (48.2%) Unlikely (84) 4/4 31/80 31/31 4 (100%) (38.8%) (100%) (4.8%) Table 2. Demographic and clinical characteristics of patients Characteristics Patients (N=140) Age, mean (range), yr 61.7 (18-96) Male 76 (54.3%) Outpatients 93 (66.4%) Previous VTE 23 (16.4%) Chronic heart and/or respiratory disease 53 (37.9%) Cancer 29 (20.7%) Immobilization or recent surgery 27 (19.3%) New or aggravating dyspnea 115 (82.1%) Chest pain 95 (67.9%) Heart rate >100/min 38 (27.1%) Hemoptysis 4 (2.9%) Clinical signs of DVT 8 (5.7%) Abbreviations: VTE, venous thromboembolism; DVT, deep vein thrombosis. Table 4. Diagnosis and D-dimer* levels Diagnosis *Sensitivity of D-dimer for the diagnosis of PE: 30/31 (96.8%). *Specificity of D-dimer for the diagnosis of PE: 42/106 (39.6%). *Negative predictive value: 42/43 (97.7%). Abbreviations: See Table 1, 2. N D-dimer D-dimer ( 230 ng/ml) (<230 ng/ml) DVT only DVT and PE PE only No VTE (with imaging) Total 능성 (clinical probability) 을점수화해서평가하는 Wells 점수체계를적용해서 D-dimer 검사의효용성을보았다. 임상적으로폐색전증이의심된환자는여자보다남자환자들에서더많았으며나이분포는비슷하였다. 대상환자들에서가장흔한임상증상은새로이발생하거나, 악화된호흡곤란 (82.1%) 과흉통 (67.9%) 이었다 (Table 2). 일반적으로늑막성 (pleuritic) 흉통이폐색전증환자의 77% 에서나타나지만 [19], 본연구의많은대상들에서문진시흉통의정확한특징을기술하지못하였다. D-dimer 검사의경계값 230 ng/ml은제조사에서권장하는경계값의범위 ng/ml의하한값으로정하였다. Curtin 등 [20] 은비슷한경계값을사용하여응급실내원환자 512명을대상으로 VTE 진단에대해민감도 100%, 특이도 38% 를나타내는보고를하였다. 본연구에서는폐색전증진단에대해민감도 96.8%, 특이도 39.6%, 음성예측도 97.7% 를보였다 (Table 4). 폐색전증진단을위해 Wells 등 [17] 이제안한임상적가능성을 likely 군과 unlikely 군으로나누어분석한결과 D-dimer 검사는폐색전증진단에있어서높은음성예측도를보여주며 unlikely 군에서 37% 의환자를배제할수있었다. PE unlike-

4 422 박노진 서영익 윤순규외 4 인 ly 군에서 D-dimer 음성인환자들 31명은모두영상검사결과가음성이었다. van Belle 등 [21] 은 2006년폐색전증이의심되는 3,306명의대상군에대한전향적연구에서 PE unlikely 군에속하면서 D-dimer 음성인환자들 1,028명중에서 3개월간의추적, 검사결과영상검사를통해서폐색전증으로진단받은환자를약 0.5% (5명) 로보고하였다. 따라서초기진단과정에서 PE unlikely 군이면서 D-dimer 음성인환자들은추가적인진단과정없이추적, 관찰하는것이더효율적이라고생각된다. 폐색전증을의심하였으나전산화단층촬영과도플러초음파검사를통해서하지의 DVT만진단받은 3명중 1명은 68세남자환자로서과거에양쪽골반의무혈성괴사로고관절대치술을받은상태로급성신부전과폐렴으로치료받다가갑자기호흡곤란이악화되어폐색전증의심하에정밀검사를하였으나양쪽하지에서 DVT만발견되었다. 또다른 1명은 44세남자환자로서급성신부전, 헤노호-쉔라인 (Henoch-Schonlein) 자반증, 패혈증으로치료중갑작스런호흡곤란으로폐색전증을의심하였으나왼쪽하지에서 DVT만발견되었다. 나머지 1명은유방암진단후폐전이가있었던 75세여자환자로서폐색전증을의심하였으나왼쪽하지의 DVT만발견되었다. D-dimer 값이 230 ng/ml 이하인 43명중에서폐색전증으로진단받은 1명은고혈압, 천식, 승모판역류가있던 79세여자환자로서호흡곤란으로입원한지 2일째에폐관류및폐환기검사를통해서진단되었고, 이어서흉부전산화단층촬영을통해서폐색전증으로확인되었다. 하지의도플러초음파에서 DVT는발견되지않았다. 환자는 Wells 점수 6.0으로임상적으로폐색전증을강하게의심하였고, D- dimer 결과는 210 ng/ml 이었다. 따라서 D-dimer 검사결과는위음성으로판단되었다. De Monye 등 [22] 에의하면 D-dimer 결과는혈전의위치와관련이있어서, 세분절 (subsegmental) 색전의경우분절 (segmental) 색전보다 D-dimer 수치가낮아서때로는 D-dimer 음성으로나올수있다고보고되지만, 환자는좌폐하엽의앞기저분절 (anterobasal segmental) 동맥의혈전으로밝혀졌다. 또한자동혈액응고분석기 (ACL 9000, Instrumental Laboratory) 에서 HemosIL D-Dimer (Instrumental Laboratory) 시약은 Hb 50 mg/dl, 빌리루빈 5 mg/dl, 중성지방 1,000 mg/dl의농도까지는영향을받지않기때문에간섭에의한결과로도보기가어렵다. 외래환자에비해입원환자에서높은 D-dimer 양성률 (91%) 을보이면서 VTE가상대적으로낮은 (32.6%) 것은입원환자들중폐색전증이의심된환자들은 D-dimer 양성을초래할만한암, 패혈증, 폐렴, 결핵성늑막염등의기저질환들을많이가지고있었기때문이라고생각된다. 이연구에서생각해볼수있는몇가지제한점은다음과같다. 첫째, 폐색전증진단을위해사용하는 Wells 점수를후향적으로적용시켰기때문에전향적으로적용시킨연구와는그결과에차이가있으리라고생각한다. 둘째, 연구에포함된대상군의수가 140명밖에되지않고, 입원환자와외래환자사이에 D-dimer 음성률이많은차이를보이고있어서통계적수치에차이가있으리라생각된다. 셋째, 모든환자들에서최소한 3개월간추적, 관찰이제대로되지않았다는점이다. 따라서 Wells 점수가 PE likely 이면서 D-dimer 검사결과도양성인데영상검사에서폐색전이발견되지않은 18명의환자들에서추적, 관찰을통한결과가제대로파악되지않았을것이다. Wells 등 [23] 이보고한바에따르면 PE likely 군과 PE unlikely 군에서의폐색전증발생률은각각 39-41% 와 5-8% 이었다. 본연구에서의폐색전증발생률은전자의군에서 48.2%, 후자의군에서 4.8% 로나타났다. Wells 등 [23] 의연구와차이가나는것은인종적인차이외에도상기의몇가지제한점에의한영향도있으리라고생각된다. 결론적으로 D-dimer 검사는폐색전증진단을위한단독검사로는사용할수없지만임상적가능성 (clinical probability) 을평가하는 Wells 점수 4.0 이하의 PE unlikely 군에서폐색전증을배제하는데도움이된다. 요약배경 : 비특이적증상을많이보이며나타나는폐색전증 (pulmonary embolism, PE) 의진단은주로도플러초음파와전산화단층촬영과같은영상검사들에의존하고있는데, 이들영상검사들은비교적힘들고고가의비용을필요로하는반면, 폐색전증으로의심된환자들중실제진단되는비율은낮다. 이연구에서는폐색전증이의심되어진단과정을거친환자들을대상으로하여임상적가능성을 Wells 점수 (Wells score) 에적용시켜서 D-dimer 검사의유용성을분석해보았다. 방법 : 폐색전증이의심되어 D-dimer 검사와함께영상검사를한 140명의외래및입원환자들을대상으로하였다. 영상검사를통해서폐색전증으로진단되거나배제된모든환자들에대해후향적으로환자의의무기록을참조하여 Wells 점수를부여하였고, D-dimer 검사의진단적유용성을분석하였다. 결과 : 대상환자군 140명중에서 D-dimer 검사양성은 97명이었고, 영상검사를통해서 PE 24명, 심부정맥혈전증 (deep vein thrombosis, DVT) 3명, PE+DVT 7명으로진단되었다. D- dimer 검사의경계값을 230 ng/ml으로정하였을때의민감도는 96.8%, 특이도는 39.6%, 음성예측도는 97.7% 이었다 PE likely 군 56명, PE unlikely 군 84명이었고, 전자에서는민

5 Utility of D-dimer for Diagnosing PE 423 감도가 96.3%, 특이도가 37.9%, 음성예측도가 91.7% 이었다. 후자에서는민감도가 100%, 특이도가 38.8%, 음성예측도가 100% 이었다. 폐색전증이의심된전체 140명의환자중에서 D- dimer 수치가 230 ng/ml 이하인 43명중에서 1명만이폐색전증으로진단받았다. 이환자는 PE likely 군에속하였다. 결론 : D-dimer 검사는폐색전증진단을위한단독검사로는사용할수없지만 Wells 점수 4.0 이하의 PE unlikely 군에서폐색전증을배제하는검사로서도움이된다. 참고문헌 1. Wells PS, Owen C, Doucette S, Fergusson D, Tran H. Does this patient have deep vein thrombosis? JAMA 2006;295: Pineda LA, Hathwar VS, Grant BJ. Clinical suspicion of fatal pulmonary embolism. Chest 2001;120: Calder KK, Herbert M, Henderson SO. The mortality of untreated pulmonary embolism in emergency department patients. Ann Emerg Med 2005;45: Zierler BK. Ultrasonography and the diagnosis of venous thromboembolism. Circulation 2004;109:I Nijkeuter M and Huisman MV. Diagnostic methods in pulmonary embolism. Eur J Intern Med 2005;16: Kelly J and Hunt BJ. A clinical probability assessment and D-dimer measurement should be the initial step in the investigation of suspected venous thromboembolism. Chest 2003;124: Perrier A, Desmarais S, Miron MJ, de Moerloose P, Lepage R, Slosman D, et al. Non-invasive diagnosis of venous thromboembolism in outpatients. Lancet 1999;353: Bounameaux H, de Moerloose P, Perrier A, Reber G. Plasma measurement of D-dimer as diagnostic aid in suspected venous thromboembolism: an overview. Thromb Haemost 1994;71: Kelly J and Hunt BJ. Role of D-dimers in diagnosis of venous thromboembolism. Lancet 2002;359: Dempfle CE. D-dimer testing and venous thromboembolism: four view points. J Thromb Haemost 2005;3: Wells PS, Anderson DR, Bormanis J, Guy F, Mitchell M, Lewandowski B. SimpliRED D-dimer can reduce the diagnostic tests in suspected deep vein thrombosis. Lancet 1998;351: Anderson DR, Wells PS, Stiell I, MacLeod B, Simms M, Gray L, et al. Thrombosis in the emergency department: use of a clinical model to safely avoid the need for urgent radiological investigation. Arch Intern Med 1999;159: Anderson DR, Kovacs MJ, Kovacs G, Stiell I, Mitchell M, Khoury V, et al. Combined use of clinical assessment and d-dimer to improve the management of patients presenting to the emergency department with suspected deep vein thrombosis (the EDITED Study). J Thromb Haemost. 2003;1: Wells PS, Anderson DR, Rodger M, Forgie M, Kearon K, Dreyer J, et al. Evaluation of D-dimer in the diagnosis of suspected deepvein thrombosis. N Engl J Med 2003;349: Wells PS, Anderson DR, Rodger M, Stiell I, Dreyer JF, Barnes D, et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and d-dimer. Ann Intern Med 2001;135: Le Gal G, Righini M, Roy PM, Sanchez O, Aujesky D, Bounameaux H, et al. Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med 2006;144: Wells PS. Integrated strategies for the diagnosis of venous thromboembolism. J Thromb Haemost 2007;5(S):S Moerloose P, Vanrusselt M, Reber G, Arnout J. Performances of the HemosIL D-dimer HS assay for the exclusion of venous thromboembolism. J Thromb Haemost 2005;3: Stein PD, Terrin ML, Hales CA, Palevsky HI, Saltzman HA, Thompson BT, et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest 1991;100: Curtin N, Highe G, Harris M, Braunstein A, Demattia F, Coss L. Extensive evaluation of the instrumentation laboratory IL test D- Dimer immunoturbidimetric assay on the ACL 9000 determines the D-dimer cutoff value for reliable exclusion of venous thromboembolism. Lab Hematol 2004;10: van Belle A, Buller HR, Huisman MV, Huisman PM, Kaasjager K, Kamphuisen PW, et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006;295: De Monye W, Sanson BJ, Mac Gillavry MR, Pattynama PM, Buller HR, van den Berg-Huysmans AA, et al. Embolus location affects the sensitivity of a rapid quantitative D-dimer assay in the diagnosis of pulmonary embolism. Am J Respir Crit Care Med 2002;165:

6 424 박노진 서영익 윤순규외 4 인 Wells PS, Anderson DR, Rodger M, Ginsberg JS, Kearon C, Gent M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 2000;83:

012임수진

012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar