번역 Lab Med Online Vol. 2, No. 3: 119-125, July 2012 진단혈액학 D-dimer 검사의실제 * D-Dimer Testing in Laboratory Practice Tripodi A. Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Internal Medicine, University of IRCCS and Mangiagalli, Milan, Italy Background: D-dimer is a reliable and sensitive index of fibrin deposition and stabilization. As such, its presence in plasma should be indicative of thrombus formation. There are many conditions unrelated to thrombosis in which D-dimer concentrations are high, however, making its positive predictive value rather poor. Content: Notwithstanding these limitations, D-dimer can be regarded as a most valuable laboratory tool to diagnose and manage a vast array of thrombosis related clinical conditions, including (a) diagnosis of venous thromboembolism (VTE), (b) identification of individuals at increased risk of first thrombotic event (both arterial and venous), (c) identification of individuals at increased risk of recurrent VTE, (d) establishment of the optimal duration of secondary prophylaxis after a first episode of VTE, (e) pregnancy monitoring, and (f) diagnosis/monitoring of disseminated intravascular coagulation (DIC). This article is aimed at reviewing the merits and pitfalls of these applications. Summary: From my analysis of the literature, I draw the following conclusions. (a) D-dimer, as measured by a sensitive test, can be safely used to exclude VTE in symptomatic outpatients, provided that it is used in combination with the pretest clinical probability. (b) High concentrations of D- dimer are associated with an increased risk of recurrent VTE. (c) Patients who present with D-dimer above cutoff after stopping the regular course of oral anticoagulation benefit from extended prophylaxis. (d) Finally, D-dimer can be used as a fibrin-related degradation marker for the diagnosis/ management of patients with DIC. Key Words: D-dimer, Venous thromboembolism, Disseminated intravascular coagulation D-dimer 는다음의 3 가지효소의작용으로생성되는섬유소덩 이 (fibrin clot) 분해의특이적산물이다. 3 가지효소로는 (a) 트롬빈 (thrombin), 응고과정의활성화로생성되어섬유소원 (fibrinogen) 을섬유소덩이로전환하는효소 ; (b) 활성화된 XIII 응고인자 (activated factor XIII), 섬유소단량체 (fibrin monomer) 사이의공유결 합을통해섬유소덩이 (fibrin clot) 를교차결합시키는효소 ; 그리고 (c) 플라스민 (plasmin), 교차결합된섬유소를분해하는섬유소용 해 (fibrinolysis) 의최종효소 [1-3] 가있다. D-dimer 의특정항원결정 인자 (epitope) 에대한단클론항체 (monoclonal antibody) 는교차 번역 : 박미영, 김인숙부산대학교의학전문대학원진단검사의학교실 E-mail: iskim0710@gmail.com Received: January 31, 2012 Revision received: January 31, 2012 Accepted: May 3, 2012 This article is available from http://www.labmedonline.org 2012, Laboratory Medicine Online This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 결합된섬유소와는반응하지만섬유소원분해산물 (fibirinogen degradation products) 이나교차결합하지않은섬유소분해산물 과는반응하지않으므로섬유소생성및안정화에대한생물학적 표지자로서 D-dimer 는높은특이도를갖는다 [4]. 많은종류의 D- dimer 검사법들이개발되어왔고, 크게세가지방법으로분류된 다. (a) 효소면역측정법 (enzyme linked immunosorbent assay, ELISA), 정량적이고높은민감도를보이나검사에많은시간이소 요된다 ; (b) 라텍스 - 기반면역검사 (latex-based immunoassays) [5], 수기로검사하고육안으로관찰하며, 반정량적이고 ELISA 에비해 덜민감하나더신속하다 [6]; (c) 면역혼탁법을이용한라텍스 - 기반 자동화검사 (latex-based automated assays) [7] 가있다. 라텍스 - 기 반자동화검사는정량적이고 ELISA 만큼민감하며매우신속하게 일반응고장비에서검사가가능하다. 항 -D-dimer 단클론항체로코 * 본원고는양잡지의발행인사이의협약에의하여 Clinical Chemistry 에실린영문논문을번역하여게재하는것으로, 본논문을인용하고자할때는다음과같이원논문을인용하여야함. 원논문의저자사사표기및기타원고의내용과관련이없는부분은번역과정에서생략하였음. 참고문헌표기방식은원문방식을그대로사용하였음. 원문인용 : Tripodi A. D-dimer testing in laboratory practice. Clin Chem 2011; 57(9):1256-62. eissn 2093-6338 www.labmedonline.org 119
팅된라텍스입자를검사할혈장과섞는다. D-dimer가없는경우, 입자는부유액에서개별적으로존재하여, 응고장비에서는높은혼탁도의신호로판독한다. D-dimer가존재할경우라텍스입자가응집을이루게되고부유액은맑아지게되어낮은혼탁도의신호로판독된다. 이러한두신호간의차이는 D-dimer 농도와비례한다. 다양한임상상태에서 D-dimer 농도는증가한다 (Table 1). D- dimer 검사는파종혈관내응고, 정맥혈전색전증, 허혈성심질환, 뇌졸중, 그리고혈전용해치료를포함하는혈전과관련된임상상태의여러질환의진단과치료에유용하게사용할수있다. 반면에혈전증과관련이없는임상상황에서도 D-dimer 농도의증가가관찰되어 (Table 1), 혈전의진단에대한 D-dimer의특이도를낮춘다. 이런제한점에도불구하고, D-dimer 검사는 (a) 정맥혈전색전증의진단, (b) 최초의혈전발병후, 고위험환자의확인 ( 동맥및정맥혈전모두 ), (c) 재발성정맥혈전색전증의고위험환자확인, (d) 정맥혈전색전증최초발병후 2차예방적치료의최적기간의결정, (e) 임신의모니터링, (f) 파종혈관내응고의진단과모니터링등에다양하게적용되어왔다. 1. 정맥혈전색전증의진단심부정맥혈전증 (deep vein thrombosis) 의임상적진단은부정확하므로, 정맥초음파가최선의검사이다 [8-10]. D-dimer 검사는예비임상적확률 (pretest clinical probability) 과함께사용시높은음성예측도때문에지난 20년간정맥혈전색전증의진단에유용한도구로이용되었다. D-dimer의폐색전증의진단에대한유용성은 Bounameaux 등 [11] 에의해처음으로제시되었고, 이들은폐색전증을가진환자들은폐색전증이없는환자들에비해 D-dimer 농도의높은중앙값을갖는것을밝혀냈다. 그러나폐색전증환자와그렇지않은환자들의 D-dimer 결과분포는겹쳤고, D-dimer 검사를통한폐색전증의확진을어렵게하였다. 이저자들은기준치 Table 1. Conditions characterized by increased D-dimer concentrations Old age Stroke Neonatal period Peripheral arteriopathy Pregnancy Aneurism Hospitalization Congestive cardiac failure Disability Hemolysis (falciform anemia) Infection Hemorrhage Tumor Acute respiratory distress syndrome Recent surgery Liver or renal disease Trauma, burns Inflammatory bowel disease DIC Thrombolytic therapy VTE Aortic dissection Ischemic cardiopathy ( 이경우에는 500 μg/l) 를적용하면, 폐색전증환자의매우소수만 이기준치보다낮은 D-dimer 농도를갖는것을알게되었다. 이사 실로이들은 D-dimer 검사는폐색전증의확진에는유용하지않지 만폐색전증을배제하는데는신뢰성있게사용할수있다고주장 하였다 [11]. 이단순한사실은곧심부정맥혈전증의진단에도확대 되었고 [12], D-dimer 가심부정맥혈전증에대한특이도는낮지만, 높은음성예측도를가지는신뢰성있는표지자라는새로운개념 을갖게했다. 2. 판정역치 (Decision Thresholds) 이런사실들을고려해볼때, 최소 2 개의 D-dimer 역치가판정 을결정하는데고려되어야한다. 첫번째는, 건강인결과분포의 95 분위수로계산된전통적인참고치이다. 이판정역치는파종혈 관내응고및관련질환에서 D-dimer 결과해석에적용해야한다. 두번째역치는정맥혈전색전증이의심되어, 정맥혈전색전증의진 단이영상검사를통해객관적으로확진된환자들의임상연구로 설정된다. 이때 D-dimer 를동시에측정하고, 정맥혈전색전증에대 해최상의진단민감도 ( 높은음성예측도 ) 를갖는 D-dimer 농도를 최적의역치를정하였다 (Fig. 1). 두번째기준은정맥혈전색전증 진단을위해서만사용해야한다. 왜냐하면, 건강인결과분포의 95 분위수에해당하는 D-dimer 값과정맥혈전색전증진단의기준치 는같은방법내에서도다를수있기때문이다. D-dimer (μg/l) 20,000 10,000 5,000 1,000 500 100 Pulmonary embolism No pulmonary embolism Fig. 1. D-dimer concentrations measured in plasma from patients with and without PE. The horizontal bold line represents the cutoff value. Reproduced from Bounameaux et al. [11] with the permission of the publisher. 120 www.labmedonline.org
3. 진단전략 (Diagnostic Strategies) D-dimer 증가는최근의수술, 종양, 임신, 입원등을포함하여 혈전증이없는상태에서도나타날수있다. 혈전증이없는상태에 서증가된 D-dimer 결과는위양성결과로여겨야한다. 반대로혈 전증이있음에도 D-dimer 가음성인상황도있다. 그런위음성결 과는낮은검사민감도, 부정확한기준치계산, 저섬유소용해 (hypofibrinolysis), 7-10 일이상경과한정맥혈전색전증증상, 그리고 항혈전치료의시작때문에일어날수있다. D-dimer 의비교적낮 은진단특이도때문에, 정맥혈전색전증의배제에대한진단의효 율을향상시키기위한여러전략들이수년간개발되어왔다 [13]. 첫 째전략은정맥혈전색전증을배제하기위하여 D-dimer 을먼저측 정하는것이다. 따라서, D-dimer 가기준치를넘는환자들만영상 검사를시행하는것이다. 이런전략은일부정맥혈전색전증환자 들을발견하지못할수있고항혈전치료를받지못할수도있으므 로안전하지는않다. 둘째전략은영상검사를먼저시행하는것이다. 이때영상검사 에서음성으로나온경우 D-dimer 을측정한다. 이런접근은차후 에근위부혈전 (proximal thrombosis) 으로진행할수있는장딴지 정맥혈전 (isolated calf vein thrombosis) 만을갖는환자의추적검 사에목적이있다. 장딴지정맥혈전환자는영상검사에서는음성이 나, D-dimer 는기준치를넘는다. 그러나, 이전략은필요없는영상 검사를너무나많이시행하게한다. 셋째전략은 D-dimer 를예비임상적확률과함께측정하는것이 다 [13]. 예비임상적확률은임상적징후, 위험인자, 심부정맥혈전증 이나폐색전증의증상, 그리고다른진단을포함하는점수체계 Table 2. Pretest clinical probability score* Deep vein thrombosis Clinical signs or symptoms Score Clinical signs or symptoms Score Active cancer 1 Clinical signs and symptoms of deep vein thrombosis Paralysis or recent immobilization (plaster) of the lower limbs Recently bedridden (>3 days) or recent major surgery PE 1 PE as likely as or more likely than alternative diagnosis 1 Heart rate >100 bpm 1.5 Localized tenderness 1 Previous immobilization or surgery (within 4 weeks) Leg swelling 1 Previous deep vein thrombosis or PE Calf swelling 1 Hemoptysis 1 Edema (symptomatic leg) 1 Malignancy 1 Collateral veins 1 Previous VTE 1 Alternative diagnosis -2 *Modified from Wells [13]; Probability of deep vein thrombosis: <1, low; 1 2, moderate; >2, high; Probability of pulmonary embolism: <2, low; 2 6, moderate; >6, high. 3 3 1.5 1.5 (scoring system) 로정해지고 (Table 2), 점수가높을수록정맥혈전 색전증의가능성이높다 (Table 2). 이접근은세계적으로혈전증 센터들에서심부정맥혈전증와폐색전증의배제를위해가장널리 사용된다 (Fig. 2). Fig. 2 에기술된과정은심부정맥혈전증의예비 임상적확률점수가계산되고 D-dimer 를측정한증상이있는외래 환자에게적용된다. 만약 D-dimer 가기준치보다낮고임상적확률 (clinical probability) 이낮다면, 심부정맥혈전증은높은확률로배 제될수있다. 반대로, 만약 D-dimer 가음성이지만, 심부정맥혈전 증의임상적확률이높다면, 영상검사를포함한추가검사가필요 하다. 마지막으로, D-dimer 가양성이라면임상적확률에상관없 이영상검사를포함한추가검사를실시한다. 폐색전증에도적절 한예비임상적확률과함께비슷한알고리듬이사용될수있다. 상 기전략은정맥혈전색전증배제에높은유용성을나타낸다는것 이증명되었다. Van Belle 등 [14] 은 3,000 명이상의증상을가진환 자를대상으로한연구에서낮은예비임상적확률과낮은 D-dimer 의조합은 3 개월추적조사에서정맥혈전색전증의발병률이 0.5% 밖에되지않고효과적으로폐색전증을배제할수있다고연구하 였다. D-dimer 농도는일반적으로종양환자에서증가한다. 따라서, D-dimer 검사가종양환자의정맥혈전색전증진단에안전하게상 용될지는불명확하다. 일반적으로진단민감도는좋으므로 [15], D- dimer 검사는정맥혈전색전증을배제하는데안전하게사용될수 있다. 그러나검사의진단특이도는좋지않아서 D-dimer 는다른 영상검사와함께사용해야한다. 4. 검사방법의선택 (Choice of Methods) D-dimer 검사에는많은방법이있다. 적절한선택을위해서는 다음과같은고려사항에주의해야한다 (Table 3). 첫째, 임상연구 를통해검사의기준치가정해지고관리연구 (management study) Diagnosis of VTE Combination of Clinical Probability and D-Dimer Negative D-dimer and low clinical probability D-dimer Negative D-dimer and high clinical probability Symptomatic VTE Clinical probability Positive D-dimer Exclude VTE Further investigation Further investigation Fig. 2. Algorithm for the diagnosis of VTE describing the usefulness of D-dimer testing in combination with pretest clinical probability. This algorithm can be applied to symptomatic outpatients. www.labmedonline.org 121
Table 3. Considerations in the choice of a D-dimer test Cutoff determined by clinical studies High diagnostic sensitivity (high negative predictive value) Acceptable diagnostic specificity Easily performed with rapid availability of results (within 30 min) Good reproducibility around cutoff Quantitative results 를통해검증되어야한다. 북미시장에서정맥혈전색전증의진단의배제에사용되는 D-dimer 검사는미국식약청에의해심사를받는다. 이심사과정은공식승인전에특정프로토콜에따른임상연구의수행을필요로한다. 방법들에따라다른기준치를나타낼수있고, 방법간 / 검사실간표준화는어렵다 [16-18]. 둘째로, 검사방법은진단적으로민감해야하지만너무많은영상검사를피할수있을정도의진단특이도를가져야한다. 셋째로, 검사방법은쉽게시행할수있고결과를빨리얻을수있어야한다. 넷째로, 검사방법은특히기준치근처에서높은재현성을가져야한다. 마지막으로, 검사방법은정략적인값을내어주어야한다. 높은 D-dimer 농도는폐색전증의중증도및불량한예후와관련이있다고보고된다 [19]. 최근, Di Nisio 등 [20] 은다른 D-dimer 방법들간진단민감도와특이도를비교한우수한연구를시행하였다. 그들은 ELISA 와라텍스- 기반정량검사가반정량적라텍스- 기반검사에비해심부정맥혈전증과폐색전증모두에서진단민감도가높음을보고하였다. 1) TAKE-HOME MESSAGES D-dimer는정맥혈전색전증의배제나확진을위하여단독으로사용해서는안된다. 증상이있는환자에서예비임상적확률과민감한방법의 D-dimer 검사를동시에시행할때정맥혈전색전증을배제하는데안전하게사용할수있다. 그러나, 다음의환자에서는혈전증이있음에도위음성으로나올수있으므로 D-dimer를안전하게사용하지못할수도있다 (Table 4). (a) 정맥혈전색전증증상이나타난지 14일이상인환자 ( 오래된혈전은플라스민에의한분해가감소하므로 D-dimer가위음성으로나타날수있다 ); (b) 저섬유소용해를가지는환자 ; (c) 정맥혈전색전증의심하에치료적헤파린이나경구용항응고제를사용하는환자 ( 이러한약제는 D- dimer 생성을억제한다 ). 마지막으로, 예비임상적확률과조합한 D-dimer 검사는노인, 입원환자또는재발한정맥혈전색전증환자에서는주의해서사용해야한다 (Table 4). 위의상태에서는낮은특이도를예상해야하고, D-dimer를사용하더라도낮은특이도때문에관련된비싼많은영상검사를시행하게된다. Table 4. Limitations on the use of D-dimer for VTE diagnosis D-dimer cannot be used safely in the following situations: Patients with symptoms of VTE for >14 days Patients with hypofibrinolysis Patients with suspected VTE receiving therapeutic heparin or oral anticoagulants D-dimer should be used with caution in the following situations: Patients presenting with recurrent VTE Elderly patients Hospitalized patients 5. 최초로발생한관상동맥심질환에대한고위험환자의확인 (Identification of Individuals at Increased Risk for First Coronary Heart Disease) 관상동맥질환과혈장표지자의관계에대해많은장기간전향적연구를통한연구결과가보고되었다 [21]. 연구결과에서가장높은상대위험도는섬유소원으로관찰되었고 ( 교차비 1.8), D-dimer는두번째로높은상대위험도를보였다 ( 교차비 1.7). 이러한값은인구집단연구 (population-based studies) 에서계산되었으나, 이상대위험도가개개인환자에도적용될수있을지는알려져있지않다. 6. 최초로발생한정맥혈전색전증에대한고위험환자의확인 (Identification of Individuals at Increased Risk for First VTE Event) Lowe [21] 에의해고찰되었듯이응고표지자의높은혈장농도와정맥혈전색전증위험도의상관성은많은환자-대조군연구 (casecontrol studies) 에서보고되었다. 가장높은상대위험도는교차비 3.0을가지는 VIII번응고인자 (Factor VIII) 로관찰되었다. D-dimer 상대위험도는교차비 3.8로더높다. 그럼에도불구하고, 이러한상대위험도는환자-대조군연구에서산정되었기때문에전향적연구에서는다른결과를나타낼수도있다. Cushman 등 [22] 은이러한쟁점에대하여약 22,000명의미국건강인에대하여 D-dimer 와향후발생할정맥혈전색전증위험도의연관성에대한 2개의전향적연구를통해제언하였다. 그들은 D-dimer가정맥혈전색전증발생과강하고확실하게연관이있고, D-dimer 분포에서상위 20% 에속하는환자는하위 20% 에속하는환자에비하여교차비가약 3.0에달할정도로, 정맥혈전색전증발생의상대위험도는 D- dimer 농도가증가함에따라높아지는것을밝혀냈다. 7. 재발성정맥혈전색전증에대한고위험환자의확인 (Identification of Individuals at Increased Risk for Recurrent VTE) Palareti 등 [23] 은비유발성 (unprovoked) 정맥혈전색전증이있는환자들에대한전향적연구방법으로정맥혈전색전증재발위험도 122 www.labmedonline.org
를처음으로연구하였다. 그결과, 항응고제치료종료후 D-dimer 의측정은정맥혈전색전증재발에대하여높은음성예측도를가지는것으로나타났다. 추적기간동안재발의누적확률은 D-dimer가기준치보다높은환자군이낮은환자군에서비해교차비약 2.5 정도로유의하게높았다. Verhovsek 등 [24] 은비유발성정맥혈전색전증에대한항응고치료중단후질환의재발을예측하는 D-dimer의사용에대한연구들에대한체계적고찰결과를발표했다. 약 2,000명의환자를 2년간추적관찰한결과, 정맥혈전색전증재발의연간위험도는 D-dimer가기준치미만인환자군에서는 3.5% 였고, D-dimer가기준치초과인환자군에서는약 9% 였다. 이연구로비유발성정맥혈전색전증의최초발병후항응고치료의최적기간을결정하는데 D-dimer 검사를이용하게되었다. 이것은정맥혈전색전증환자의치료에있어중요한문제이고최근까지는, 그러한결정은임상적기준에만기초해서이루어졌었다. Palareti 등 [25] 은항응고제치료의최적기간을결정하는데 D-dimer 검사의이용에대하여보고하였다. 그들의연구는비유발성정맥혈전색전증이처음발생한후최소 3개월간정규과정의경구용항응고제를복용한환자들을대상으로하였다. D-dimer는경구용항응고제중단후 1개월째측정하였다. D-dimer가기준치미만인환자들은경구용항응고제를계속복용하지않은반면, 기준치초과인환자들은무작위로경구용항응고제를계속중단하거나복용하도록하였다. 모든환자는객관적으로확진된정맥혈전색전증의재발을확인하기위하여 1.5 년간추적관찰하였다. 결과의누적발생률은 D-dimer가기준치초과인환자군중경구용항응고제를복용하지않은환자군에서 100명을기준으로연간 11건이었고, 기준치초과이지만항응고제를복용한환자군에서는 100명을기준으로연간 2건뿐이었다. 이러한차이는통계적으로유의하고, 비교적엄격한신뢰구간으로위험도 4.3에해당한다. 1) TAKE-HOME MESSAGES 높은 D-dimer 농도는정맥혈전색전증재발의높은위험도와연관이있다. 그리고, 정규과정의경구용항응고제복용중단후 D- dimer가기준치보다높은환자들에서는예방적약물복용을연장하는것이이득이있다. 8. 임신 D-dimer 농도는임산부에서일반여성에비해증가한다. 그리고, 임신이진행할수록농도는증가한다 [26, 27]. 산욕기에는농도가감소하는데출산후한달까지는완전히정상으로돌아오지않는다 [26, 27]. 이러한양상은임신및산욕기와연관된과응고상태의개념과일치한다. 1) TAKE HOME-MESSAGES 이러한사실이실질적으로의미하는것은임신및산욕기에는이시기에적절한기준치가없다면, D-dimer를정맥혈전색전증배제를위해사용해서는안된다는것이다. 그러나, 임신및산욕기의적절한기준치는실질적으로정하기가어렵다. 게다가, 이시기에는 D-dimer 검사와병용할예비임상적확률평가기준이없다. 일반적으로, D-dimer는정맥혈전색전증배제에사용할수있는진단적민감도를가졌지만 [28], 낮은특이도때문에비용-효과적이지않다 ( 이후비교적많은영상검사가필요하다 ). 이론적으로 D-dimer 검사는적어도임신의비혈전적결과를예상하는데사용될수는있으나그유용성의범위는입증되어야한다. 9. 파종혈관내응고의진단과모니터링파종혈관내응고는응고와섬유소용해를활성화시키고결과적으로소모성응고장애를일으키는여러기저질환에이차적으로오는복합증후군이다 [29]. 파종혈관내응고의적절한관리는원인질환을제거하기위한적극적인시도가필요할뿐아니라, 검사결과도도움이된다. 2001년에 International Society on Thrombosis and Hemostasis (ISTH) 의분과에서파종혈관내응고에대한임상적및검사실기준 (clinical and laboratory criteria) 과점수체계를발표했다 [30]. ISTH의점수체계는먼저해당환자가파종혈관내응고와연관되었다고알려진기저질환을가지고있는가에대한답을구한다. 그러한경우라면, 다음으로혈소판수, 프로트롬빈시간 (prothrombin time), 섬유소원, 그리고섬유소연관분해산물 ( 예를들어, 가용성섬유소단량체, 섬유소분해산물, 또는 D-dimer) 을검사한다. 검사결과에따라, 점수체계는계산된다. 제시된도식에따라, 섬유소연관분해표지자의결과는점수가 2 또는 3점으로점수체계에중요한영향을미친다. 혈소판수치에따라낮은혈소판수치는 0-2점으로매겨지고, 프로트롬빈시간은참고치상한으로증가된정도에따라 0-2점, 섬유소원은농도의저하에따라 1-2점으로점수가매겨진다. 이체계에따르면 5점이상은현성 (overt) 파종혈관내응고에해당하고, 점수는질환의진행을모니터링하기위하여매일반복적으로계산되어야한다. 총점수 5점미만은비현성 (non-overt) 파종혈관내응고를나타내고 ( 확정적이지않다 ) 다음 1-2일간다시계산해봐야한다. 일부항목에서 ISTH와는다른점수체계를일본후생성에서제시하였다 [31]. 검사실검사는두가지점수체계에서같지만, 일본체계에서는출혈증상이나, 장기부전이추가되었다. Wada 등 [32] 은파종혈관내응고를위한두가지점수체계를비교하였다. 그들은파종혈관내응고가의심되는 1,200명이상의환자를대상으로하였고, 두체계간일치도는 67% 였다 [32]. ISTH와일본점수체계모두 D-dimer에대해특별히언급하지는않았지만, 이검사는이 www.labmedonline.org 123
미대부분의검사실에서검사가능하고아주간단하고빨리검사되므로파종혈관내응고의섬유소연관분해표지자로널리사용된다. D-dimer의정확한역할은아직은모르지만섬유소분해산물이나가용성섬유소단량체와같은다른섬유소-연관분해표지자와비교하여 D-dimer의가치에대한추가연구가필요하다. 10. D-dimer의다른이용 (Other Uses of D-Dimer) D-dimer 농도의증가가복부대동맥류에서도관찰되지만 D-dimer의측정이이질환의진단과치료에유용한지는아직논란이있다. 비교적큰규모의메타분석에따르면, 높은 D-dimer와섬유소원이복부대동맥류의 1차진단방법으로초음파를대치하지는않을것이라고하였다 [33]. 아마도이런검사실검사는이미진단받은환자의모니터링에사용할수있을것이다. 결론 D-dimer는섬유소침착과안정화의믿을만하고민감한표지자이다. 즉, 혈장에서 D-dimer의존재는혈전형성을의미한다. 그러나혈전과관련없는많은상태에서 D-dimer가증가하므로 D-dimer의양성예측도는좋지않다. 이러한제한점에도불구하고, D- dimer는많은종류의혈전증과관련된임상적상태들의진단과치료에가장유용한검사방법중하나로여겨질수있다. 참고문헌 1. Medved L, Nieuwenhuizen W. Molecular mechanisms of initiation of fibrinolysis by fibrin. Thromb Haemost 2003;89:409-19. 2. Gaffney PJ. Distinction between fibrinogen and fibrin degradation products in plasma. Clin Chim Acta 1975;65:109-15. 3. Gaffney PJ. Fibrin degradation products: a review of structures found in vitro and in vivo. Ann N Y Acad Sci 2001;936:594-610. 4. Rylatt DB, Blake AS, Cottis LE, Massingham DA, Fletcher WA, Masci PP, et al. An immunoassay for human D dimer using monoclonal antibodies. Thromb Res 1983;31:767-78. 5. Greenberg CS, Devine DV, McCrae KM. Measurement of plasma fibrin D-dimer levels with the use of a monoclonal antibody coupled to latex beads. Am J Clin Pathol 1987;87:94-100. 6. Elms MJ, Bunce IH, Bundesen PG, Rylatt DB, Webber AJ, Masci PP, et al. Rapid detection of cross-linked fibrin degradation products in plasma using monoclonal antibody-coated latex particles. Am J Clin Pathol 1986;85:360-4. 7. Froehling DA, Daniels PR, Swensen SJ, Heit JA, Mandrekar JN, Ryu JH, et al. Evaluation of a quantitative D-dimer latex immunoassay for acute pulmonary embolism diagnosed by computed tomographic angiography. Mayo Clin Proc 2007;82:556-60. 8. Lensing AW, Prandoni P, Brandjes D, Huisman PM, Vigo M, Tomasella G, et al. Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med 1989;320:342-5. 9. Cogo A, Lensing AW, Koopman MM, Piovella F, Siragusa S, Wells PS, et al. Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998;316:17-20. 10. Heijboer H, Büller HR, Lensing AW, Turpie AG, Colly LP, ten Cate JW. A comparison of real-time compression ultrasonography with impedance plethysmography for the diagnosis of deep-vein thrombosis in symptomatic outpatients. N Engl J Med 1993;329:1365-9. 11. Bounameaux H, Cirafici P, de Moerloose P, Schneider PA, Slosman D, Reber G, et al. Measurement of D-dimer in plasma as diagnostic aid in suspected pulmonary embolism. Lancet 1991;337:196-200. 12. Wells PS, Anderson DR, Rodger M, Forgie M, Kearon C, Dreyer J, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003;349:1227-35. 13. Wells PS. Integrated strategies for the diagnosis of venous thromboembolism. J Thromb Haemost 2007;5 Suppl 50. 14. van Belle A, Büller 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;295:172-9. 15. King V, Vaze AA, Moskowitz CS, Smith LJ, Ginsberg MS. D-dimer assay to exclude pulmonary embolism in high-risk oncologic population: correlation with CT pulmonary angiography in an urgent care setting. Radiology 2008;247:854-61. 16. de Maat MP, Meijer P, Nieuwenhuizen W, Haverkate F, Kluft C. Performance of semiquantitative and quantitative D-dimer assays in the ECAT external quality assessment program. Semin Thromb Hemost 2000;26:625-30. 17. Meijer P, Kluft C. The harmonization of quantitative test results of different D-dimer methods. Semin Vasc Med 2005;5:321-7. 18. Tripodi A, Chantarangkul V. Performance of quantitative D-dimer methods: results of the Italian External Quality Assessment Scheme. J Thromb Haemost 2007;5:185-6. 19. Galle C, Papazyan JP, Miron MJ, Slosman D, Bounameaux H, Perrier A. Prediction of pulmonary embolism extent by clinical findings, D- dimer level and deep vein thrombosis shown by ultrasound. Thromb 124 www.labmedonline.org
Haemost 2001;86:1156-60. 20. Di Nisio M, Squizzato A, Rutjes AW, Büller HR, Zwinderman AH, Bossuyt PM. Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: a systematic review. J Thromb Haemost 2007; 5:296-304. 21. Lowe GD. Can haematological tests predict cardiovascular risk? The 2005 Kettle Lecture. Br J Haematol 2006;133:232-50. 22. Cushman M, Folsom AR, Wang L, Aleksic N, Rosamond WD, Tracy RP, et al. Fibrin fragment D-dimer and the risk of future venous thrombosis. Blood 2003;101:1243-8. 23. Palareti G, Legnani C, Cosmi B, Guazzaloca G, Pancani C, Coccheri S. Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost 2002;87:7-12. 24. Verhovsek M, Douketis JD, Yi Q, Shrivastava S, Tait RC, Baglin T, et al. Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med 2008;149:481-90. 25. Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A, et al.; PRO- LONG Investigators. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006;355:1780-9. 26. Kline JA, Williams GW, Hernandez-Nino J. D-dimer concentrations in normal pregnancy: new diagnostic thresholds are needed. Clin Chem 2005;51:825-9. 27. Epiney M, Boehlen F, Boulvain M, Reber G, Antonelli E, Morales M, et al. D-dimer levels during delivery and the postpartum. J Thromb Haemost 2005;3:268-71. 28. Chan WS, Chunilal S, Lee A, Crowther M, Rodger M, Ginsberg JS. A red blood cell agglutination D-dimer test to exclude deep venous thrombosis in pregnancy. Ann Intern Med 2007;147:165-70. 29. Levi M. Pathogenesis and treatment of DIC. Thromb Res 2005;115 Suppl 1:54-5. 30. Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M; Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001;86:1327-30. 31. Wada H, Wakita Y, Nakase T, Shimura M, Hiyoyama K, Nagaya S, et al. Outcome of disseminated intravascular coagulation in relation to the score when treatment was begun. Mie DIC Study Group. Thromb Haemost 1995;74:848-52. 32. Wada H, Gabazza EC, Asakura H, Koike K, Okamoto K, Maruyama I, et al. Comparison of diagnostic criteria for disseminated intravascular coagulation (DIC): diagnostic criteria of the International Society of Thrombosis and Hemostasis and of the Japanese Ministry of Health and Welfare for overt DIC. Am J Hematol 2003;74:17-22. 33. Takagi H, Manabe H, Kawai N, Goto S, Umemoto T. Plasma fibrinogen and D-dimer concentrations are associated with the presence of abdominal aortic aneurysm: a systematic review and metaanalysis. Eur J Vasc Endovasc Surg 2009;38:273-7. www.labmedonline.org 125