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1 ISSN: (Print)/ (Online) Tuberc Respir Dis 2011;71: CopyrightC2011. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 한번의말초정맥주사로유발되어파국적으로진행된 Trousseau 증후군 1 예 1 의료법인한전의료재단한일병원내과, 한양대학교의과대학 2 내과학교실, 3 영상의학교실문지용 1,2, 김사일 2, 곽현정 2, 송순영 3, 김인순 2, 김상헌 2, 김태형 2, 손장원 2, 윤호주 2, 신동호 2, 박성수 2 Case Report A Case of Trousseau's Syndrome with Catastrophic Course Triggered by an Intravenous Injection Ji-Yong Moon, M.D. 1,2, Sa-Il Kim, M.D. 2, Hyunjung Kwak, M.D. 2, Soon Young Song, M.D. 3, In Soon Kim, M.D. 2, Sang-Heon Kim, M.D. 2, Tae Hyung Kim, M.D. 2, Jang Won Sohn, M.D. 2, Ho Joo Yoon, M.D. 2, Dong Ho Shin, M.D. 2, Sung Soo Park, M.D. 2 1 Department of Internal Medicine, Hanil General Hospital, KEPCO Medical Foundation, Departments of 2 Internal Medicine, and 3 Radiology, Hanyang University College of Medicine, Seoul, Korea Trousseau's syndrome is an unexplained thrombotic event that precedes the diagnosis of an occult visceral malignancy or appears concomitantly with the tumor. Upper extremity deep vein thrombosis is prevalent in patients with a central venous catheter. Furthermore, a peripheral intravenous injection may cause upper extremity deep vein thrombosis as well. However, a deep vein thrombosis has not been reported in the form of Trousseau's syndrome with a catastrophic clinical course triggered by a single peripheral intravenous injection. A 48-year-old man presented with a swollen left arm on which he was given intravenous fluid at a local clinic due to flu symptoms. Contrast computed tomgraphy scans showed thromboses from the left distal brachial to the innominate vein. The patient developed multiple cerebral infarctions despite anticoagulation treatment. He was diagnosed with stomach cancer by endoscopic biopsy to evaluate melena and had a persistently positive lupus anticoagulant. After recurrent and multiple thromboembolic events occurred with treatment, he died on day 20. Key Words: Upper Extremity Deep Vein Thrombosis; Antiphospholipid Syndrome; Stomach Neoplasms 서 Armand Trousseau 가정맥혈전과악성종양사이에관계가있음을처음보고한뒤최근까지악성종양과관련되어나타나는다양한혈전색전증과과다응고상태를설명하는의미로 Trousseau 증후군이사용되어왔다. 그러나, 역사적인기원을보면 Trousseau 증후군이란악성종양이발견되기전이나악성종양과함께발현된이유가뚜렷하지않은혈전성질환이라할수있다 1. Address for correspondence: Dong Ho Shin, M.D. Department of Internal Medicine, Hanyang University College of Medicine, 17, Haengdang-dong, Seongdong-gu, Seoul , Korea Phone: , Fax: shindh@hanyang.ac.kr Received: Apr. 29, 2011 Accepted: May 23, 2011 론 상지심부정맥혈전증 (deep vein thrombosis, DVT) 은모든정맥에서발생한혈전증의약 10% 를차지하며, 위험요인으로는중심정맥카테터, 심박동기, 악성종양, 항암제투여, 상지또는어깨의수술, 피임제등이있다. 그중중심정맥카테터가가장흔한원인이지만 2, 드물게말초정맥카테터에의해서도상지심부정맥혈전증이생길수있다 3,4. 국내에보고된 Trousseau 증후군은하지정맥, 하지동맥, 폐동맥, 내경정맥, 뇌혈관의혈전증으로발현된예들이보고된바가있으나, 상지에생긴정맥혈전증으로발현된예는아직없었다. 더욱이중심정맥카테터가아닌말초정맥주사로유발된상지심부정맥혈전증은보고된바가없다. 이에저자들은상지말초혈관에정맥주사를투여받은뒤발생한상지심부정맥혈전증으로내원하여치료중에도다발성으로빠르게진행된동ㆍ정맥혈전증및 134

Tuberculosis and Respiratory Diseases Vol. 71. No. 2, Aug. 2011 이와관련된잠재암의예를경험하였기에문헌고찰과함께보고한다. 증례환자 : 48세, 남자주소 : 왼쪽상지와왼쪽전흉부의종창및통증현병력 : 평소건강하게지내던환자가내원 10일전기침, 가래와인후통으로지역의원을방문하였다.

2 Tuberculosis and Respiratory Diseases Vol. 71. No. 2, Aug 이와관련된잠재암의예를경험하였기에문헌고찰과함께보고한다. 증례환자 : 48세, 남자주소 : 왼쪽상지와왼쪽전흉부의종창및통증현병력 : 평소건강하게지내던환자가내원 10일전기침, 가래와인후통으로지역의원을방문하였다. 환자는감기라고듣고증상에대한약을처방받았으며, 8.5% 아미노산수액제제를왼쪽상지의정맥을통해투여받았다. 이후기침, 가래, 인후염은호전되었으나내원 7일전부터왼쪽상지와왼쪽전흉부, 왼쪽얼굴이부으면서통증이동반되고, 호흡곤란이나타나본원에방문하였다. 과거력 : 약물과민성이나혈액학적질환등의특이소견은없었다. 내원 6개월전타병원에서시행한위내시경을포함한건강검진에서이상소견은없었다. 가족력 : 특이사항없음개인력 : 흡연력은약 15갑년이었고, 음주는거의하지않았다. 직업력 : 호텔식당의매니저로일하고있었으며, 가끔의자들을나르곤하였으나육체적인노동은많지않았다. 진찰소견 : 급성병색을보였으나의식은명료하였다. 체온은 36.4 o C, 맥박수는 70회 / 분, 호흡수는 20회 / 분, 혈압은 120/80 mm Hg이었다. 흉부진찰시심잡음이나호흡부잡음은청진되지않았다. 왼쪽목, 왼쪽위팔과왼쪽전흉부의종창및얕은정맥의팽창이관찰되었다. 복부진찰에서압통이나반발통은없었고간비대등의이상소견은없었다. 검사실소견 : 전체혈구계산에서백혈구 8,800/mm 3, 혈색소 11.2 g/dl, 혈소판 98,000/μL 이었고, 실내공기에서측정한동맥혈가스는 ph 7.43, PCO mm Hg, PaO mm Hg, 동맥산소포화도 98.4% 였다. 혈액응고검사에서프로트롬빈시간 17.1 초, INR 1.57, 활성화부분트롬보플라스틴시간 30초였으며, C단백활성도 68%, S단백활성도 61% 였고 homocysteine-s 11.1μmol/L, 루푸스항응고인자양성, 항카디오리핀항체는음성이었다. 파종혈관내응고검사에서섬유소원 2.03 g/l, 섬유소분해산물 >20μg/mL, D-dimer mg/l, 항트롬빈 -III 105% 였다. Factor V Leiden 및프로트롬빈 G20210A의돌연변이검사는음성이었다. 혈청생화학검사와전해질및심전도검사는정상소견을보였다. 방사선소견 : 흉부단순촬영은정상소견이었으나혈관조영흉부컴퓨터단층촬영 (computed tomography, CT) 및좌측상지 CT에서좌측쇄골상림프절과액와림프절, 다수의흉부와복부림프절비대가보였고, 좌측내경정맥, 쇄골하정맥, 일부폐동맥에조영증강이되지않았다 (Figure 1). 또한좌측액와정맥, 상완정맥과팔오금의여러정맥에서혈전에의한조영결손이의심되었다. 치료및경과 : Dalteparin 60 mg을하루 2번피하조직에주사하여항응고제투여를시작하였으나, 환자가좌측 4 번째, 5번째손가락의저린감을호소하여입원 2일째에카테터를상완정맥에삽입한후국소적으로혈전용해를시도하였다. 카테터를통해 heparin 3,000 Unit을한번에주입하고 1,000 Unit/hr를유지하면서우로키나아제를 80,000 Unit/hr의속도로 7시간동안관통시켜혈전을용해시켰다 (Figure 2). 혈전의완벽한제거는이루지못했으나왼쪽상지와왼쪽흉부의종창및통증은빠르게호전되었다. 입원 6일째부터와파린만으로항응고치료를유지하던중, 7일째갑작스럽게구음장애와좌측상지의쇠약감및의식저하가생겨시행한뇌자기공명영상 (magnetic resonance imaging, MRI) 에서우측대뇌반구에뇌경색병변이보여 (Figure 3), 환자를중환자실로옮겨미분획헤파린을투여하며뇌압상승에대한치료도시작하였다. 흉부 CT에서보인다수의복부림프절비대및높게측정된암표식자 (CEA ng/ml, CA19-9>1,000 U/mL) 결과를토대로잠재암을찾기위해검사한복부CT에서복막비후, 다수의복부림프절종대, 비장과양측신장의경색 Figure 1. Axial scan of upper extremity CT angiography shows luminal expanding low attenuation thrombi (arrows) in the left subclavian vein. CT: computed tomography. 135

JY Moon et al: A case of Trousseau's syndrome triggered by an intravenous injection Figure 2.

There are collateral venous channels at lower neck.

Although small amount of intraluminal thrombi are still remained in the axillary vein, most of collaterals have disappeared. Figure 3.

occiptial. 증이관찰되었다. 12일째에환자는흑색변을보이면서혈색소가 9.7 g/dl에서 6.9 g/dl로감소하였으며, 위내시경에서는출혈성궤양이관찰되어항응고치료는잠시중단하였다 (Figure 4).

3 JY Moon et al: A case of Trousseau's syndrome triggered by an intravenous injection Figure 2. (A) Left upper extremity venogram shows occlusion of left subclavian and innominate vein due to intraluminal thrombi (arrows). There are collateral venous channels at lower neck. (B) Left upper extremity venogram obtained after overnight catheter directed thrombolysis shows restored flow through the left subclavian and innominate vein. Although small amount of intraluminal thrombi are still remained in the axillary vein, most of collaterals have disappeared. Figure 3. Axial diffusion weighted magnetic resonance image shows high signal intensity foci suggesting acute infarct at right temporal, right frontal and left occiptial. 증이관찰되었다. 12일째에환자는흑색변을보이면서혈색소가 9.7 g/dl에서 6.9 g/dl로감소하였으며, 위내시경에서는출혈성궤양이관찰되어항응고치료는잠시중단하였다 (Figure 4). 2일뒤출혈이중단된것을확인하고, 항응고치료를 dalteparin 으로다시시작하였으나, 환자의신경학적증상은악화되었으며추적검사한뇌MRI 에서도뇌경색이진행되었다. 환자는위조직검사에서반지세포형의위암으로판명되었고폐렴과다장기부전으로입원 Figure 4. Endoscopy shows bleeding from gastric ulcer in the greater curvature of mid body. The ulcer was suspicous for advanced gastric cancer (Borrmann type II). 20 일째에사망하였다. 고 Trousseau 증후군은악성종양이발견되기전이나악성종양과함께발현된원인이뚜렷하지않은혈전성질환을말한다. Trousseau 증후군의정의가연구자에따라조금씩다르게사용되어왔기때문에아직역학적인빈도나임상적인특징이체계적으로정리되지는않았는데, 지금까지 찰 136

4 Tuberculosis and Respiratory Diseases Vol. 71. No. 2, Aug 알려진바로는주로췌장암, 폐암, 전립선암, 위암등에서잘발생하며혈전증의주된호발부위는사지, 얼굴, 내장기관의혈관으로동맥보다는정맥이다 1. 암과사지에생긴심부정맥혈전증의연관성은상지와하지를비교한결과 23.7% 대 11.1% 로상지가더높다고보고된바있으며 5, 이경우암의발병장기와조직형및원격전이여부가중요한인자로작용한다. 카테터와관련된상지심부정맥혈전증을대상으로조사한연구에서암이발생한장기별로는난소암이, 조직형으로는폐암, 두경부암및식도암에서평편암보다는선암이더연관성이높았고 2, 특히원격전이가있는환자에서없는환자에비해 12배가량혈전의위험도가증가된다고알려졌다 6. 상지심부정맥혈전증은하지심부정맥혈전증에비하여젊고마른사람에서발생하는데, 특히암진단과연관성이더높다. 또한, 하지심부정맥혈전증에비하여폐색전혈전증및 post-thrombotic syndrome 의발생율이낮고, 선천성또는후천성혈전성향증과의관련성도낮다. 위험요인의유무에따라원발성및이차성으로나뉘며, 그중이차성이환자의약 80% 를차지한다. 이차성의대부분은암및중심정맥카테터에의한혈전증이지만, 드물게상지의혈전증이말초정맥카테터에의해서도생길수있다. Chengelis 등 3 은심부정맥혈전증이없는말초혈관염이생긴환자들을대상으로평균일주일간도플러초음파로추적검사한결과약 11% 의환자에서심부정맥혈전증이생겼음을보고하였는데, 이것은말초혈관에생긴화학적인혈관염이상지의깊은혈관계로퍼졌다고볼수있다. 또한 Sydney Medically Supervised Injecting Centre에서주사제사용자를대상으로 6년간조사한결과반복적인주사와관련된손상으로환자의약 4% 에서혈전증이발생하였음이보고된바있다 4. 하지만본증례와같이한번의주사로정맥혈전증이발생할위험이어느정도인지는알려진바가없는데, 기존의위험인자들 2 을고려해볼때혈전성향및암과같은기저질환의유무, 혈관의위치및상태, 카테터의재질, 형태및굵기, 항암제와같은주사제의종류, 환자의활동성및투약상태와관련이있을것으로생각된다. 항인지질항체 ( 루푸스항응고인자나항카디오리핀항체또는 Anti-β2 glycoprotein-i 항체 ) 중 1개이상이지속적으로양성을보이면서혈전증이동반된경우를항인지질증후군이라하는데, 본환자의경우혈전증과함께루푸스항응고인자가입원시및사망직전까지수차례검사에서양성반응을보였다. 항인지질항체가악성종양그자체 의부수적인현상인지, 그리고그것이혈전증을유발하는지는아직명확히밝혀지지않았는데, 정상인에비해암환자에서항인지질항체의양성빈도가높으며, 암환자중에서도항인지질항체가양성인경우에혈전증의빈도가높음이보고된바있다 7. 또한항인지질항체와함께 1주내에 3개이상의장기에생긴미세혈전증이조직학적으로증명된경우를파국적항인지질증후군이라하며, 감염, 수술, 불충분한항응고치료, 약제, 산과합병증, 암등이유발요인으로알려져있다 8. 본증례의경우는짧은기간에상지, 폐, 뇌, 신장, 비장을침범하는혈전증및항인지질항체양성을보였으나, 조직학적인확인은하지못해파국적항인지질증후군을진단할수없었다. 상지심부정맥혈전증과 Trousseau 증후군및항인지질증후군의치료는원인을제거하고항응고제투여로재발의위험도를낮추는것이다 1,2,7. 상지심부정맥혈전증의경우는일부환자에서카테터를통한혈전용해술을시행해볼수있는데, 문헌에의하면그적응증으로이전에건강했던사람, 최근에발생한심한부종, 침범된상지의기능적인이상등을제시하고있다 2. 본증례의경우잠복암이발견되기전에빠른회복을위해 catheter-directed 혈전응고를시도하여잠시나마호전을보였지만, 헤파린을중단한뒤뇌경색이나타나며혈전증이악화되었다. 이때악화의원인으로정맥의혈전이심장의결손을통과해동맥의색전을일으키는모순색전증을의심해볼수있지만, 심초음파검사에서뇌경색의원인이될만한이상은없었다. 이보다는 Trousseau 증후군의항응고제치료로와파린보다는헤파린이선호되는기존연구결과들 2,9,10 과관련이있을것으로보이며, 본증례와비슷하게헤파린을중단한뒤빠른악화를보인예도보고된바있다 1. 또한, 정맥혈전증은적절한항응고요법이이루어지더라도재발할수있는데, 암환자들은재발의위험도가 3 4배가량높으며이는암의확산정도와관련이있다고알려져있다 11. 암환자에게생긴정맥혈전증의치료로저분자량헤파린이기존의미분획헤파린보다생존율을향상시킴이여러임상시험과메타분석을통해증명되었지만 2,9,10, 여러저분자량헤파린중에서어떤것이더효과가좋은지는추가연구가필요하다 9. 본증례의경우잠재암의여부를알지못했던환자에게지역의원에서투여한주사에의해좌측팔오금의말초정맥에혈전증이발생한후, 이것이이미전격전이가생긴환자의잠재암과이에따른과응고성향으로인해상지심부정맥혈전증으로발전하여 Trousseau 증후군의증상이 137

5 JY Moon et al: A case of Trousseau's syndrome triggered by an intravenous injection 시작된것으로생각된다. 지금까지보고된문헌에따르면상지에발현된 Trousseau 증후군은국내에서는보고된바가없었으며, 국외에서도 1예만이확인되었다 12. 이는암환자에서상지심부정맥혈전증이잘생긴다는연구들과모순적인데, Trousseau 증후군이 MeSH (Medical Subject Heading) 에등재되어있지않듯이아직학문적인정의가명확하지않은이유도있지만, 역으로이미알려진암환자가아닌상지심부정맥혈전증이첫증상으로발현된환자에서아직발견되지않은암과의연관성을임상의들이반대의경우에비해간과해온때문일수도있다. 이처럼원인이뚜렷하지않은혈전증에서는잠복암의가능성을염두에두고적극적으로찾아야하는데, 원인이뚜렷하지않은혈전증환자를무작위배정한뒤실험군을대상으로적극적으로잠복암에대한조사를한결과약 13% 의환자가암에이환되어있었으며, 2년간추적관찰한뒤에는대조군에비해암과관련된사망률을낮추었음이보고된바있다 13. 국내에서는현재까지폐암 14, 위암 15, 난소암, 담관암에서동반된다양한혈전증이 Trousseau 증후군으로보고된바가있으나, 하지에비하여드물게발생하는상지의혈전증으로발현된예는없었다. 또한암과관련된과응고성향의환자에서는말초혈관주사에의해서도심부정맥의혈전증이발생할수있다는것을시사한다. 따라서원인이뚜렷하지않은혈전증, 특히주사와관련하여상지의혈전증소견을보이는환자에서는 Trousseau 증후군을반드시고려하고, 이와동반된잠재암을찾으려는노력이필요하다. 참고문헌 1. Varki A. Trousseau's syndrome: multiple definitions and multiple mechanisms. Blood 2007;110: Kucher N. Clinical practice. Deep-vein thrombosis of the upper extremities. N Engl J Med 2011;364: Chengelis DL, Bendick PJ, Glover JL, Brown OW, Ranval TJ. Progression of superficial venous thrombosis to deep vein thrombosis. J Vasc Surg 1996;24: Salmon AM, Dwyer R, Jauncey M, van Beek I, Topp L, Maher L. Injecting-related injury and disease among clients of a supervised injecting facility. Drug Alcohol Depend 2009;101: Girolami A, Prandoni P, Zanon E, Bagatella P, Girolami B. Venous thromboses of upper limbs are more frequently associated with occult cancer as compared with those of lower limbs. Blood Coagul Fibrinolysis 1999;10: Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Old and new risk factors for upper extremity deep venous thrombosis. J Thromb Haemost 2005;3: Miesbach W. Antiphospholipid antibodies and antiphospholipid syndrome in patients with malignancies: features, incidence, identification, and treatment. Semin Thromb Hemost 2008;34: Miesbach W. Malignancies and catastrophic anti-phospholipid syndrome. Clin Rev Allergy Immunol 2009;36: Pruemer J. Treatment of cancer-associated thrombosis: distinguishing among antithrombotic agents. Semin Oncol 2006;33(2 Suppl 4):S Akl EA, Rohilla S, Barba M, Sperati F, Terrenato I, Muti P, et al. Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer: a systematic review. Cancer 2008;113: Piccioli A, Falanga A, Baccaglini U, Marchetti M, Prandoni P. Cancer and venous thromboembolism. Semin Thromb Hemost 2006;32: Rigdon EE. Trousseau's syndrome and acute arterial thrombosis. Cardiovasc Surg 2000;8: Piccioli A, Lensing AW, Prins MH, Falanga A, Scannapieco GL, Ieran M, et al. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial. J Thromb Haemost 2004;2: An JY, Lee JE, Park HW, Lee JH, Yang SA, Park YK, et al. Lung cancer presented as painful swelling of lower legs. Tuberc Respir Dis 2006;61: Park MH, Jeong SI, Kee YW, Shin YJ, Oh DH, Seo KS, et al. A case of gastric adenocarcinoma presented as internal jugular vein thrombosis. Korean J Med 2002;63:

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