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J Korean Academy of Advanced General Dentistry 2013;2:33-38 Coumadin 을복용중인환자의치주치료후발생한술후과다출혈 조지헌, 방난심, 김기덕, 정복영, 박원서 * 연세대학교치과대학통합진료학과 ABSTRACT Excessive Bleeding after Periodontal Treatment in the Patient who Takes Coumadin Ji Hun Jo, Nan-Sim Pang, Kee-Deog Kim, Bock-Young Jung, Wonse Park* Department of Advanced General Dentistry, Yonsei University College of dentistry, Seoul, Korea 치과치료후환자의지혈에문제가발생했다면우선국소적으로지혈을방해하는요소가있는지, 전신적인문제인지를감별하는것이중요하다. 만약전신적인원인이존재한다면국소적인압박지혈만으로는출혈을조절하기힘든상황이발생할수있다. Coumadin 은대표적인항응고제약물로판막수술, 부정맥등에사용된다. 그러나이약물의 safe zone이매우좁아서투약방법, 환자의식습관, 약물투여등에민감하게영향을받을수있고 Coumadin toxicity 가발생할가능성이높다. 본증례에서는판막수술후 Coumadin 을복용중인환자에서치주치료후발생한술후과다출혈증례를경험한바, 술후출혈의원인과예방법에대해정리하고자한다. Key Words : Coumadin toxicity, INR, 출혈, 지혈 서론 Coumadin은 1954년에처음으로시판되기시작하여현재까지많이사용되고있는항응고제약물이다. 이약물은 vitamin K의 antagonist 및 vitamin K 의존성항응고인자 II(Prothrombin), VII, IX, X의생성을방해함으로써항응고효과를나타낸다. Coumadin 한알복용후최대효과는복용 48시간뒤에나타나며 5일간지속된다 1-3. 위와같은효능때문에 thrombosis 를예방해야하는부정맥, 협심증, 심근경색같은심장질환및심장판막수술그리고뇌경색, 폐색전증의경우에 Coumadin 은널리사용되고 Correspondence : Wonse Park Department of Advanced General Dentistry, Dental Hospital of Yonsei University 250 Seongsanno, Seodaemun-gu, Seoul, Korea. Tel: +82-2-2228-8980, Fax: +82-2 2227-8906, E mail: WONSE@yuhs.ac Received: Jan. 20, 2013; Revised: Feb. 21, 2013; Accepted: Mar. 8, 2013 Figure 1. Sites of anticoagulation action. Coagulation cascade of 2ndary hemostasis and site of action of drugs in the cascade. Adapted from http://en.wikpedia.org/wiki/coagulation. 33

JOURNAL OF KOREAN ACADEMY OF ADVANCED GENERAL DENTISTRY 있다. 그러나 narrow therapeutic index 및출혈의위험성때문에정기적으로 INR을확인하며주의깊게사용해야하는약물이다. 최근우리나라가고령화사회로들어가면서부정맥, 판막질환, 심뇌혈관질환자들이치과에내원하는빈도가증가하고있다. 이에따라, 항혈소판제와항응고제를예방혹은치료의목적으로복용하는환자수도많아지고있다. 본증례에서는 Coumadin 을복용중인환자에서치과시술후발생한 Coumadin toxicity, 즉술후출혈이발생한예를보고하면서, Coumadin 을복용하는환자를치료하기전과후에치과의사로서생각해봐야하는점들에대해서살펴보고자한다. 증례보고 본 77세여환은이틀전개인치과에서아래앞니부분에치료를받은후피가멈추지않는다는주소로연세대학교치과대학병원통합진료과에내원하였다. 환자의과거병력상 1986년세브란스병원심장혈관병원심장혈관외과에서심내막염, 부정맥치료를위한판막수술을받았으며 1991 년에다시판막수술을받은후현재본원심장내과에서정기검진중이었다. 투약중인약물은강심제 (Concor R 2.5mg/T), 혈압강하제 (Kanarb R 60mg/T), 이뇨제 (Lasix R 40mg/T), 동맥경화용제 (Livalo R 2mg/T) 였으며 Coumadin R 을 5mg/daily 로복용중이었다. 내원당시아래앞니부분에거즈를물고있는상황이었으나출혈은계속되고있었으며지속적인 oozing 양상을보였다 (Fig. 2,3). 환자분진술에의하면이틀전개인치과에서마취를하고아래앞니부분에잇몸치료를받았다고하였으므로 curettage 를한것으로추정되었다. 그당시임의로 Coumadin 을하루끊었으며처음거즈를물고있는동안에는지혈이되는듯하였으나그이후로시간이지나니다시출혈이되기시작했다고하였다. 시술받은당일저녁에다시 Coumadin 을한번복용하였으며본원에내원당시에는 Coumadin을복용하지않은상태였다. 본환자는 2008년본원에처음으로내원하였고그당시심장내과와협진결과다수의치아를발치하는경우에는입원후 Heparinization 을하며치료하도록권고받았고, 출혈경향이높지않은치료를하는경우에는 Kymoxin 2.0g 으로 premedication 후치료 5일전에 3일간은 Coumadin 복용을중단하고 2일전부터는다시복용하고치료하는것이추천되었다. 2008 년 5월부터 2009 년 6월까지다수의치아를발치하기위해입원한경우를제외하고치주치료, 신경치료및보철치료를시행하는동안은후자의협진내용에준하여치료를시행하였으며큰문제없이치료가진행되었고마무리되었다. 그이후내원하지않다가 2012 년 12월에위아래부분틀니가맞지않는다는주소로본과에재내원하였으나다음번 Figure 2. Oral frontal photograph during the patient's initial visit. Uncontrolled bleeding is observed in mandibular anterior region. Figure 3. Mandibular Occlusal photograph during the patient's initial visit. Uncontrolled bleeding is observed. 34

Ji Hun Jo, et al. 약속에내원하지않았고 2013년 2월에아래앞니출혈을주소로다시내원하였다. 이당시심장내과에서권고한지침을지키지않고임의로 Coumadin 을중단및복용하였으며예방적항생제도복용하지않고치과치료를받은후지속적출혈이발생하고있는상황이었다. 에피네프린이포함된국소마취제를주사하고압박거즈를적용하면서국소적으로지혈을방해하는요소가있는지아래앞니 periapical X-ray 를촬영하였다. 방사선사진상으로지혈을방해할정도로문제가있어보이는소견은발견되지않았다 (Fig. 4). 압박지혈등국소적인지혈법이효과적이지않았음으로 Figure 4. Periapical radiograph of mandibular incisors during the initial visit. No local insults was visible, which may have contributed to the uncontrolled bleeding. 전신적인출혈원인이있을것으로추측되어시행한혈액응고검사결과, PT(sec)=83.4, PT(INR)=7.20 으로, Coumadin Toxicity 가의심되어본원심장내과로의뢰하였다. 이전 INR 은 2.0~3.0 사이로유지되고있었다. 심장내과기록을확인해본결과, 몇주전부터어깨가아파서개인병원에서진통제를처방받아복용하였으며일주일전부터는약국에서개인적으로진통제를사서복용하였다고했다. 심장내과에서는 Coumadin toxicity 로진단하에 Coumadin 2일간복용중단및 Vitamin K 처방, Coumadin 복용법지도를하였으며 1일및 1주일정기점진을하였다. 환자분께전화로지혈잘유지되고있음을확인후다음번심장내과내원시본원에내원하여구강내출혈여부를확인하기로하였다. 1주일후내원당시특별한치과적처치없이지혈이잘된모습을확인할수있었다 (Fig. 5,6). 토론 Coumadin(Warfarin) toxicity는 INR이목표치 (2.0~3.0) 를벗어나증가한상태를말하며출혈경향이증가하여지혈에문제가발생할가능성이높아진다. INR 수치가 2.0이상올라가면출혈경향이증가하기시작하며 5.0이상증가하면 Figure 5. Oral frontal photograph taken 1 week after the patient's initial visit. Bleeding has stopped without additional treatment in mandibular anterior region. Figure 6. Mandibular occlusal photograph taken 1 week after the patient's initial visit. Bleeding has stopped with no additional treatment. 35

JOURNAL OF KOREAN ACADEMY OF ADVANCED GENERAL DENTISTRY INDICATION INR GOAL DVT prophylaxis 2.0~3.0 Treatment of DVT 2.0~3.0 Treatment of PE 2.0~3.0 Prevention of systemic embolism Tissue heart valves Acute MI 2.0~3.0 Valvular heart disease Atrial fibrillation Mechanical prosthetic valves 2.5~3.5 Bileaflet mechanical valve in aortic position 2.0~3.0 Figure 7. Indication and INR goal Ref: Horton J and Bushwick BM. Warfarin Therapy: Evolving strategies in anticoagulation. Am Fam Physician 1999; 59 (3):635-646. Medication Effect on INR (International Normalized Ratio) Proposed Mechanism acetaminophen increase inhibition of metabolism allopurinol increase inhibition of metabolism aprepitant/fosaprepitant decrease induction of CYP2C9 metabolism azathioprine decrease decrease in absorption, increase on metabolism azithromycin increase inhibition of CYP3A4 carbamazepine decrease induction of metabolism celecoxib increase inhibition of CYP2C9 clprofloxacin increase inhibition of CYP3A4 & CYP1A2 clarithromycin increase inhibition of CYP3A4 corticosteroids increase/decrease direct pharmacologic action cyclosporine decrease inhibition of CYP3A4 direct thrombin inhibitors (argatroban, lepirudin) additive anti-coagulant activity direct pharmacologic action erythromycin increase inhibition of CYP3A4 fluconazole increase inhibition of CYP3A4 and CYP2C9 fluoroquinolones increase inhibition of CYP1A2 heparin/ low molecular weight heparin additive anti-coagulant activity direct pharmacologic action itraconazole increase inhibition of CYP3A4 metronidazole increase inhibition of CYP2C9 NSAIDs no effect increase bleeding risk omeprazole increase inhibition of CYP2C19 phenytoin/fosphenytoin increase/decrease changes in metabolism of CYP2C9,CYP2C19 and CYP3A4 rifampin decrease inducation of metabolism SSRIs increase changes in metabolism sulfamethoxazole increase inhibition of CYP2C9 Figure 8. List of medications which may interfere with the normal actions of coumadin. Ref: Lisa K. Lohr, PharmD, BCPS, BCOP, Warfarin drug interactions can affect INR values, HemOnc Today, June 25, 2008. 36

Ji Hun Jo, et al. OVERDOSE/TOXICITY GUIDELINES INR PATIENT SITUATION ACTION >3.0 & 5.0 AND >5.0 & 9.0 AND AND No bleeding, No need for rapid reversal (i.e. Surgery) No bleeding >9.0 & 20.0 AND No bleeding >20.0 AND Need rapid reversal for urgent surgery or dental extraction Serious bleeding or major warfarin overdose Figure 9. Guidelines for coumadin toxicity or overdose. Omit next and restart at lower dose when INR approaches 3.0 If no risk factors for bleeding : a. Omit next 1 or 2 doses b. Monitor INR frequently c. Reinstitute at lower dose OR If increased risk for bleeding : Vit K PO 1.0~2.5mg Vit K PO 2.0~4.0mg (expected INR within 24hrs) If still high at 24hrs, may give additional Vit K PO 1.0~2.0mg Vit K PO 3.0~5.0mg (expected INR within 24~48hrs) Vit K 10mg slow IV infusion with supplemental fresh plasma transfusion or prothrombin complex concentrate depending on urgency Ref: Hirsch J, Dalen, JE, Deykin D, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1998:114 (5); 445S-469S. 기하급수적으로증가하게된다. 일반적인 INR 목표치는 Fig. 7과같다 4. 이러한현상은 Coumdain의 overdose, 음식물의상호작용, 약물간의상호작용등에의해서나타날수있다. Coumadin 은 narrow therapeutic index 및유전적으로개인차가큰약물이라사용시정기적으로 INR을확인해야하며 overdose 에유의해야한다. 또한여러다른약물과상호작용에의해서 INR 수치가올라갈수있다 2. 상호작용가능한대표적인약물은 Fig. 8에나와있다 5. 올라간 INR을낮추기위해크게 3가지방법으로접근가능하다. 첫번째로 Coumadin 복용을중단하고, 두번째로 vitamin K를섭취하고, 세번째로 fresh plasma 혹은 prothrombin complex concentrate를주입하는것이다. Coumadin toxicity 가발생한상황에대한적절한 Guideline 은 Fig. 9에나와있다 6. Coumadin을복용하고있는환자에서제일큰합병증은출혈경향의증가라고할수있다. 그러므로담당주치의에게협진을보내고답장을확인한후에진료를시작해야 한다. 특히협진결과전신적인상태를고려시 Coumadin 을유지하며치과진료를해야하는상황이라면더욱조심해야할것이다. 가능하면입원후 Heparinization을하며치료하거나, 외래로 LMWH(Low Molecular Weight Heparin) 요법을사용하는것이적절하겠지만상황이그렇지못하다면국소적인지혈을위한만반의준비를하고시작해야한다 ( 지혈제, fresh plasma 혹은 prothrombin complex concentrate). 지혈은국소적인부분과전신적인부분으로나눠서생각해보아야한다. 국소적으로시술부위의염증정도, 치석의유무등을고려해야하고전신적으로는항혈소판제혹은항응고제약물을복용중인지확인해야한다. 본증례의환자처럼 Coumadin 을복용중인환자는치료를시작하기전에 Coumadin 과상호작용가능한약물이나음식을섭취한적이있는지병력청취를하고반드시 INR을검사한후적절한수치를유지하고있음을확인할필요가있다. INR 이적절하게유지된다는전제하에국소적으로지혈을시도해야만성공적인치료의마무리가될수있다. 37

JOURNAL OF KOREAN ACADEMY OF ADVANCED GENERAL DENTISTRY 본증례의경우약물상호작용에의해서 INR 수치가상승한 Coumadin toxicity 상태에서출혈이발생할수있는치과치료를시행한것이다. 초반에압박지혈로지혈이되는듯하나시간이지남에따라지속적인출혈이발생하게되었다. Coumadin 을복용중인환자에서치과시술후지속적인출혈이발생하는경우에는혈액검사를통해 INR 수치를확인하는것이필수적이다. INR 수치가목표치에포함된다면국소적인출혈원인을제거후압박지혈만으로도지혈이가능하겠지만, 본증례처럼 INR 수치가비정상적으로높아져있다면국소적인압박지혈만으로는지혈이불가능하며근본적으로 INR 수치를낮추기위한적절한조치가필요한상황이된다. 결론 Coumadin 을복용하는환자에서치과시술직전의 PT(INR) 값을미리측정하는것이만에하나발생할수있는출혈등 Coumadin toxicity 에의해발생가능한문제점을예방할수있을것으로기대된다. References 1. Subir Kumar Banerjee, Kaushik Saha, Somnath Maitra, Kolkata: WARFARIN TOXICITY MANAGEMENT, Medicine update 2012;Vol.22:10:6. 2. Irina Piatkov, Colin Rochester, Trudi Jones and Steven Boyages, Warfarin Toxicity and Individual Variability- Clinical Case, Toxins 2010;2:2584-92. 3. James O'Donnell, Anticoagulants: Therapeutics, Risks, and Toxicity--Special Emphasis on Heparin-Induced Thrombocytopenia(HIT), Journal of Pharmacy Practice 2012;25:22. 4. Horton J and Bushwick BM. Warfarin Therapy: Evolving strategies in anticoagulation. Am Fam Physician 1999;59(3):635-46. 5. Lisa K. Lohr, PharmD, BCPS, BCOP, Warfarin drug interactions can affect INR values, HemOnc Today, June 25, 2008. 6. Hirsch J, Dalen, JE, Deykin D, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1998;114(5): 445S-69S. 38