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1 대한수혈학회지 : 제 29 권제 1 호, 2018 The Korean Journal of Blood Transfusion Vol. 29, No. 1, 79-85, April pissn eissn Case Report 급성용혈수혈반응환자에서혈장교환을통한원인항체의제거 김남수 1 ㆍ이재현 1,2 ㆍ김달식 1,2 ㆍ이혜수 1,2 ㆍ최삼임 1,2 ㆍ조용곤 1,2 전북대학교의학전문대학원진단검사의학교실 1, 전북대학교임상의학연구소 - 전북대학교병원의생명연구원 2 Elimination of Causative Antibody by Plasma Exchange in a Patient with an Acute Hemolytic Transfusion Reaction Namsu Kim 1, Jaehyeon Lee 1,2, Dal Sik Kim 1,2, Hye Soo Lee 1,2, Sam Im Choi 1,2, Yong Gon Cho 1,2 Department of Laboratory Medicine, Chonbuk National University Medical School 1, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital 2, Jeonju, Korea An ABO-incompatible transfusion is a very rare event but it can cause severe adverse effects, including death. The prognosis is affected by various factors, such as the volume of infusion, underlying diseases, and immunologic state. Until now, however, there has been no consensus regarding the treatment of an ABO-incompatible transfusion except for conservative treatment. A 57 year-old male patient visited the authors emergency unit with multiple trauma due to a car accident. He had a deep laceration on his left neck accompanied by severe bleeding. Because of his low blood pressure and low hemoglobin level due to bleeding, an emergency transfusion was attempted. Unfortunately, one unit of RBC was transfused incorrectly into the patient due to a clerical error during the identification of the patient. The patient was typed as O, RhD positive; the RBC administered was A, RhD positive. After the transfusion, the patient showed an acute hemolytic transfusion reaction due to gross hematuria. Plasma exchange was attempted and medical treatment with high dose steroid with diuretics was done simultaneously. Two cycles of plasma exchange were done and the patient appeared to recover from the acute adverse effects of the transfusion. The plasma exchange was stopped and medical treatments for the transfusion reactions were maintained for ten days. The patient recovered fully and was discharged after one month. Based on this case, although more studies are necessary for approval as a standard therapy, this case suggests that immediate plasma exchange with medical treatment can be very helpful for eliminating the isoagglutinins in ABO-incompatible transfusions. (Korean J Blood Transfus 2018;29:79-85) Key words: ABO incompatible transfusion, Plasma exchange, Acute hemolytic transfusion reaction Received on February 23, Revised on March 19, Accepted on March 19, 2018 Correspondence to: Yong Gon Cho Department of Laboratory Medicine, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju 54907, Korea Tel: , Fax: , choyg@jbnu.ac.kr, ORCID: This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright C 2018 The Korean Society of Blood Transfusion

2 Korean J Blood Transfus Vol. 29, No. 1, 79-85, Apr 서론 ABO 부적합수혈은급성용혈수혈반응에의해치명적인부작용을일으킬수있다. 이러한 ABO 부적합수혈의원인들중에서가장흔한경우는환자식별오류이다 [1]. 문헌에따르면 50 ml 이상의 ABO 부적합수혈을받은환자의 17% 가사망하였고, 100 ml 이상의 ABO 부적합수혈을받은환자사망한경우는 67% 로, 수혈량이많을수록사망률이증가하였다 [2,3]. 급성용혈수혈반응의대표적인증상은빈맥, 발열, 오한, 호흡곤란, 허리나등의통증또는복통등이며저혈압, 파종성혈관내응고증, 급성신부전등의심각한합병증도나타날수있다. 이러한증상은수혈된적혈구항원에대한환자혈액내항체의항원-항체반응으로시작되어보체계활성화를통해일어난다. 보체활성화산물중 C3를 C3a와 C3b로분할시키고 C3b에의해막공격복합체가형성되면적혈구막이파괴되어용혈이일어나고 C5a, C3a와함께비만세포에서히스타민과세로토닌의분비를유도하여혈관의확장과호흡기와소화기계통의평활근수축을유발한다. C3a, C5a는단핵구, 대식세포, 혈관내피세포등에서인터루킨과종양괴사인자를방출시키고혈액응고기전을활성화시켜파종성혈관내응고증을유발하는것으로알려져있다 [4,5]. 급성용혈수혈반응에의한합병증의치료는수혈을중단하고수액과이뇨제의사용으로저혈압과신부전을방지하며적절한대증요법을시행하는것이일반적이나정립된치료법이존재하지않는것이현실이다. 혈장교환 (plasma exchange) 은환자의순환혈장으로부터병적성분을분리하여제거하며, 혈장교환과정에서반출된만큼의혈장을보충용액으로대체하므로혈액응고인자등의혈액내중요한기질을공급해주는치 료이므로, 급성용혈수혈반응의부작용치료에사용할만한가치가있다고할수있다. 본저자들은다발성외상으로내원한환자에서 200 ml이상의 ABO 부적합수혈로인해심각한합병증을보였음에도불구하고빠른혈장교환과내과적치료를통해완전히회복된증례를경험하였기에보고하는바이다. 증례환자는 57세남자로경부의깊은열상과출혈을동반한다발성외상으로본원응급실로내원하였다. 내원당시혈압은 80/50 mmhg, 심박수는분당 108회, 호흡수분당 23회, 체온 34.7 o C였으며, 혈액형은 O형, RhD 양성, 비예기항체선별검사는음성이었다. 환자는경부열상의지속적인출혈로추적관찰한혈색소가내원당시 (13.3 g/dl, 참고범위 g/dl) 보다크게감소하였고 (10.6 g/dl), 수축기혈압이 60 mmhg로바뀌면서의식상태가저하되어기도삽관을시행하였으며, 빠른속도로응급수혈을시행하면서출혈부위에대한응급수술을위해수술실로이동하였다. 그러나, 수술직전소변백의색깔이붉은색으로바뀐것을발견한의료진에의해환자의혈액형과다른 A형, RhD 양성인적혈구가수혈되었음을알게되었으나이미한단위의농축적혈구가모두 (250 ml) 수혈된상황이었다. 육안적혈뇨가관찰된소변의요검사결과, RBC 1-4/HPF, WBC 5-9/HPF, occult blood 3+ 였다. 혈액응고검사에서 prothrombin time (PT) 15.9 초 ( 참고범위 초 ), PT INR 1.50 ( 참고범위 ) 로연장되었고, D-dimer는 mg/l ( 참고범위 0.5 mg/l), FDP는 g/ml ( 참고범위 2.01 g/ml), 혈청 lactate dehydrogenase

3 김남수외 : 급성용혈수혈반응환자에서혈장교환을통한원인항체의제거 (LD) 는 1,313 IU/L ( 참고범위 IU/L) 로증가되어파종성혈관내응고증소견을보였다. ABO 부적합수혈 4시간후시행한직접항글로불린검사 (polyspecific) 는양성 (2+) 이었고, 동종응집소 (isoagglutinin) 의역가검사는환자의혈청을 DTT (dithiothreitol) 로처리하지않고생리식염수로계단희석한검체 (25 L) 를 0.8% A형적혈구부유액 (50 L) 과함께미세원주응집카드 (LISS-Coombs/ NaCl-Enzyme card) (BioRad, Cressier sur Morat, Switzerland) 에첨가하여 37 o C에서 15분간반응시킨후판독한결과, total (LISS-Coombs)/IgM (NaCl- Enzyme) anti-a는각각 1,024 이상 /512를나타내 어혈장교환을시행하였다. 혈장교환에는 Spectra Optia (Terumo BCT, Lakewood, CO, USA) 를사용하였다. 환자의체중은 75 kg, 헤마토크릿은 30.2% 로계산된혈장량은 3,434 ml (Nadler s equation)[6] 이었다. 혈장교환목표량을 3,400 ml로, 치환용액으로 20% 알부민 3 단위 ( 총 300 ml) 와생리식염수 1,200 ml를사용하여제조한용액과신선동결혈장 12 단위 ( 총 1,920 ml) 를준비하였다. 시술에따라실제주입된치환용액은신선동결혈장 1,864 ml과항응고제 (acid citrate dextrose, ACD) 98 ml를포함하여총 3,462 ml이었고, 제거한혈장량은 3,547 ml Table 1. Profile of the laboratory tests Parameters (unit, NR) Admission Post-transfusion Post-TPE (1st) Post-TPE (2nd) After 1 week WBC ( 10 3 / L, ) Hb (g/dl, ) Hematocrit (%, 42 52) Platelets ( 10 3 / L, ) PT (sec, ) PT (%, ) PT (INR, ) aptt (sec, ) D-dimer ( g/ml, ) Fibrinogen (mg/dl, ) FDP ( g/ml, <2.01) AT III (%, ) T-bilirubin (mg/dl, ) D-bilirubin (mg/dl, <0.4) LD (IU/L, ) RBC (Urine) (/HPF, 1 4) nt WBC (Urine) (/HPF, 1 4) nt OB (Urine) (negative) nt Negative 1+ DAT (negative) nt 2+ ± nt - Isoagglutinin titer (total/igm anti-a) nt >1,024/512 8/2 1,024/2 nt Abbreviations: NR, normal range; PT, prothrombin time; aptt, activated partial thromboplastin time; FDP, fibrin degradation product; AT III, antithrombin III; Hb, Hemoglobin; WBC, white blood cell; LD, lactate dehydrogenase, HPF; high power field, OB; occult blood, DAT; direct antiglobulin test, nt; not tested

4 Korean J Blood Transfus Vol. 29, No. 1, 79-85, Apr 이었다. 첫번째혈장교환후환자의동종응집소역가 (total/igm anti-a) 는각각 8/2 이하, 직접항글로불린검사 (IgG) 도약양성, LD도 890 IU/L로감소하였다 (Table 1, Fig. 1). 다음날시행한두번째혈장교환에서환자의혈장교환목표량은 3,700 ml로설정하였고, 치환용액은 20% 알부민 3 단위 ( 총 300 ml) 와생리식염수 1,200 ml를사용하여제조한용액과신선동결혈장 14 단위 ( 총 2,240 ml) 를준비하였고, 신선동결혈장 2,239 ml와항응고제 88 ml를포함하여 3,827 ml를주입하였고, 3,910 ml의혈장을제거하였다. 두번째혈장교환후동종응집소역가 (total/igm anti-a) 는 1,024/2이었고, LD는 718 IU/L, occult blood 결과는음성으로전환되었다. 혈액응고검사결과 PT 12.6초 ( 참고범위 초 ), PT INR 1.19 ( 참고범위 ), aptt 32.3초 ( 참고범위 초 ) 로정상화되었다. D-dimer 1.59 mg/l ( 참고범위 0.5 mg/l), FDP 5.47 g/ml ( 참고범위 2.01 g/ml) 의결과를포함한전체적인검사결과는환자의급성용혈수혈반응이회복되는양상을나타내었고임상적으로혈압저하와혈뇨등의증상도정상으로호전되어추가적인혈장교환은시행하지않았다. 2회의혈장교환과병행하여시작한내과적치료, 즉이뇨제와수액치료, 그리고고용량스테로이드등은 10일동안더지속하였고수혈과관련된부작용이모두회복된것으로판단되어내과적치료도중지하였다. 환자는입원한달후외상과관련된문제가해결된후퇴원하였다. 고찰 Fig. 1. Representative changes in some of the laboratory profiles between transfusion and TPE showing the effects of TPE in the ATHR. Abbreviations: ATHR, acute transfusion hemolytic reaction; PT, prothrombin time; FDP, fibrin degradation product; LD, lactate dehydrogenase; TPE, therapeutic plasma exchange. ABO 부적합혈액은 10 ml의수혈에도급성용혈수혈반응을일으킬수있다 [7]. ABO 부적합수혈의가장흔한원인은환자식별오류인데뉴욕주에서 1990년부터 1999년까지 10년간보고된수혈보고서를분석한문헌에따르면총 462건의수혈오류중 171건 (37%) 이환자확인과정의오류였다. 또한 237건의 ABO 부적합수혈가운데 117건에서용혈수혈반응이나타났으며환자사망은 5건이발생하였다 [1]. 급성용혈수혈반응이발생하였을때면역반응의산물들이환자의증상과합병증, 예후와도관련이있기때문에신속한제거가필요하다. 더불어저혈압방지및신혈류량유지를위한내과적치료가병용되어야한다. 증례환자의경우저혈압과급성신손상을방지하기위해시간당 150 ml의소변량유지를목표로결정질수액과이뇨제를처방하여신혈류량을유지시켰고실제로

5 김남수외 : 급성용혈수혈반응환자에서혈장교환을통한원인항체의제거 BUN(11 mg/dl, 참고범위 8 23 mg/dl), creatine (0.38 mg/dl, 참고범위 mg/dl) 결과등을통해환자에게급성신손상이유발되지않았음을확인하였다. 급성용혈수혈반응의주요병태생리적기전이헌혈자적혈구에대한수혈자항체의면역반응에의한용혈과그로인한연쇄작용이므로면역반응의원인항원이나항체를제거함으로써면역반응을감소시키거나연쇄작용에관여하는단계를차단하는치료방법을생각해볼수있다. Weinstock 등은 ABO 부적합수혈을받은환자에서면역복합체형성으로인한보체계의활성을차단하는 Eculizumab을이용하여환자를치료한증례를보고하였다 [8]. Eculizumab은 C5에대한 IgG 단클론항체로 C5에결합하여 C5가 C5a와 C5b로분할되어막공격복합체를형성하는것을방해하여그효과를나타낸다. 하지만많은양의 ABO 부적합혈액을수혈받은환자에대한효과가검증되지않았고, 치료제자체가매우고가이며, 1회투여로치료가끝나지않기때문에치료비상승등의현실적인문제로사용에제한이있다. 이미수혈된적혈구, 즉항원을제거하는방법은어려우므로항체및면역복합체를제거하여수혈자의혈중항체가를낮추는방법이유효한방법이될수있다. 혈장교환은환자의혈중에존재하는항체및항원항체복합체와그외각종면역반응산물을효과적으로제거하고부족한혈액응고인자등의보충이가능하다는점에있어서급성용혈수혈반응의치료로적용할수있다. 증례환자의경우파종성혈관내응고증의징후를보이고있었기때문에조기시술은부작용의진행의예방에도도움을줄수있다고판단하였다. 2017년일본에서수술중 O형, RhD 양성환자에게 B형, RhD 양성적혈구 280 ml가수혈된환자를지속적투석여과법 (continuous hemodiafiltration) 과혈장교환으로치료한증례가보고되었다 [9]. 다만혈역학적으로불안정한환자에있어서혈장교환은시술자체가환자에위험요소로작용할수있으므로금기로알려져있다 [10]. 증례환자의경우출혈과용혈반응에따른부작용으로인해혈역학적으로매우불안정한상태였으나, 지혈수술및적극적인내과적치료로혈역학적으로안정화되어혈장교환을시행할수있었다. 또한혈장교환으로인한항응고제의과다투입이나혈역학적불안정등의부작용발생가능성을낮추기위해환자의혈장량 (1 plasma volume) 을치환목표로혈장교환을시행하였다. 실제로많은양의혈장교환을시행할경우, 응고장애나구연산독성또는전해질불균형등의위험을높이는것으로알려져있다 [11]. 첫번째혈장교환이후환자의동종응집소역가가유의하게감소함을확인하였고, 그외검사지표들도정상화되는소견을보여혈장교환이효과가있다고판단하였다. 두번째혈장교환을시행후환자의다른검사지표는회복되는양상이지속되었고 IgM 동종응집소의증가없이 IgG 동종응집소의역가만상승하는소견을보였다. 이는 IgM이혈관내에 75% 정도분포하고생성속도가느려제거가잘되지만, IgG는혈관내 45%, 혈관외에 55% 정도분포하며생성속도가빠르고일단제거후에혈관외에존재하던 IgG의유입이쉽기때문인것으로보인다 [12]. 증례환자의경우, 첫번째혈장교환이후이러한반응이나타나지않았으나두번째혈장교환후에반동현상이나타난이유는항체생성에필요한시간때문으로생각된다. 즉처음혈장교환이후에는다시혈관내로유입될 IgG 항체가많지않아반동현상을보이지않았지만두번째혈장교환을시행한시기에는충분한 IgG 항체가생성되어혈관외에다른조직으로부터혈관내로유입된결과

6 Korean J Blood Transfus Vol. 29, No. 1, 79-85, Apr 가반동현상으로나타났을것으로추정된다. 2 회의혈장교환이후환자는임상적으로대부분의증상이사라져추가적인혈장교환은시행하지않고내과적인치료만지속하였다. 비록 ABO 불일치에의한급성용혈수혈반응환자에서혈장교환을이용한원인항체인동종응집소의즉각적인제거가표준치료법으로인정되려면더많은연구가필요하겠지만, 본증례를통해서볼때 ABO 부적합수혈이이루어진상황에서가능한최단시간내에혈장교환을시행하는것은환자의예후에긍정적인효과를나타낼것으로기대된다. 요약 ABO 부적합수혈은매우드물게발생하지만, 사망등심각한부작용을초래할수있다. 예후는주입된양이나기저질환, 면역상태등의다양한요소에의해영향을받으나, 지금까지 ABO 부적합수혈의치료에대해보존적치료외에는일치된치료법이없었다. 57세남자환자가교통사고로인한다발성외상으로응급실을방문하였다. 환자는심한출혈을동반한왼쪽목에깊은열상을보였다. 출혈로인해혈압이낮고헤모글로빈이감소하였기때문에응급상황에서수혈을시도하였다. 그러나한단위의적혈구가환자식별에있어서의사무적오류로인해환자에게잘못수혈되었다. 환자는 O, RhD 양성이었고, 투여된적혈구는 A, RhD 양성이었다. 수혈후발견된혈뇨로인하여환자의급성용혈수혈반응이확인되었다. 혈장교환과이뇨제를포함한고용량스테로이드치료를동시에시행하였다. 혈장교환은 2회수행되었고환자는수혈의급성부작용으로부터회복된것으로판단되어, 혈장교환을중단하고수혈반 응을위한내과적치료를 10 일동안유지하였다. 환자는 1 개월후완전히회복되어퇴원하였다. 혈장교환이표준치료법으로승인을받기위해서는더많은연구가필요하겠지만, 이사례를바탕으로, ABO 부적합수혈에서즉각적인혈장교환은내과적치료와함께동종응집소를제거하는데매우도움이될수있다고제안하는바이다. References 1. Linden JV, Wagner K, Voytovich AE, Sheehan J. Transfusion errors in New York State: an analysis of 10 years' experience. Transfusion 2000;40: Janatpour KA, Kalmin ND, Jensen HM, Holland PV. Clinical outcomes of ABO-incompatible RBC transfusions. Am J Clin Pathol 2008;129: Sazama K. Reports of 355 transfusionassociated deaths: 1976 through Transfusion 1990;30: Fung MK. Chapter 27 Noninfectious Complications of Blood Transfusion. In: Fung MK, Grossman BJ, Hillyer CD, Westhoff CM. Technical manual. 18th ed. Bethesda, MD: American Association of Blood Banks, 2014: Han KS, Park KU, Song EY. Chapter 6 Adverse Transfusion Reactions. In: Han KS, Park KU, Song EY. Transfusion medicine. 4th ed. Seoul: Korea Medical Book Publisher, 2014: Nadler SB, Hidalgo JH, Bloch T. Prediction of blood volume in normal human adults. Surgery 1962;51: Strobel E. Hemolytic transfusion reactions. Transfus Med Hemother 2008;35: Weinstock C, Möhle R, Dorn C, Weisel K, Höchsmann B, Schrezenmeier H, et al. Success

7 김남수외 : 급성용혈수혈반응환자에서혈장교환을통한원인항체의제거 ful use of eculizumab for treatment of an acute hemolytic reaction after ABO-incompatible red blood cell transfusion. Transfusion 2015;55: Namikawa A, Shibuya Y, Ouchi H, Takahashi H, Furuto Y. A case of ABO-incompatible blood transfusion treated by plasma exchange therapy and continuous hemodiafiltration. CEN Case Rep 2018;7: McGuckin S, Westwood JP, Webster H, Collier D, Leverett D, Scully M. Characterization of the complications associated with plasma exchange for thrombotic thrombocytopenic purpura and related thrombotic microangiopathic anaemias: a single institution experience. Vox Sang 2014;106: Mokrzycki MH, Kaplan AA. Therapeutic plasma exchange: complications and management. Am J Kidney Dis 1994;23: Korean Society for Laboratory Medicine. Chapter 84 Therapeutic Apheresis. In: Korean Society for Laboratory Medicine. Laboratory medicine. 5th ed. Seoul: Panmun Education, 2014:

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untitled 대한수혈학회지 : 제 29 권제 1 호, 2018 The Korean Journal of Blood Transfusion Vol. 29, No. 1, 73-78, April 2018 https://doi.org/10.17945/kjbt.2018.29.1.73 pissn 1226-9336 eissn 2383-6881 Case Report ABO 부적합수혈에의한급성용혈수혈반응