대한수혈학회지 : 제 29 권제 2 호, 2018 The Korean Journal of Blood Transfusion Vol. 29, No. 2, 188-193, August 2018 https://doi.org/10.17945/kjbt.2018.29.2.188 pissn 1226-9336 eissn 2383-6881 Case Report 고빈도항원음성혈액형가진겸상적혈구빈혈환아 1 예 이현지 1, * ㆍ신경화 2, * ㆍ김혜림 2 ㆍ정세리 3 ㆍ공섬김 4 ㆍ김형회 2 양산부산대학교병원진단검사의학과 1, 부산대학교병원진단검사의학과 2, 고신대학교의과대학진단검사의학과 3, 고신대학교의과대학소아청소년과 4 A Case of Sickle Cell Anemia with a Lack of High Frequency Red Blood Cell Antigen Hyun-Ji Lee 1, *, Kyung-Hwa Shin 2, *, Hyerim Kim 2, Seri Jeong 3, Seom Gim Kong 4, Hyung Hoi Kim 2 Department of Laboratory Medicine, Pusan National University Yangsan Hospital 1, Yangsan, Department of Laboratory Medicine, Pusan National University Hospital 2, Department of Laboratory Medicine 3 and Pediatrics 4, Kosin University College of Medicine, Busan, Korea Patients with sickle cell anemia are chronically transfused. Therefore, it is important to prevent the alloimmunization of RBC antigens. The authors identified a high frequency antigen-negative blood group in patients with sickle cell anemia. As the number of foreigners residing in Korea is increasing, it is necessary to know what to consider when transfusing blood to sickle cell anemia patients. Patients with sickle cell anemia should be informed of the exact blood group type using extended RBC typing to confirm the ABO, Rh, Kell, and Duffy blood types at diagnosis or before the first blood transfusion. Extended matched blood transfusion can reduce the risk of alloimmunization of RBC antigens. (Korean J Blood Transfus 2018;29:188-193) Key words: Duffy blood-group system, High frequency RBC antigen, Anemia, Sickle cell 서론겸상적혈구빈혈은말라리아에대응하기위해적혈구가적응하여발생하는질환으로말라리아유병률이높은지역에서높은빈도로나타난다 [1]. 겸상적혈구빈혈은만성수혈이요구되는대 표적인질환으로, 환자들은만성수혈로인한불규칙항체의발생빈도가높다. 더불어겸상적혈구빈혈환자의적혈구는적혈구막의변형이어려워혈관내용혈이증가하고이를보상하기위해헤모글로빈농도가높게유지되고, 백혈구제거농축적혈구제제를제조하는경우적혈구가응집 Received on June 12, 2018. Revised on July 16, 2018. Accepted on July 16, 2018 Correspondence to: Hyung Hoi Kim Biomedical Research Institute, Pusan National Univestiy Hospital Clinical Trial Center (CTC), Department of Laboratory Medicine and BioMedical, Informatics Unit Pusan National University School of Medicine, 179 Gudeok-ro, Seo-gu, Busan 49241, Korea Tel: 82-51-240-7419, Fax: 82-51-247-6560, E-mail: hhkim@pusan.ac.kr, ORCID: http://orcid.org/0000-0003-3989-2037 *Hyun Ji Lee and Kyung-Hwa Shin contributed equally as co-first authors. This study was supported by a 2017 research grant from Pusan National University Hospital. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) 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 - 188 -
이현지외 : 고빈도항원음성혈액형가진겸상적혈구빈혈환아 1 예 하여필터를통과하지못하게된다. 이에겸상적혈구빈혈환자가헌혈할경우, 이혈액제제를동일질환환자혹은신생아가수혈받으면다양한장기에경색을일으키게된다 [2]. 미국에서는아프리카계흑인에서흔한겸상적혈구빈혈환자의수혈과헌혈에서주의점을제시하고있지만 [3] 국내에서는겸상적혈구빈혈의보고가드물어수혈과헌혈에서의주의점에대한경험이적다. 따라서본증례에서는겸상적혈구빈혈및 Fy a 음성 Fy b 음성인혈액형이확인된한국에거주하는아프리카계환자에대해보고하고, 겸상적혈구빈혈환자에서의수혈및헌혈시고려할점을확인하고자하였다. 증례 8세여아가 2일전부터발생한발열, 인후통, 구토, 설사를주소로내원하였다. 환자는한국에거주하고있는나이지리아에서출생한흑인이였다. 발열의원인을확인하기위해검사를시행하였다. 혈액검사결과는 Hb 8.6 ( 참고범위 11.5 15.5) g/dl, MCV 94.7 ( 참고범위 77 90) fl, RDW 15.3 ( 참고범위 11.6 14.3)%, WBC 18,930 ( 참고범위 4,500 13,500)/uL (Segmented neutrophil 61%, band form neutrophil 14%, lymphocyte 16%, monocyte 8%), Platelet 218,000 ( 참고범위 169000 365000)/uL, Reticulocyte count 8.4%, PT 16.7 ( 참고범위 11.0 15.0) 초, aptt 32.6 ( 참고범위 27 45) 초이었다. ESR 27 ( 참고범위 1 20) mm/hr, CRP 7.11 ( 참고범위 0 0.75) mg/dl, AST/ALT 47 ( 참고범위 5 40)/35 ( 참고범위 3 40) IU/L, LDH 1019 ( 참고범위 200 450) IU/L, total bilirubin 2.58 ( 참고범위 02 1.2) mg/dl, direct bilirubin 0.56 ( 참고범위 0 0.4) mg/dl 이었다. 비예기항체선별검사결과는음성이었다. 빈혈의원인을파악하기위해말초혈액도말검사를시행하였다 (Fig. 1). 환자의혈액검사에서겸상적혈구빈혈이의심되어추가로시행한혈색소전기영동에서 Hemoglobin (Hb) A 16.4%, Hb F 20.9%, HbS 60.2%, HbA2 2.5% 로확인되어 HbF와 Fig. 1. Peripheral blood smear showing microcytic hypochromic RBCs with sickle cells (Wright stain, 1,000). Fig. 2. Electrophoresis of hemoglobin in patients showing abnormal fraction of Hb S (60.2%) and Hb F (20.9%). - 189 -
Korean J Blood Transfus Vol. 29, No. 2, 188-193, Aug. 2018 HbS 가연령에비해증가된소견이확인되었다 (Fig. 2). 확진검사를위해시행한 human beta globin (HBB) 유전자염기서열에서 c. 20A>T (p.glu7val) 으로 Homozygous (HbS/HbS) 가확인되었다 (Fig. 3). ID CORE XT system (Progenika Biopharma- Grifols, Bizkaia, Spain) 를사용하여 37개의적혈구항원을검사하였다. 환자의적혈구항원유전자검사결과는 Table 1과같다 KELL 유전자의 Js a 양성, Js b 음성결과가확인되었고, FY*B 유전자의 67T>C 변이로인한 Fy a -Fy b - 표현형이확인되었다. 혈액배양검사에서는 no growth였으나, 패혈증에준하여 cefotaxime, vancomycin 투여하였으며이후발열이호전되고혈액배양음성으로확인되어퇴원하였다. 퇴원시검사결과는 Hb 7.9 ( 참고범위 11.5 15.5) g/dl MCV 93.3 ( 참고범위 77 90) fl, RDW 16 ( 참고범위 11.6 14.3)%, WBC 7,660 ( 참고범위 4,500 13,500)/ L (neutrophil 46% band 0% lympho 43% mono 9%), PLT 224,000 ( 참고범위 169000 365000)/mm 3, Reticulocyte count 7.6%, CRP 2.79 ( 참고범위 0 0.75) mg/dl AST/ ALT 44 ( 참고범위 5 40)/28 ( 참고범위 3 40) IU/L, Total bilirubin/direct Bilirubin 1.43 ( 참고범위 02 1.2)/0.39 ( 참고범위 0 0.4) mg/dl, LDH 1027 ( 참고범위 200 450) IU/L 이였다. 환자는수혈은시행하지않았고, 증상이조절되어특이사항없이퇴원하였고, 퇴원이후 amoxicillin 일 주일간복용하였다. 환자형제관계는 2남 1녀였고, 두명의형제에서 HBB 유전자염기서열에서 c. 20A>T (p.glu7val) 으로 Homozygous (HbS/HbS) 가확인되었고, FY*B 유전자의 67T>C 변이로인한 Fy a -Fy b - 표현형이동일하게확인되었다. Table 1. Genotyping and predicted phenotyping of red blood cells in patients Blood group system 고찰 겸상적혈구빈혈은 HBB 유전자의여섯번째자리에위치한 GAG 가 GTG 로바뀌어아미노산이 Glutamate가 Valine으로변경되는과오돌연변이 Genotype result Predicted phenotype result Rh RHCE*ce C-E-c+e+Cw-Vhr+VS-hr + Kell KEL*k_KPB_JSB, KEL*k_KPB_JSA K-k+Kp a -Kp b + Js a +Js b - Kidd JK*A Jk a +Jk b - Duffy FY*B_GATA Fy a -Fy b - MNS GYPA*M M+N-S-s+ MNS GYPB*s U+Mi a - Diego DI*B Di a -Di b + Dombrock DO*B Do a -Do b +Hy+Jo a + Colton CO*A Co a +Co b - Cartwright YT*A Yt a +Yt b - Lutheran LU*B Lu a -Lu b + Fig. 3. Direct sequencing results of the human beta globin (HBB) gene. c.20a>t (p.glu7val). - 190 -
이현지외 : 고빈도항원음성혈액형가진겸상적혈구빈혈환아 1 예 (missense) 에의한 HbS에의해발생된다 [1]. 겸상적혈구빈혈은만성수혈이필요한질환인동시에감염에취약하기때문에감염예방과수혈이치료의핵심이다 [1]. 국내에외국인의활발한증가에더불어, 국내거주하는아프리카, 중동그리고인도지역출신외국인은약 12,000여명으로 [4] 이지역에서호발하는질환에대한고려가필요하겠다. 본증례에서는국내에서보고가드문겸상적혈구빈혈이확인된아프리카계흑인소아에서확인된고빈도항원음성혈액형을보고하였다. 고빈도항원은어떤인구집단의 99% 이상이갖고있을경우이다 [5]. 이분류에따르면본환자에서는 Fy a -Fy b - 및 Js a +Js b - 로표현되는한국의고빈도항원음성혈액형이확인되었다. FY*B 유전자의 67T>C 변이는 promotor region 인 GATA region 의변이로 FY*A와 FY*B 유전자의전사 (transcription) 을억제한다. 67T>C 변이를가진사람은아프리카인에서흔하고 (60% 이상 ) 대개 Fy a -Fy b - 표현형으로나타나게된다 [6]. Fy a 항원발현빈도는나라에따라다른데, 해외에서는 10 99.5%[7-10], 한국에서는 99% 보고되고있다 [7]. Duffy는적혈구항원중 ABO, Rh, KELL 혈액형다음으로면역원성이강한항원으로 [9] 동종항체생성이환자에게큰영향을미칠수있다. Duffy 항원음성 (Fy a - b -) 인적혈구는말라리아낭충의침입을막기때문에말라리아유병율이높은지역에서그항원음성빈도가높다 [9]. 또한본환자에서 Jsa 양성이확인되었는데 Js a 발현빈도는아프리카인에서는 16%, Js a +Js b -인경우는 1% 이다 [7]. 감염또는염증이동반되면동종면역의위험도가증가하게되는데, 겸상적혈구빈혈환자는감영이있을때증상이악화되어, 용혈이발생하고, 수혈을받게된다. 따라서겸상적혈구빈혈환자의수혈로인한동종면역의빈도는높은편이다. 겸상적혈구빈혈환자의동종면역빈도는적 혈구맞춤수혈을시행하지않았을경우 19 43% 로보고되고있다 [11,12]. 만성적으로수혈을받을경우, 수혈량이증가함에따라동종면역빈도가증가하게된다. 이에따라적합혈액을선별하기힘들어지고, 최소부적합혈액제제등을수혈할가능성이높아지므로수혈후이상반응이일어날가능성이높다. 그러므로동종면역을예방하기위해, 적혈구맞춤수혈이필요하고, 수혈예정환자에있어서적혈구맞춤수혈을시행하는것이제시되고있다. 만성수혈환자에서적혈구맞춤수혈을어느단계까지하는지에대한세계적인가이드라인은없지만, 지중해성빈혈에서는최소 C, E, K 맞춤수혈을하는것이권장되고더많은적혈구항원을맞추어수혈을할수록 (perfect match) 동종면역빈도가낮아지고, 수혈후이상반응의빈도도감소하는것으로알려져있다 [13]. Perfect match 되지않은혈액제제를수혈하는경우 4 11% 의겸상적혈구빈혈환자에서급성용혈성수혈반응이일어난다고보고되어있다. Jk b, Fy, S를확대맞춤수혈할경우동종항체생성을더줄여줄수있겠다 [14,15]. 겸상적혈구빈혈환자의수혈의목표는 Hb S <30% 와 Hemoglobin <10 g/dl 이다 [2]. 구체적수혈방법으로는동종면역, 감염예방을위해백혈구제거적혈구제제를사용한다. 또한만성적으로수혈을받기때문에철분침착으로인한합병증도문제가된다. 수혈의주기를최대한늘리기위해, 보관기간이짧은적혈구제제를수혈하는것도고려해야한다 [2]. 따라서겸상적혈구빈혈환자에서적혈구항원맞춤수혈은해외에서는 C, E, K 맞춤수혈을최소한으로권장하고있다 [2]. 겸상적혈구빈혈환자는 Fy a -Fy b - 혈액형을가지는데, 우리나라에서는 Fy a 는고빈도항원으로항원음성적합혈액을찾기어렵다. 그러므로, 우리나라의겸상적혈구빈혈환자의맞춤수혈은최소한 - 191 -
Korean J Blood Transfus Vol. 29, No. 2, 188-193, Aug. 2018 C, E, K, Fy a, Fy b 맞춤을해야할것으로생각된다. 이를위해서는 Fy a -Fy b - 빈도가높은아프리카인종의헌혈자를확보하는것이필요하겠다 [2,9]. 본환자처럼고빈도항원의항원발현음성인경우는동종항체생성율이높을수있다. 내국인보다외국인들에서유병율이높아앞으로국내유병율이높아질것으로예상되는겸상적혈구빈혈의수혈지침을수혈가이드라인에서정해줄필요가있겠다. 요약 겸상적혈구빈혈환자는만성적으로수혈을받게되므로, 동종면역을예방하는것이중요하다. 저자들은겸상적혈구빈혈환자에서의고빈도항원음성혈액형을확인하였다. 한국에서거주하는외국인이증가하고있으므로겸상적혈구빈혈환자의수혈시고려해야할내용들을숙지할필요가있다. 겸상적혈구빈혈환자는진단시또는최초수혈전 ABO, Rh, Kell, Duffy 혈액형을확인하고, 확대맞춤수혈을통해정확한혈액형항원양상을알고이를통해적합한혈액제제를공급받아동종면역의위험도를감소시킬수있겠다. References 1. Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med 2017;376:1561-73 2. Smith-Whitley K, Thompson AA. Indications and complications of transfusions in sickle cell disease. Pediatr Blood Cancer 2012;59:358-64 3. Shaz BH, Zimring JC, Demmons DG, Hillyer CD. Blood donation and blood transfusion: special considerations for African Americans. Transfus Med Rev 2008;22:202-14 4. Ministry of Justice. Ministry of Justice s statistical yearbook of foreign policy on immigration in 2016. http://www.moj.go.kr/hp/ COM/bbs_03/ListShowData.do?str NbodCd= noti0096&strwrtno=130&stransno=a&strnb odcd=noti0703&strfilepath=moj/&strrtnurl =MOJ_40402000&strOrgGbnCd=104000&strTh ispage=4&strnbodcdgbn= [Online] (last visited on 12 June 2018) 5. Seltsam A, Wagner FF, Salama A, Flegel WA. Antibodies to high-frequency antigens may decrease the quality of transfusion support: an observational study. Transfusion 2003;43:1563-6 6. Fung MK. Other blood group systems and antigens. In: Fung MK, Grossman BJ, Hillyer CD, Westhoff CM, American Association of Blood Banks. Technical manual. 18th ed. Bethesda: American Association of Blood Banks, 2014:337-66 7. Han KS, Park KU, Song EY. Transfusion medicine. 4th ed. Seoul: Korean Medical Book Publisher, 2014:221-2 8. Reid ME, Lomas-Francis C. The blood group antigen factsbook. 2nd ed. Boston: Elsevier/ Academic Press, 2004 9. Lim CS, Kim KH. Characteristics of Duffy blood group antigens and their global distribution. Korean J Blood Transfus 2013;24: 13-20 10.Mcpherson RA, Pincus MR, Abraham NZ, Ashihara Y, Banki K. Henry s clinical diagnosis and management by laboratory methods. 22nd ed. Philadephia: Elsevier Saunders, 2011:675-710 11. Alkindi S, AlMahrooqi S, AlHinai S, AlMarhoobi A, Al-Hosni S, Daar S, et al. Alloimmunization in patients with sickle cell disease and thalassemia: experience of a single centre in Oman. Mediterr J Hematol Infect Dis 2017; 9:e2017013 12. Josephson CD, Su LL, Hillyer KL, Hillyer CD. Transfusion in the patient with sickle cell - 192 -
이현지외 : 고빈도항원음성혈액형가진겸상적혈구빈혈환아 1 예 disease: a critical review of the literature and transfusion guidelines. Transfus Med Rev 2007;21:118-33 13. Matteocci A, Pierelli L. Red blood cell alloimmunization in sickle cell disease and in thalassaemia: current status, future perspectives and potential role of molecular typing. Vox Sang 2014;106:197-208 14. Danaee A, Inusa B, Howard J, Robinson S. Hyperhemolysis in patients with hemoglobinopathies: a single-center experience and review of the literature. Transfus Med Rev 2015;29:220-30 15. Belsito A, Magnussen K, Napoli C. Emerging strategies of blood group genotyping for patients with hemoglobinopathies. Transfus Apher Sci 2017;56:206-13 - 193 -