대한수혈학회지 : 제 24 권제 3 호, 2013 The Korean Journal of Blood Transfusion Vol. 24, No. 3, 286-290, December 2013 ISSN 1226-9336 Case Report 면역혈소판감소자색반병환자에서치료용면역글로불린투여후항 -D 항체가분리된 1 예 장정현ㆍ김희정ㆍ양회주ㆍ권석운 울산대학교의과대학서울아산병원진단검사의학과 Isolation of Anti-D after Administration of Intravenous Immune Globulin in a Patient with Immune Thrombocytopenic Purpura Jeonghyun Chang, Hee-Jung Kim, Hoi-Joo Yang, Seog-Woon Kwon Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Intravenous immune globulin (IVIG) is widely used in treatment of hypogammablobulinemia and for immunomodulation. Passive transfer of anti-d activity through administration of IVIG may cause difficulty in serologic assessment of patients. Here we report on a case of passive anti-d from IVIG in a D positive patient. The patient was a 72-year-old Korean woman who was hospitalized for refractory immune thrombocytopenic purpura that is not cured after steroid therapy. IVIG 6,000 mg was administered for treatment of immune thrombocytopenic purpura. After IVIG administration for two days, we identified anti-d in the patient and a positive direct antiglobulin test was demonstrated. The patient s hemoglobin level remained unchanged. After IVIG administration for 10 days, the patient s specimen was negative for anti-d, as would be expected with passively acquired antibody. Antibodies in IVIG may confuse and complicate serologic testing of transfusion candidates. Therefore, passive transfer of anti-d should be considered when anti-d is detected, especially when the patient has received IVIG, as in this case. (Korean J Blood Transfus 2013;24:286-290) Key words: IVIG, Anti-D, Immune thrombocytopenic purpura 서론정주용면역글로불린은저감마글로불린혈증같은면역결핍질환이나면역혈소판감소증, 가와사키병같은자가면역질환등의치료에 FDA의승인을받아널리쓰이는치료제로 1) 다량의혈장 을원료로하여제조한다. 면역글로불린의제작과정에서는혈장에존재하는여러항체들이포함될수있는데, 그중항 D항체로인해면역글로불린치료를받은 Rh 양성환자에서직접항글로불린검사에서위양성을보일수있다는보고가있다. 2) 따라서치료목적의면역글로불린을제 Received on November 1, 2013. Revised on December 3, 2013. Accepted on December 3, 2013 Correspondence to: Seog-Woon Kwon Department of Laboratory Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea Tel: 82-2-3010-4504, Fax: 82-2-478-0884, E-mail: swkwon@amc.seoul.kr 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. Copyright C 2013 The Korean Society of Blood Transfusion - 286 -
장정현외 : 면역혈소판감소자색반병환자에서치료용면역글로불린투여후항 -D 항체가분리된 1 예 작하는데에항 -D 항체의역가는최대치가 1:8 이상넘지않아야한다는보고가있다. 3) 최근 (2013 년 6 월 ) 서울아산병원의혈액은행에 서는교차시험과정중부적절한비예기항체를의미하는반응양상을보이는성인환자에서항- D 항체를분리하였다. 환자의혈액형은 D+였고, 10일후실시한재검에서항-D 항체가음성전환되었음을확인했다. 증례 환자는 72세여자로내원 2일전부터잇몸출혈과반상출혈이생겨 2013년 6월본원에내원하였다. 환자는내원 15년전심한코피와반상출혈로연고지병원방문하여면역혈소판감소자색반병 (immune thrombocytopenic purpura, ITP) 을진단받고스테로이드제제 (deflazacort) 를복용하며조절하였으나내원 3년전부터는스테로이드제제로조절이잘안되어다시혈소판감소가있었다. 하지만그정도가심하지않아치료제제를그대로유지하였으며 2013년 4월 2일부터는다른종류의스테로이드제제 (Danazol) 를추가하여복용하였다. 내원 10일전에건강검진에서의유방암검사를위해유방촬영술을시행하고나서유방에반상출혈이발생하였고, 내원 2일전에는잇몸출혈이생기고목욕후전신에반상출혈이발생하여혈액내과로내원하였다. 입원당일검사실소견에서환자의혈액형은 A, Rh+였고일반혈액검사상혈색소및적혈구용적률은 8.7 g/dl, 29.1% 이고백혈구수치는 10,900/μL, 혈소판수치는 7,000/μL로관찰되었다. 내원당일혈소판 20 단위를투여하였고, 면역글로불린리브감마에스앤주 (SK 케미칼, 성남, 한국 ) 를입원한당일과이튿날에걸쳐각각 3,000 mg 투여하였다. 면역글로불린투여후입원 3일째날혈소판 Table 1. Antibody identification after 2 days of IVIG administration Rh-hr Kell Duffy Kidd Lewis P MNS Luth. Xg Result Donor Enzyme D C E c e C w K k Kp a Kp b Js a Js b Fy a Fy b Jk a Jk b Le a Le b P1 M N S s Lu a Lu b Xg a LISS/ Coombs 1 ++ 0 0 ++ 0 + 0 + Nt Nt + 0 + 0 0 + + 0 + 0 + 0 + + ±w 2+w 2 ++ 0 0 + 0 ++ 0 + Nt Nt 0 + 0 + 0 + 0 + 0 ++ 0 + Nt ±w 2+w 3 + 0 ++ 0 0 0 + 0 + Nt Nt + 0 0 + 0 + + + + + + 0 + + ± 2+w 4 0 + 0 ++ 0 0 + 0 + Nt Nt 0 + 0 + 0 + + + 0 0 + 0 + + - - 5 0 0 +++ 0 0 + 0 + Nt Nt + + + + 0 0 + 0 + 0 + 0 + + - - 6 0 0 0 ++ 0 ++ 0 + Nt Nt + + + 0 0 + + + + + 0 0 + + - - 7 0 0 0 ++ 0 0 + + + Nt Nt + 0 0 + 0 + + 0 + + 0 0 + + - - 8 + 0 0 ++ 0 0 + 0 + 0 Nt 0 0 + 0 0 + + + + + + 0 + + - 1+s 9 0 0 0 ++ 0 ++ 0 + Nt Nt + 0 0 + + 0 0 + 0 ++ + + + - - 10 0 0 0 ++ 0 0 + 0 + Nt Nt 0 + 0 + 0 + 0 + 0 + 0 0 + + - - 11 0 0 0 ++ 0 0 + 0 + Nt Nt + 0 + + 0 0 0 0 + 0 + + + + - - Abbreviation: NT, not tested. - 287 -
Korean J Blood Transfus Vol. 24, No. 3, 286-290, Dec. 2013 Fig. 1. Platetet count and hemoglobin level of the patient during hospitalized days. Black arrow: IVIG administration, White arrow: splenectomy. 수치는 191,000/μL로상승하였고이후정상수치를유지하였다. 하지만환자가스테로이드제제를장기간복용하면서의인성쿠싱증후군이발생하였기때문에스테로이드제제의감량이필요하다고판단하여비장절제술을시행하기로하였다. 수술준비과정중시행한비예기항체선별검사에서양성을보여, 이후 ID-DiaPanel (Bio-RAD, Cressier, Switzerland) 으로시행한항체동정검사에서실온생리식염수와 LISS/Coombs, 효소단계에서모두항-D 항체가동정되었다 (Table 1). 직접항글로불린검사는양성이었다. 이후환자의혈소판수치는정상수치로유지되었고내원 7일째비장절제술을시행하고나서도안정적인경과를보였다 (Fig. 1). 수술중적혈구 1단위를수혈한것이외에는더이상의수혈은시행하지않았으며, 환자의혈색소수치도비슷한수준으로유지되었다 (Fig. 1). 내원 11일되던날말초혈액으로비예기항체동정검사를다시시행한결과음성전환되었다 (Table 2). Table 2. Antibody identification after 10 days of IVIG administration Rh-hr Kell Duffy Kidd Lewis P MNS Luth. Xg Result Donor Enzyme D C E c e C w K k Kp a Kp b Js a Js b Fy a Fy b Jk a Jk b Le a Le b P1 M N S s Lu a Lu b Xg a LISS/ Coombs 1 ++ 0 0 ++ 0 + 0 + Nt Nt + 0 + 0 0 + + 0 + 0 + 0 + + NT - 2 ++ 0 0 + 0 ++ 0 + Nt Nt 0 + 0 + 0 + 0 + 0 ++ 0 + Nt NT - 3 + 0 ++ 0 0 0 + 0 + Nt Nt + 0 0 + 0 + + + + + + 0 + + NT - 4 0 + 0 ++ 0 0 + 0 + Nt Nt 0 + 0 + 0 + + + 0 0 + 0 + + NT NT 5 0 0 +++ 0 0 + 0 + Nt Nt + + + + 0 0 + 0 + 0 + 0 + + NT NT 6 0 0 0 ++ 0 ++ 0 + Nt Nt + + + 0 0 + + + + + 0 0 + + NT NT 7 0 0 0 ++ 0 0 + + + Nt Nt + 0 0 + 0 + + 0 + + 0 0 + + NT NT 8 + 0 0 ++ 0 0 + 0 + 0 Nt 0 0 + 0 0 + + + + + + 0 + + NT - 9 0 0 0 ++ 0 ++ 0 + Nt Nt + 0 0 + + 0 0 + 0 ++ + + + NT NT 10 0 0 0 ++ 0 0 + 0 + Nt Nt 0 + 0 + 0 + 0 + 0 + 0 0 + + NT NT 11 0 0 0 ++ 0 0 + 0 + Nt Nt + 0 + + 0 0 0 0 + 0 + + + + NT NT Abbreviation: See Table 1. - 288 -
장정현외 : 면역혈소판감소자색반병환자에서치료용면역글로불린투여후항 -D 항체가분리된 1 예 고찰 면역혈소판감소자색반병은혈소판자가항체에의해혈소판감소증이나타나는질병이다. 미국혈액학회에서는면역혈소판감소자색반병의치료로스테로이드, 정주용면역글로불린, 항-D 항체등을일차치료제로사용하고치료에반응이없거나재발성인경우비장절제술등을고려할것을제시하고있다. 4) 본증례의환자는일차치료로스테로이드제제를사용하다가정주용면역글로불린을추가하고비장절제술을시행한사례이다. 치료용면역글로불린제제는여러사람의혈장을원료로하여만들어지며혈장중 20% 는혈액기증자로부터, 80% 는혈장기증자로부터얻어진다. 5) 따라서치료용면역글로불린제제에는상당한양의항-A, 항-B, 그리고비-ABO 항체가포함되어있다. 6) 이들은대부분 IgG 항체로항-D 항체또한여기에포함될수있으며, 이들은대부분낮은 titer로존재하지만항체선별검사와직접항글로불린검사에서일정기간양성결과를보일수있어 7) 결과해석에혼란을야기한다. 8) 본증례는면역글로불린치료후항-D 항체가동정되고면역글로불린의효과가사라진후반복측정시항-D 항체도사라진것을확인한경우였다. 치료용면역글로불린제제에포함된항-D 항체가수동적으로환자에게주입되어환자에게용혈이발생하고다른부작용이생길수있다는보고는 1971년치료용면역글로불린안의 Rh 항체로인해적혈구가감작된사례보고 9) 를비롯하여여럿있어왔다. 2,10) 치료용면역글로불린의부작용으로는일반적으로보체활성화, 저혈압, 신기능저하등이있으며 5) 포함된항체로인한부작용은적혈구용혈과수혈전검사가늦어져서발생하는수혈준비지연등이있다. 2) 우리나라에 서도치료용면역글로불린제제로인해 D+인환자에서항-D 항체가분리된보고가있다. 11) 하지만이전보고들에서는단순히항체를분리한것에그쳤던것에비해현재의보고에서는일정시간이흐른후항-D 항체가음성전환된것을확인하였다. 면역글로불린투여 10일후에항체음성전환을확인했으므로환자의항-D 항체는 10일이내의어느시점에서음성화되었다고생각할수있으며, 이는 1주일이내에항체가음성전환되었다는이전증례와맥락을같이한다. 7) 이는명백히치료용면역글로불린사용으로비롯한위양성결과인것을확인한것에의의가있다. 우리나라에서사용하는치료용면역글로불린제제의대부분은외국혈장에의존하고있고, 여기에포함되는여러항체의종류와최대역가에대해서는규정된바가없다. 본증례의환자는치료용면역글로불린제제안에포함된항-D 항체로인해발생한것이었지만다른비예기항체의다양성을생각해볼때, 치료용면역글로불린제제를제작하는데있어더많은관심을기울여야할필요성이있다. 그리고해석에있어서도치료용면역글로불린제제에다양한종류의혈액형항체가포함될수있다는것을염두에두어불필요한추가검사를하지않도록해야한다. 요약 저자들은교차시험과정중부적합을보이는면역혈소판감소자색반병환자에서항-D 항체를동정하였다. 환자의혈액형은 D+로동정가능성이없는항체였고환자를조사하던중항체의출처가치료용면역글로불린제제투여시수동적으로전달된것임을확인하였다. 10일후재검사에서는항-D 항체가음성전환되었음을확인할 - 289 -
Korean J Blood Transfus Vol. 24, No. 3, 286-290, Dec. 2013 수있었다. 치료용면역글로불린내에포함된혈액형항체로인해비예기항체동정검사결과에혼란을줄수있으며환자의수혈준비에불필요한추가검사를시행하여시간이지체될수있다. 따라서치료용면역글로불린에포함된다양한종류의혈액형항체에관심을기울이고면역글로불린투여후에는항체동정검사결과해석에주의를해야할것이다. References 1. Darabi K, Abdel-Wahab O, Dzik WH. Current usage of intravenous immune globulin and the rationale behind it: the Massachusetts General Hospital data and a review of the literature. Transfusion 2006;46:741-53 2. Friedman DF, Lukas MB, Larson PJ, Douglas SD, Manno CS. Clinical impact of anti-d in intravenous immunoglobulin. Transfusion 1997; 37:450-2 3. Thorpe SJ, Fox BJ, Dolman CD, Lawrence J, Thorpe R. Batches of intravenous immunoglobulin associated with adverse reactions in recipients contain atypically high anti-rh D activity. Vox Sang 2003;85:80-4 4. Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA; American Society of Hematology. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011; 117:4190-207 5. Knezevic-Maramica I, Kruskall MS. Intravenous immune globulins: an update for clinicians. Transfusion 2003;43:1460-80 6. Gordon JM, Cohen P, Finlayson JS. Levels of anti-a and anti-b in commercial immune globulins. Transfusion 1980;20:90-2 7. Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion 1986;26:410-2 8. Steiner EA, Butch SH, Carey JL, Oberman HA. Passive anti-d from intravenous immune serum globulin. Transfusion 1983;23:363 9. Oberman HA, Beck ML. Red blood cell sensitization due to unexpected Rh antibodies in immune serum globulin. Transfusion 1971;11: 382-4 10. Salama A, Mueller-Eckhardt C, Kiefel V. Effect of intravenous immunoglobulin in immune thrombocytopenia. Lancet 1983;2:193-5 11. Song JW, Lee JS, Shin JW, Kim HO. Unexpected crossmatch-incompatible results by anti-d in intravenous immune globulin. Korean J Blood Transfus 1999;10:239-43 - 290 -