적혈구교환수혈이시행된겸상적혈구 -β 지중해빈혈증 1 예

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1 대한수혈학회지 : 제 23 권제 3 호, 2012 The Korean Journal of Blood Transfusion Vol. 23, No. 3, , December 2012 ISSN Case Report 적혈구교환수혈이시행된겸상적혈구 -β 지중해빈혈증 1 예 최리화 1 ㆍ송주선 1 ㆍ정혜경 1 ㆍ김세미 1 ㆍ정철원 2 ㆍ박형두 1 ㆍ기창석 1 ㆍ강은숙 1 ㆍ김대원 1 성균관대학교의과대학삼성서울병원진단검사의학과 1, 내과 2 A Case of Red Blood Cell Exchange Transfusion in a Patient with Hemoglobin S/β-Thalassemia Rihwa Choi 1, Jusun Song 1, Hae-Kyung Jung 1, Semi Kim 1, Chul Won Jung 2, Hyung-Doo Park 1, Chang-Seok Ki 1, Eun-Suk Kang 1, Dae-Won Kim 1 Departments of Laboratory Medicine and Genetics 1 and Medicine 2, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Sickle cell disease and β-thalassemia are caused by abnormal hemoglobin (Hb) derived from mutation of the HBB gene encoding β-globin. Compound heterozygous status for both mutations results in Hb S/β-thalassemia (sickleβ-thalassemia). Vaso-occlusive phenomena and hemolysis are the clinical hallmarks and major causes of mortality. Due to the limited availability of hematopoietic stem cell transplantation with or without gene therapy, red blood cell (RBC) exchange transfusion is the first-line adjunctive therapy. Here we report on a successful reduction of Hb S level in a Tunisian male sickle-β-thalassemia patient by RBC exchange transfusion for primary prophylactic transfusion therapy before flying to his country. Results of both Ion exchange high-performance liquid chromatography and HBB gene mutation analysis indicated sickle-β-thalassemia. Pre-erythrocytapheresis Hb S level was 80.6% of total Hb. Two volumes of RBC exchange were performed using automated erythrocytapheresis with the COBE Spectra Apheresis System (Version 7.0, Caridian BCT, CO, USA). Post-erythrocytapheresis Hb S level was 23.4% of total Hb and hematocrit level was 32.6%, both of which met the target end points. This is the first case report in Korea on successful RBC exchange transfusion in a patient with sickle-β-thalassemia for rapid reduction of pathologic RBCs with Hb S. (Korean J Blood Transfus 2012;23: ) Key words: Sickle cell disease, Thalassemia, Blood transfusion Introduction Hemoglobin S/β-thalassemia (Hb S/β-thalassemia, sickle-β-thalassemia) is a genetic disorder with two kinds of HBB gene mutations on chromosome 11p15.5 (total 3 coding exons) which are involved Received on November 20, Revised on December 11, Accepted on December 12, 2012 Correspondence to: Dae-Won Kim Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul , Korea Tel: , Fax: , dwsmc.kim@samsung.com 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 2012 The Korean Society of Blood Transfusion

2 Rihwa Choi, et al: RBC Exchange Transfusion for Sickle-β-Thalassemia in hemoglobin (Hb) production. Compound heterozygosity in which one allele for Hb S and the other for β-thalassemia together results in sickle-β-thalassemia. 1) Abnormal Hb derived from these mutations has impaired function to deliver oxygen which can cause anemia and hypoxic organ damage and die prematurely. In patients with sickle-β-thalassemia accelerated hemolysis or vaso-occlusion may develop in several circumstances and they are the major causes of mortality. Red blood cell (RBC) transfusion in the form of simple transfusion or exchange transfusion is the first-line adjunctive therapy in acute and chronic complications. Especially, RBC exchange transfusion is a safe and rapid procedure for reducing the percentage of circulating Hb S. 2) Here we report an experience of successful RBC exchange transfusion using automated erythrocytapheresis for a Tunisian patient with sickle-β-thalassemia for the first time in Korea. Case Report A 28-year-old Tunisian male who was staying in Korea as a foreign exchange student visited International Health Services outpatient clinic in Samsung Medical Center with known diagnosis of sickle-β- Table 1. Patient s laboratory data before and after erythrocytapheresis Laboratory tests Before erythrocytapheresis After erythrocytapheresis Reference range Hb 8.6 g/dl 10.9 g/dl g/dl Hct 25.1% 32.6% % MCV 61.5 fl 79.9 fl fl MCH 21.1 pg 26.7 pg pg MCHC 34.3 g/dl 33.4 g/dl g/dl RDW-CV 24.1% 23.7% % RBC count /μl /μl /μl WBC count 16,890/μL 14,130/μL 3,800 10,580/μL Platelet count /μl /μl /μl Reticulocyte 9.85% 7.45% % AST 42 U/L NT 0 40 U/L ALT 27 U/L NT 0 40 U/L ALP 71 U/L NT U/L Serum total bilirubin 2.2 mg/dl NT mg/dl Blood urea nitrogen 7.1 mg/dl NT 8 22 mg/dl Serum creatinine 0.71 mg/dl NT mg/dl Lactate dehydrogenase 888 IU/L NT IU/L Serum iron μg/dl NT μg/dl TIBC μg/dl NT μg/dl Transferrin mg/dl NT mg/dl Serum ferritin ng/ml NT ng/ml Abbreviation: NT, not tested

3 Korean J Blood Transfus Vol. 23, No. 3, , Dec thalassemia. He was diagnosed as sickle-β-thalassemia at the age of five and confirmed by the quantitative analysis of Hemoglobin (Hb) electrophoresis at Centre National de Greffe de la Moelle Osseuse in Tunis. He was the second child of a two degree related Tunisian parents. There had been no history of symptomatic hemoglobinopathy in his family until he was diagnosed. According to the medical records from the hospital in Tunis, Hb electrophoretic pattern of his father showed a sickle cell trait, and that of his mother showed β-thalassemia minor. The mean steady state Hb level was 9 g/dl in Tunis. He was taking supplementary folic acid daily to maintain effective erythropoiesis. At the time of visiting Samsung Medical Center, his vital sign was stable and he had no definite symptoms of acute complication although he experienced intermittent episodes of bone pain crisis approximately two times a year. Because he had a plan to go back to Tunis by flight, his tolerability to vulnerable oxygenation status during flight was of major clinical concern. To prevent complications which could occur in hypoxic condition during a flight, he had received a manual RBC exchange transfusion at a medical center in Tunis before trip to Korea. He had no history of RBC transfusion since the last RBC exchange transfusion in Tunis. Physical examination showed no definite abnormality. Relevant abnormal blood test results are shown in Table 1. His blood type was O+. His peripheral blood smear showed microcytic hypochromic RBCs with severe anisopoikilocytosis (Fig. 1). RBCs with nuclear remnants such as Pappenheimer bodies, Howell-Jolly bodies and nucleated RBCs were also observed. His reticulocyte index was Fig. 1. Peripheral blood smear showed microcytic hypochromic RBCs with anisocytosis, severe poikilocytosis including burr cells, target cells, sickle cells, schistocytes, Pappenheimer bodies and polychromasia (Wright-Giemsa stain, 1,000). Spherocytes, Howell-Jolly bodies and nucleated RBCs were also observed although they are not seen in this view. 2.71%. Ion exchange high-performance liquid chromatography (HPLC) using a VARIANT II (Bio Rad Laboratories, Inc., CA, USA) operating with a β-thalassemia dual program kit was used for the quantitative assessment of Hb variants. There were peaks of Hb F (7.5% of total Hb) and Hb S (80.6% of total Hb). HBB gene mutation analysis with direct sequencing method using genomic DNA isolated from peripheral blood leukocytes revealed compound heterozygosity of β-globin gene mutations; a known missense mutation (c.20a>t; p.glu7val) corresponding to sickle cell and a known nonsense mutation (c.118c>t; p.gln40*) corresponding to β-thalassemia (Fig. 2). Automated therapeutic erythrocytapheresis was performed by the COBE Spectra Apheresis System

4 Rihwa Choi, et al: RBC Exchange Transfusion for Sickle-β-Thalassemia Fig. 2. Genomic DNA direct sequencing of β-globin gene from the patient showed compound heterozygous mutations of β-globin gene mutations; a known missense mutation (c.20a>t; p.glu7val) corresponding to sickle cell (A) and a known nonsense mutation (c.118c>t; p.gln40*) corresponding to β-thalassemia (B). (Version 7.0, Caridian BCT, CO, USA) using the RBC exchange procedure and kit. The estimated replacement RBC volume was calculated using following equation. 2,3) One RBC volume=body weight (kg) 70 (ml/kg) hematocrit (Hct) level. One unit of leuko-reduced packed RBC derived from 400 ml collection generally contains 220 ml to 260 ml of RBCs with Hct of 55% to 65%. His one RBC volume was 1,225 ml because his body weight and Hct were 70 kg and 25%, respectively. Because two volumes of RBC exchange transfusion were needed to achieve the level of Hb S; 25 30% and Hct; 30±3% at the end of the procedure, eleven units of O+ leuko-reduced irradiated fresh (<3 days old) packed RBCs were used. Peripheral vascular access was used because he had good peripheral veins; a 16 gauge needle for blood withdrawal and an 18 gauge needle for return. Inlet blood flow rate was 50 ml per minute and the anticoagulant, ACD-A was infused at a ratio of 1:13 between ACD-A and blood. The patient tolerated well and did not experience any adverse reactions during 107 minutes of RBC exchange transfusion procedure. Post-RBC exchange transfusion assessed 2 hours after the end of the procedure, Hb level was 10.9 g/dl and Hct was maintained at the level of 32.6%. In ion exchange HPLC, the Hb S level was markedly decreased as 23.4% of total Hb which was intended level to achieve. In this patient, RBC exchange transfusion was needed only once to achieve the target levels of both Hct and Hb S. Automated RBC exchange transfusion was an effective therapeutic approach for rapid reduction of pathologic RBCs with Hb S level to prevent complications of sickle-β-thalassemia. Discussion Sickle-β-thalassemia is a sickling variant of sickle cell disease. A life-long cure for this illness is available only through hematopoietic stem cell transplantation with or without gene therapy. However

5 Korean J Blood Transfus Vol. 23, No. 3, , Dec RBC exchange transfusion is the first-line adjunctive therapy because of limited availability due to donor match and the risk of severe adverse effects of stem cell transplantation. 1,2) RBC exchange transfusion is a procedure to remove abnormal RBCs and replace them with normal RBCs for treating RBC disorders due to genetic or acquired causes. RBC exchange transfusion is most commonly performed in the setting of sickle cell anemia to reduce the burden of Hb S and to provide donor RBCs containing Hb A world-widely. 3) RBC exchange transfusion has some advantages of reducing Hb S rapidly by replacing RBCs containing Hb S with normal RBCs without causing hyperviscosity, volume overload, or transfusional iron accumulation (American Society for Apheresis guidelines: category I-II). 2) Despite the different goals of transfusion which maintain total Hb level, automated exchange transfusion in thalassemia have demonstrated a reduction in net red blood cell requirements of 30% to 50%, either by reducing the amount of blood administered at the usual transfusion interval or by prolonging the interval between transfusions. 1) However, because RBC exchange transfusion is associated with significantly higher blood requirements than simple transfusion, it causes increased blood donor exposure. 2,4) The strategies to reduce the risk of allo-immunization were suggested due to the concerns about not only the risk of viral transmission but also the risk of RBC allo-immunization. 4,5) Although there has been no randomized controlled trial, some published data comparing RBC allo-immunization rate between simple transfusion and exchange transfusion reported that allo-immunization rate was not as high as concerned. 6,7) Further studies would be needed to be able to allay the fear of increased immunization with RBC exchange transfusion and lead to improved utilization of this therapeutic modality. Sickle cell anemia including sickle-β-thalassemia is more common in certain ethnic groups of African descent, African-Americans, Hispanic-Americans, Saudi Arabian, Caribbean, and South and Central American Indian descent. 1) To our knowledge, there have been no reported cases of sickle cell anemia among Korean and there were no reported cases of diagnosis and management for sickle cell anemia from foreign countries. Currently, more than 1.4 million foreign people, which are about 2.8% of total population including foreign laborers, intermarriage immigrants, and international students are living in Korea. 8) Considering the mixed ethnic population of foreign residents, it increases the demand of understanding hemoglobinopathies including sickle cell anemia with the management of the diseases. Here we report the first case of RBC exchange transfusion using automated erythrocytapheresis for primary prevention of stroke in a Tunisian patient with sickle-β-thalassemia. Our experience demonstrates that automated RBC exchange transfusion is a safe and effective therapeutic approach for rapid reduction of pathologic RBCs and Hb S level to prevent complications of sickle-β-thalassemia. Summary 겸상적혈구-β지중해빈혈증은겸상적혈구증을일으키는혈색소의 β 글로빈유전자의돌연변이와 β지중해빈혈증을일으키는돌연변이의복합성이형접합체에의해일어나는질병이다. 이질환의특징적인임상양상은비정상혈색소에의한

6 Rihwa Choi, et al: RBC Exchange Transfusion for Sickle-β-Thalassemia 혈관폐쇄및용혈현상이며, 이는사망의주요원인이된다. 이질환의완치는유전자치료와함께혹은단독으로시행되는조혈모세포이식이지만임상적적응에제한이있기때문에, 적혈구수혈이중요한 1차적인부가적치료방법이다. 저자들은국내에서처음으로겸상적혈구-β지중해빈혈증을가진튀니지남자환자에게뇌졸중의일차적합병증을예방하기위한목적으로자동화장비를이용한적혈구교환수혈을성공적으로경험하였기에이를보고하는바이다. 본증례에서는총적혈구용적의 2배에해당하는 11단위의방사선조사, 백혈구제거, 신선적혈구를사용하여, S형혈색소를 80.6% 에서 23.4% 로매우효과적으로감소시켰고, 적혈구교환수혈이후측정한적혈구용적율또한목표값에도달하였다. 이에저자들은겸상적혈구-β지중해빈혈증환자에서높은 S형혈색소수치를가진병적인적혈구의빠른제거를위한치료적적혈구교환수혈의국내첫시행경험을보고하면서, 세계인구이동의영향으로많은외국인들이국내로유입되고있는현상황에서, 겸상적혈구증을포함한혈색소질환에대한관심과치료에대한이해가필요함을제언하는바이다. References 1. Hoffman R, Benz EJ. Hematology: basic principles and practice. 5th ed. Philadelphia, PA: Churchill Livingston Elsevier Inc., 2008: Szczepiorkowski ZM, Winters JL, Bandarenko N, Kim HC, Linenberger ML, Marques MB, et al; Apheresis Applications Committee of the American Society for Apheresis. Guidelines on the use of therapeutic apheresis in clinical practice--evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher 2010;25: Roback JD. Technical manual. 17th ed. Bethesda, Md: American Association of Blood Banks, 2011:707-25, Yazdanbakhsh K, Ware RE, Noizat-Pirenne F. Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management. Blood 2012;120: Vichinsky EP, Luban NL, Wright E, Olivieri N, Driscoll C, Pegelow CH, et al; Stroke Prevention Trail in Sickle Cell Anemia. Prospective RBC phenotype matching in a strokeprevention trial in sickle cell anemia: a multicenter transfusion trial. Transfusion 2001;41: Venkateswaran L, Teruya J, Bustillos C, Mahoney D Jr, Mueller BU. Red cell exchange does not appear to increase the rate of allo- and auto-immunization in chronically transfused children with sickle cell disease. Pediatr Blood Cancer 2011;57: Wahl SK, Garcia A, Hagar W, Gildengorin G, Quirolo K, Vichinsky E. Lower alloimmunization rates in pediatric sickle cell patients on chronic erythrocytapheresis compared to chronic simple transfusions. Transfusion 2012;52: The Ministry of Public Administration and Security (MOPAS) Status of foreign residents in local government. Korea. serlayout/bulletin/userbtview.action?userbtb ean.bbsseq= &userbtbean.ctxcd=1258 &userbtbean.ctxtype= &userbtbean.c ategorycd= [Online] (last visited on 11 December 2012)