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Fatal hemolytic disease of the fetus and newborn caused by anti-Jra antibody: A case report and literature review
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
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Case Report
Fatal hemolytic disease of the fetus and newborn caused by anti-Jra antibody: A case report and literature review ⁎
Min-Sun Kima, Jin Seok Kima, Hyewon Parkb, Yousun Chungc, Hyungsuk Kimd, Dae-Hyun Koa, , Sang-Hyun Hwanga, Hye-Sung Wone, Heung-Bum Oha a
Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea Seegene Medical Foundation, Seoul, Republic of Korea c Department of Laboratory Medicine, Kangdong Sacred Heart Hospital, Seoul, Republic of Korea d Department of Laboratory Medicine, Seoul National University Hospital, Seoul, Republic of Korea e Department of Obstetrics and Gynecology, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea b
A R T I C LE I N FO
A B S T R A C T
Keywords: Fatality Hemolytic disease of the fetus and newborn Anti-Jra ABCG2
The Jra antigen of the JR blood group system is a highly prevalent red blood cell antigen. Although antiJra–associated hemolytic disease of the fetus and newborn (HDFN) is generally considered mild-to-moderate, a rare fatal case was recently reported. We report the third example of HDFN-related anti-Jra with fatal outcomes. The clinical significance of anti-Jra antibody as a cause of HDFN should be reassessed.
1. Introduction Jra, a high-prevalence antigen, is currently the only antigen in the JR blood group system. Jra is expressed on ABCG2, a multi-pass membrane-protein family member of the adenosine triphosphate (ATP)-binding cassette transporters. While it is extremely rare in other races, the Jra-negative phenotype is relatively prevalent in East Asia, and 0.03% of the Japanese population is Jra negative [1–3]. The clinical significance of anti-Jra remains unknown. Mild, delayed hemolytic transfusion reactions and one case of an acute hemolytic transfusion reaction have been reported to be caused by anti-Jra [4,5]. Although the anti-Jra–associated hemolytic disease of the fetus and newborn (HDFN) is generally considered mild-to-moderate, two fatal cases have previously been published [6,7]. We report an extremely severe case of HDFN associated with antiJra alloimmunization that required aggressive intrauterine treatment. 2. Case report A healthy 37-year-old woman was admitted in the 30 + 5 week of her second pregnancy. Her first pregnancy ended with intrauterine death of unknown origin. She had no history of a previous transfusion. Fetal growth was mildly restricted; the peak systolic velocity of the fetal middle cerebral artery (MCA-PSV) was above the upper limit of the reference range, with 54–77 cm/s and 1.29–1.5 multiples of the median
⁎
(MoM). Although no signs of hydrops fetalis were detected on ultrasonography, MCA-PSV persisted at 1.5 MOM. The complete maternal blood count revealed no significant findings; viral test results were negative. Her blood group was O, Rh positive; direct antiglobulin test results were negative. Her serum showed reactivity with all red blood cells (RBCs) used for antibody screening and identification tests. She was suspected of having antibodies against a high-prevalence RBC antigen. To confirm whether she was negative for a high-prevalence antigen, RBCs were tested with anti-Jra antiserum; no reactivity was observed. The specificity of the maternal antibody could be anti-Jra, with a 1:128 titer determined by a reference laboratory (the Central Laboratory of the Swiss Red Cross, Bern, Switzerland). Because Jra-negative blood donor is extremely rare, we prepared washed maternal RBCs, and intrauterine fetal transfusion (IUT) was performed via the umbilical cord. Fetal Hb and hematocrit levels increased from 3.8 g/dL to 8.9 g/dL and 12% to 27%, respectively. However, emergency cesarean section was performed owing to deceleration of the fetal heart rate. The blood type of the male neonate was O, Rh positive; direct (antiIgG) and indirect antiglobulin test results were positive (1+). Antigen test for Jra could not be performed owing to the small sample volume. An initial laboratory analysis on the infant showed pancytopenia and hyperkalemia. Acute peritoneal dialysis was performed to correct hyperkalemia & volume overload. Despite continuous transfusion and two
Corresponding author at: University of Ulsan, College of Medicine and Asan Medical Center, 88 Olympic-Ro 43-Gil, Songpa-gu, 05505, Seoul, Republic of Korea. E-mail address: [email protected] (D.-H. Ko).
https://doi.org/10.1016/j.transci.2019.06.029 Received 14 February 2019; Received in revised form 1 April 2019; Accepted 3 June 2019 1473-0502/ © 2019 Published by Elsevier Ltd.
Please cite this article as: Min-Sun Kim, et al., Transfusion and Apheresis Science, https://doi.org/10.1016/j.transci.2019.06.029
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
M.-S. Kim, et al.
Fig. 1. Changes in laboratory test results of the neonate’s blood cell count (A) and general chemistry results (B). Pancytopenia persisted after a session of exchange transfusion. There was a marked elevation in liver enzyme levels and a gradual increase in creatinine levels. Hyperkalemia continued throughout the hospital course. AST, aspartate aminotransferase in ×10−1 IU/L; ALT, alanine aminotransferase in ×10−1 IU/L; Ca, calcium in mg/dL; Cr, creatinine in mg/dL; Hb, hemoglobin in g/dL; Hct, hematocrit in %; K, potassium in mmol/L; PLT, platelet count in ×104/μL; T-Bil, total bilirubin in mg/dL; WBC, white blood cell count in ×102/mL.
provide one possible explanation for this difference [6,7,17]. In IgG subclass analysis for anti-Jra antibodies, IgG1, associated with complement activation, was the predominant clone [6]. We could not, unfortunately, analyze the subclass of the anti-Jra antibody in our case. Severe HDFN owing to anti-Jra antibody has been characterized by hydrops fetalis in fetal ultrasonography, multiparity, and high anti-Jra antibody titer. Our patient also showed multiparity and a high anti-Jra antibody titer. Although hydrops fetalis was not noted in our case, we examined PSV-MCA to predict severe fetal anemia. The case reports by Ishihara et al. and Fujita et al. described severe fetal anemia in which IUT prevented catastrophic outcomes [10,11]. The patient from the former report was transfused with unrelated Jranegative blood for IUT, while the latter lacks detailed donor information. In our case, IUT was performed using washed maternal blood, which was Jra negative. Maternal blood may be the best source of donor RBCs for IUT, where multiple antibodies are present [18,19]. The advantage of maternal RBCs for IUT is the prevention of additional RBC antibodies that may be generated by the new donor RBC antigen [19]. In a previous report, maternal IUTs resulted in a significant improvement in the fetal hematocrit reduction rate [20]. One disadvantage of maternal blood is that we cannot be sure whether the antibody is completely removed by washing and how much remnant antibody is present in maternal autologous RBCs before IUT. The remnant maternal antibody in IUT could cause the poor general condition of the fetus. Direct ABCG2 gene sequencing for the mother and baby revealed the responsible variant, a nonsense mutation (ABCG2*01 N.01; rs72552713, c.376C > T, p.Gln126*) in exon 4. Deletion/duplication analysis was not performed in this case because the ABCG2*01 N.01 allele is commonly found in Asians [21,22]. ABCG2*01N.01 heterozygosity was found in 1.9% and 1% of Korean and Japanese individuals,
exchange transfusions, pancytopenia and hepatic failure deteriorated (Fig. 1). The Apgar score was 2 and 4 at 1 and 5 min, respectively. He required immediate chest compression and intubation after birth. Immediate exchange transfusion was performed with least incompatible O, RhD-positive-type RBC mixed AB frozen fresh plasma. However, the neonate’s general state declined rapidly with hyperkalemia (potassium level: 7.7 mmol/L), and he died three days later. ABCG2 analysis of the mother revealed a homozygous nonsense variant c.376C > T (ABCG2*01 N.01) in exon 4 (p.Gln126*) (Fig. 2-A); the infant was heterozygous for the same change (Fig. 2-B).
3. Discussion The clinical significance of anti-Jra antibody remains unclear. Some researchers reported none-to-moderate hemolytic transfusion reactions after incompatible Jra-positive blood transfusions in recipients with anti-Jra [5,8,9]. In one report, the mother harbored anti-Jra antibodies in her serum, although HDFN was not observed [4]. As shown in Table 1, the patients in three reports [6,7,10] showed severe HDFN clinical manifestations, and two [6,7] experienced abortion. Our case is the third reported fetal death owing to severe fetal anemia [4,6,7]. The main feature of previous reports [2,6,7,10–17], including severe cases, is multiparity. In our case, immunization might have occurred during a previous abortion. Anti-Jra antibody–associated HDFN may occur in subsequent pregnancies. A Jra-negative patient with anti-Jra antibody who was transfused with Jra-positive RBCs showed no severe complication [5]. This diversity in clinical manifestations might be because of the different in vivo activity of the anti-Jra antibody, and antibody subclasses can
Fig. 2. Results of ABCG2 sequencing in exon 4. (A) A maternal sample showed the homozygous variation for the ABCG2*01N.01 allele (c.376C > G, p.Gln126*), (B) the same variation was found in the heterozygous condition of the neonate. 2
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
Abbreviations: DAT, direct antiglobulin test; IAT, indirect antiglobulin test; US, ultrasonography; IUGR, intrauterine growth retardation; IUT, intrauterine transfusion; NT, not tested; G, gravida; P, parity; A, abortion.
Dead Dead Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive No No Yes No Yes No No No No No No No No No Cardiomegaly, hepatomegaly, IUGR Hydrops fetalis Hydrops fetalis, polyhydramnios Normal NT NT NT NT NT NT NT NT NT NT Caucasian Caucasian Japanese Japanese Japanese Japanese Korean Japanese Japanese Unknown Spanish Japanese Japanese Japanese 1 [6] 2 [7] 3 [10] 4 [25] 5 [11] 6 [12] 7 [26] 8 [13] 9 [2] 10 [14] 11 [15] 12 [27] 13 [16] 14 [17]
28 39 40 20 28 20 33 23 30 Unknown 28 27 Unknown 32
35 Unknown 29 27 28 28 32 Unknown Unknown Unknown 27 First trimester 20/27 Unknown
G4P1A3 G5P3A2 G4P3A1 G1 G3P2 G2P1 G1 G2P1 G3P2A1 G2P2 G2P1A1 G1 G5P2 G4P3
1024 128 512 64 512 1024 Unknown 64 64-128 2048 Unknown 64 512/256 32
NT Positive/NT NT NT NT NT Negative/Negative Negative/Negative NT NT Negative/Positive Positive/NT NT Positive/NT
IUT Pregnancy history Gestational age (weeks) Maternal age (years) Race Case
Table 1 Clinical characteristics and laboratory data of cases showing Jra antibody during pregnancy.
Anti-Jra titer
DAT/IAT
US
Fetal outcome
M.-S. Kim, et al.
respectively [23]. Because Jra is a high-prevalence antigen, it is extremely difficult to identify Jra–negative blood in the general inventory. Finding compatible donors among family members or inquiry of rare donor registries could provide solutions. In Korea, the rare donor registry program has just begun, although the Jr blood group system is not included in the program [24]. The rare donor program in the region should be expanded to include the Jr blood group system in Asia. In conclusion, we report the third case of fatal HDFN caused by antiJra. In contrast to the general idea that the anti-Jra antibody causes mild HDFN, the antibody can cause fatal HDFN. The time has come to reconsider the clinical significance of the anti-Jra antibody. Acknowledgements We appreciate Bio-Rad Korea and Bio-Rad Laboratories (Cressier FR, Switzerland) for helping us identify the specificity of the antibody. References [1] Castilho L, Reid ME. A review of the JR blood group system. Immunohematology 2013;29:63–8. [2] Nakajima H, Ito K. An example of anti-Jra causing hemolytic disease of the newborn and frequency of Jra antigen in the Japanese population. Vox Sang 1978;35:265–7. [3] Vedo M, Reid ME. Anti-Jra in a Mexican American. Transfusion 1978;18:569. [4] Fung MK, Grossman BJ, Hillyer CD, Westhoff CM. Technical manual. 18th ed. Bethesda: American Association of Blood Banks; 2014. [5] Chung HJ, Lim JH, Park HJ, Kwon SW. Transfusion of Jra-positive red blood cells to a Jra-negative patient with anti-Jra. Korean J Blood Transfus 2007;18:111–5. [6] Peyrard T, Pham BN, Arnaud L, Fleutiaux S, Brossard Y, Guerin B, et al. Fatal hemolytic disease of the fetus and newborn associated with anti-Jr. Transfusion 2008;48:1906–11. https://doi.org/10.1111/j.1537-2995.2008.01787.x. [7] Arriaga F, Gomez I, Linares MD, Gascon A, Carpio N, Perales A. Fatal hemolytic disease of the fetus and newborn possibly due to anti-Jr. Transfusion 2009;49:813. https://doi.org/10.1111/j.1537-2995.2008.02087.x. [8] Yuan S, Armour R, Reid A, Abdel-Rahman KF, Rumsey DM, Phillips M, et al. Case report: massive postpartum transfusion of Jr(a+) red cells in the presence of antiJra. Immunohematology 2005;21:97–101. [9] Kwon MY, Su L, Arndt PA, Garratty G, Blackall DP. Clinical significance of anti-Jra: report of two cases and review of the literature. Transfusion 2004;44:197–201. [10] Ishihara Y, Miyata S, Chiba Y, Kawai T. Successful treatment of extremely severe fetal anemia due to anti-Jra alloimmunization. Fetal Diagn Ther 2006;21:269–71. https://doi.org/10.1159/000091354. [11] Fujita S, Kashiwagi H, Tomimatsu T, Ito S, Mimura K, Kanagawa T, et al. Expression levels of ABCG2 on cord red blood cells and study of fetal anemia associated with anti-Jr(a). Transfusion 2016;56:1171–81. https://doi.org/10.1111/trf.13515. [12] Sasamoto N, Tomimatsu T, Nagamine K, Oshida M, Kashiwagi H, Koyama S, et al. Fetal and neonatal anemia associated with anti-Jr(a): a case report showing a poorly hemolytic mechanism. J Obstet Gynaecol Res 2011;37:1132–6. https://doi. org/10.1111/j.1447-0756.2010.01477.x. [13] Takabayashi T, Murakami M, Yajima H, Tsujiei M, Ozawa N, Yajima A. Influence of maternal antibody anti-Jra on the baby: a case report and pedigree chart. Tohoku J Exp Med 1985;145:97–101. [14] Tritchler JE. An example of anti-Jra. Transfusion 1977;17:177–8. [15] Bellver-Pradas J, Arriaga-Chafer F, Perales-Marin A, Maiques-Montesinos V, SerraSerra V. Obstetric significance of anti-Jr(a) antibody. Am J Obstet Gynecol 2001;184:75–6. [16] Endo Y, Ito S, Ogiyama Y. Suspected anemia caused by maternal anti-Jra antibodies: a case report. Biomark Res 2015;3:23. [17] Azar PM, Kitagawa H, Fukunishi A, Yasuda T, Oki M, Saji H, et al. Uneventful transfusion of Jr (a+) red cells in the presence of anti-Jra. J Jpn Soc Blood Transfus 1988;34:406–10. [18] Watson WJ, Wax JR, Miller RC, Brost BC. Prevalence of new maternal alloantibodies after intrauterine transfusion for severe Rhesus disease. Am J Perinatol 2006;23:189–92. https://doi.org/10.1055/s-2006-934092. [19] Schonewille H, Klumper FJ, van de Watering LM, Kanhai HH, Brand A. High additional maternal red cell alloimmunization after Rhesus- and K-matched intrauterine intravascular transfusions for hemolytic disease of the fetus. Am J Obstet Gynecol 2007;196(143):e1–6. https://doi.org/10.1016/j.ajog.2006.10.895. [20] el-Azeem SA, Samuels P, Rose RL, Kennedy M, O’Shaughnessy RW. The effect of the source of transfused blood on the rate of consumption of transfused red blood cells in pregnancies affected by red blood cell alloimmunization. Am J Obstet Gynecol 1997;177:753–7. [21] Zelinski T, Coghlan G, Liu XQ, Reid ME. ABCG2 null alleles define the Jr(a-) blood group phenotype. Nat Genet 2012;44:131–2. https://doi.org/10.1038/ng.1075. [22] Lee SS, Jeong HE, Yi JM, Jung HJ, Jang JE, Kim EY, et al. Identification and functional assessment of BCRP polymorphisms in a Korean population. Drug Metab Dispos 2007;35:623–32. https://doi.org/10.1124/dmd.106.012302. [23] Kobayashi D, Ieiri I, Hirota T, Takane H, Maegawa S, Kigawa J, et al. Functional assessment of ABCG2 (BCRP) gene polymorphisms to protein expression in human placenta. Drug Metab Dispos 2005;33:94–101. https://doi.org/10.1124/dmd.104.
3
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Invest 2010;69:81–3. https://doi.org/10.1159/000259724. [26] Kim H, Park MJ, Sung TJ, Choi JS, Hyun J, Park KU, et al. Hemolytic disease of the newborn associated with anti-Jra alloimmunization in a twin pregnancy: the first case report in Korea. Korean J Lab Med 2010;30:511–5. https://doi.org/10.3343/ kjlm.2010.30.5.511. [27] Toy P, Reid M, Lewis T, Ellisor S, Avoy DR. Does anti-Jra cause hemolytic disease of the newborn? Vox Sang 1981;41:40–4.
001628. [24] Hong YJ, Chung Y, Hwang SM, Park JS, Kwon JR, Choi YS, et al. Genotyping of 22 blood group antigen polymorphisms and establishing a national recipient registry in the Korean population. Ann Hematol 2016;95:985–91. https://doi.org/10.1007/ s00277-016-2645-7. [25] Masumoto A, Masuyama H, Sumida Y, Segawa T, Hiramatsu Y. Successful management of anti-Jra alloimmunization in pregnancy: a case report. Gynecol Obstet
4
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Case Report
Fatal hemolytic disease of the fetus and newborn caused by anti-Jra antibody: A case report and literature review ⁎
Min-Sun Kima, Jin Seok Kima, Hyewon Parkb, Yousun Chungc, Hyungsuk Kimd, Dae-Hyun Koa, , Sang-Hyun Hwanga, Hye-Sung Wone, Heung-Bum Oha a
Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea Seegene Medical Foundation, Seoul, Republic of Korea c Department of Laboratory Medicine, Kangdong Sacred Heart Hospital, Seoul, Republic of Korea d Department of Laboratory Medicine, Seoul National University Hospital, Seoul, Republic of Korea e Department of Obstetrics and Gynecology, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea b
A R T I C LE I N FO
A B S T R A C T
Keywords: Fatality Hemolytic disease of the fetus and newborn Anti-Jra ABCG2
The Jra antigen of the JR blood group system is a highly prevalent red blood cell antigen. Although antiJra–associated hemolytic disease of the fetus and newborn (HDFN) is generally considered mild-to-moderate, a rare fatal case was recently reported. We report the third example of HDFN-related anti-Jra with fatal outcomes. The clinical significance of anti-Jra antibody as a cause of HDFN should be reassessed.
1. Introduction Jra, a high-prevalence antigen, is currently the only antigen in the JR blood group system. Jra is expressed on ABCG2, a multi-pass membrane-protein family member of the adenosine triphosphate (ATP)-binding cassette transporters. While it is extremely rare in other races, the Jra-negative phenotype is relatively prevalent in East Asia, and 0.03% of the Japanese population is Jra negative [1–3]. The clinical significance of anti-Jra remains unknown. Mild, delayed hemolytic transfusion reactions and one case of an acute hemolytic transfusion reaction have been reported to be caused by anti-Jra [4,5]. Although the anti-Jra–associated hemolytic disease of the fetus and newborn (HDFN) is generally considered mild-to-moderate, two fatal cases have previously been published [6,7]. We report an extremely severe case of HDFN associated with antiJra alloimmunization that required aggressive intrauterine treatment. 2. Case report A healthy 37-year-old woman was admitted in the 30 + 5 week of her second pregnancy. Her first pregnancy ended with intrauterine death of unknown origin. She had no history of a previous transfusion. Fetal growth was mildly restricted; the peak systolic velocity of the fetal middle cerebral artery (MCA-PSV) was above the upper limit of the reference range, with 54–77 cm/s and 1.29–1.5 multiples of the median
⁎
(MoM). Although no signs of hydrops fetalis were detected on ultrasonography, MCA-PSV persisted at 1.5 MOM. The complete maternal blood count revealed no significant findings; viral test results were negative. Her blood group was O, Rh positive; direct antiglobulin test results were negative. Her serum showed reactivity with all red blood cells (RBCs) used for antibody screening and identification tests. She was suspected of having antibodies against a high-prevalence RBC antigen. To confirm whether she was negative for a high-prevalence antigen, RBCs were tested with anti-Jra antiserum; no reactivity was observed. The specificity of the maternal antibody could be anti-Jra, with a 1:128 titer determined by a reference laboratory (the Central Laboratory of the Swiss Red Cross, Bern, Switzerland). Because Jra-negative blood donor is extremely rare, we prepared washed maternal RBCs, and intrauterine fetal transfusion (IUT) was performed via the umbilical cord. Fetal Hb and hematocrit levels increased from 3.8 g/dL to 8.9 g/dL and 12% to 27%, respectively. However, emergency cesarean section was performed owing to deceleration of the fetal heart rate. The blood type of the male neonate was O, Rh positive; direct (antiIgG) and indirect antiglobulin test results were positive (1+). Antigen test for Jra could not be performed owing to the small sample volume. An initial laboratory analysis on the infant showed pancytopenia and hyperkalemia. Acute peritoneal dialysis was performed to correct hyperkalemia & volume overload. Despite continuous transfusion and two
Corresponding author at: University of Ulsan, College of Medicine and Asan Medical Center, 88 Olympic-Ro 43-Gil, Songpa-gu, 05505, Seoul, Republic of Korea. E-mail address: [email protected] (D.-H. Ko).
https://doi.org/10.1016/j.transci.2019.06.029 Received 14 February 2019; Received in revised form 1 April 2019; Accepted 3 June 2019 1473-0502/ © 2019 Published by Elsevier Ltd.
Please cite this article as: Min-Sun Kim, et al., Transfusion and Apheresis Science, https://doi.org/10.1016/j.transci.2019.06.029
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
M.-S. Kim, et al.
Fig. 1. Changes in laboratory test results of the neonate’s blood cell count (A) and general chemistry results (B). Pancytopenia persisted after a session of exchange transfusion. There was a marked elevation in liver enzyme levels and a gradual increase in creatinine levels. Hyperkalemia continued throughout the hospital course. AST, aspartate aminotransferase in ×10−1 IU/L; ALT, alanine aminotransferase in ×10−1 IU/L; Ca, calcium in mg/dL; Cr, creatinine in mg/dL; Hb, hemoglobin in g/dL; Hct, hematocrit in %; K, potassium in mmol/L; PLT, platelet count in ×104/μL; T-Bil, total bilirubin in mg/dL; WBC, white blood cell count in ×102/mL.
provide one possible explanation for this difference [6,7,17]. In IgG subclass analysis for anti-Jra antibodies, IgG1, associated with complement activation, was the predominant clone [6]. We could not, unfortunately, analyze the subclass of the anti-Jra antibody in our case. Severe HDFN owing to anti-Jra antibody has been characterized by hydrops fetalis in fetal ultrasonography, multiparity, and high anti-Jra antibody titer. Our patient also showed multiparity and a high anti-Jra antibody titer. Although hydrops fetalis was not noted in our case, we examined PSV-MCA to predict severe fetal anemia. The case reports by Ishihara et al. and Fujita et al. described severe fetal anemia in which IUT prevented catastrophic outcomes [10,11]. The patient from the former report was transfused with unrelated Jranegative blood for IUT, while the latter lacks detailed donor information. In our case, IUT was performed using washed maternal blood, which was Jra negative. Maternal blood may be the best source of donor RBCs for IUT, where multiple antibodies are present [18,19]. The advantage of maternal RBCs for IUT is the prevention of additional RBC antibodies that may be generated by the new donor RBC antigen [19]. In a previous report, maternal IUTs resulted in a significant improvement in the fetal hematocrit reduction rate [20]. One disadvantage of maternal blood is that we cannot be sure whether the antibody is completely removed by washing and how much remnant antibody is present in maternal autologous RBCs before IUT. The remnant maternal antibody in IUT could cause the poor general condition of the fetus. Direct ABCG2 gene sequencing for the mother and baby revealed the responsible variant, a nonsense mutation (ABCG2*01 N.01; rs72552713, c.376C > T, p.Gln126*) in exon 4. Deletion/duplication analysis was not performed in this case because the ABCG2*01 N.01 allele is commonly found in Asians [21,22]. ABCG2*01N.01 heterozygosity was found in 1.9% and 1% of Korean and Japanese individuals,
exchange transfusions, pancytopenia and hepatic failure deteriorated (Fig. 1). The Apgar score was 2 and 4 at 1 and 5 min, respectively. He required immediate chest compression and intubation after birth. Immediate exchange transfusion was performed with least incompatible O, RhD-positive-type RBC mixed AB frozen fresh plasma. However, the neonate’s general state declined rapidly with hyperkalemia (potassium level: 7.7 mmol/L), and he died three days later. ABCG2 analysis of the mother revealed a homozygous nonsense variant c.376C > T (ABCG2*01 N.01) in exon 4 (p.Gln126*) (Fig. 2-A); the infant was heterozygous for the same change (Fig. 2-B).
3. Discussion The clinical significance of anti-Jra antibody remains unclear. Some researchers reported none-to-moderate hemolytic transfusion reactions after incompatible Jra-positive blood transfusions in recipients with anti-Jra [5,8,9]. In one report, the mother harbored anti-Jra antibodies in her serum, although HDFN was not observed [4]. As shown in Table 1, the patients in three reports [6,7,10] showed severe HDFN clinical manifestations, and two [6,7] experienced abortion. Our case is the third reported fetal death owing to severe fetal anemia [4,6,7]. The main feature of previous reports [2,6,7,10–17], including severe cases, is multiparity. In our case, immunization might have occurred during a previous abortion. Anti-Jra antibody–associated HDFN may occur in subsequent pregnancies. A Jra-negative patient with anti-Jra antibody who was transfused with Jra-positive RBCs showed no severe complication [5]. This diversity in clinical manifestations might be because of the different in vivo activity of the anti-Jra antibody, and antibody subclasses can
Fig. 2. Results of ABCG2 sequencing in exon 4. (A) A maternal sample showed the homozygous variation for the ABCG2*01N.01 allele (c.376C > G, p.Gln126*), (B) the same variation was found in the heterozygous condition of the neonate. 2
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
Abbreviations: DAT, direct antiglobulin test; IAT, indirect antiglobulin test; US, ultrasonography; IUGR, intrauterine growth retardation; IUT, intrauterine transfusion; NT, not tested; G, gravida; P, parity; A, abortion.
Dead Dead Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive Alive No No Yes No Yes No No No No No No No No No Cardiomegaly, hepatomegaly, IUGR Hydrops fetalis Hydrops fetalis, polyhydramnios Normal NT NT NT NT NT NT NT NT NT NT Caucasian Caucasian Japanese Japanese Japanese Japanese Korean Japanese Japanese Unknown Spanish Japanese Japanese Japanese 1 [6] 2 [7] 3 [10] 4 [25] 5 [11] 6 [12] 7 [26] 8 [13] 9 [2] 10 [14] 11 [15] 12 [27] 13 [16] 14 [17]
28 39 40 20 28 20 33 23 30 Unknown 28 27 Unknown 32
35 Unknown 29 27 28 28 32 Unknown Unknown Unknown 27 First trimester 20/27 Unknown
G4P1A3 G5P3A2 G4P3A1 G1 G3P2 G2P1 G1 G2P1 G3P2A1 G2P2 G2P1A1 G1 G5P2 G4P3
1024 128 512 64 512 1024 Unknown 64 64-128 2048 Unknown 64 512/256 32
NT Positive/NT NT NT NT NT Negative/Negative Negative/Negative NT NT Negative/Positive Positive/NT NT Positive/NT
IUT Pregnancy history Gestational age (weeks) Maternal age (years) Race Case
Table 1 Clinical characteristics and laboratory data of cases showing Jra antibody during pregnancy.
Anti-Jra titer
DAT/IAT
US
Fetal outcome
M.-S. Kim, et al.
respectively [23]. Because Jra is a high-prevalence antigen, it is extremely difficult to identify Jra–negative blood in the general inventory. Finding compatible donors among family members or inquiry of rare donor registries could provide solutions. In Korea, the rare donor registry program has just begun, although the Jr blood group system is not included in the program [24]. The rare donor program in the region should be expanded to include the Jr blood group system in Asia. In conclusion, we report the third case of fatal HDFN caused by antiJra. In contrast to the general idea that the anti-Jra antibody causes mild HDFN, the antibody can cause fatal HDFN. The time has come to reconsider the clinical significance of the anti-Jra antibody. Acknowledgements We appreciate Bio-Rad Korea and Bio-Rad Laboratories (Cressier FR, Switzerland) for helping us identify the specificity of the antibody. References [1] Castilho L, Reid ME. A review of the JR blood group system. Immunohematology 2013;29:63–8. [2] Nakajima H, Ito K. An example of anti-Jra causing hemolytic disease of the newborn and frequency of Jra antigen in the Japanese population. Vox Sang 1978;35:265–7. [3] Vedo M, Reid ME. Anti-Jra in a Mexican American. Transfusion 1978;18:569. [4] Fung MK, Grossman BJ, Hillyer CD, Westhoff CM. Technical manual. 18th ed. Bethesda: American Association of Blood Banks; 2014. [5] Chung HJ, Lim JH, Park HJ, Kwon SW. Transfusion of Jra-positive red blood cells to a Jra-negative patient with anti-Jra. Korean J Blood Transfus 2007;18:111–5. [6] Peyrard T, Pham BN, Arnaud L, Fleutiaux S, Brossard Y, Guerin B, et al. Fatal hemolytic disease of the fetus and newborn associated with anti-Jr. Transfusion 2008;48:1906–11. https://doi.org/10.1111/j.1537-2995.2008.01787.x. [7] Arriaga F, Gomez I, Linares MD, Gascon A, Carpio N, Perales A. Fatal hemolytic disease of the fetus and newborn possibly due to anti-Jr. Transfusion 2009;49:813. https://doi.org/10.1111/j.1537-2995.2008.02087.x. [8] Yuan S, Armour R, Reid A, Abdel-Rahman KF, Rumsey DM, Phillips M, et al. Case report: massive postpartum transfusion of Jr(a+) red cells in the presence of antiJra. Immunohematology 2005;21:97–101. [9] Kwon MY, Su L, Arndt PA, Garratty G, Blackall DP. Clinical significance of anti-Jra: report of two cases and review of the literature. Transfusion 2004;44:197–201. [10] Ishihara Y, Miyata S, Chiba Y, Kawai T. Successful treatment of extremely severe fetal anemia due to anti-Jra alloimmunization. Fetal Diagn Ther 2006;21:269–71. https://doi.org/10.1159/000091354. [11] Fujita S, Kashiwagi H, Tomimatsu T, Ito S, Mimura K, Kanagawa T, et al. Expression levels of ABCG2 on cord red blood cells and study of fetal anemia associated with anti-Jr(a). Transfusion 2016;56:1171–81. https://doi.org/10.1111/trf.13515. [12] Sasamoto N, Tomimatsu T, Nagamine K, Oshida M, Kashiwagi H, Koyama S, et al. Fetal and neonatal anemia associated with anti-Jr(a): a case report showing a poorly hemolytic mechanism. J Obstet Gynaecol Res 2011;37:1132–6. https://doi. org/10.1111/j.1447-0756.2010.01477.x. [13] Takabayashi T, Murakami M, Yajima H, Tsujiei M, Ozawa N, Yajima A. Influence of maternal antibody anti-Jra on the baby: a case report and pedigree chart. Tohoku J Exp Med 1985;145:97–101. [14] Tritchler JE. An example of anti-Jra. Transfusion 1977;17:177–8. [15] Bellver-Pradas J, Arriaga-Chafer F, Perales-Marin A, Maiques-Montesinos V, SerraSerra V. Obstetric significance of anti-Jr(a) antibody. Am J Obstet Gynecol 2001;184:75–6. [16] Endo Y, Ito S, Ogiyama Y. Suspected anemia caused by maternal anti-Jra antibodies: a case report. Biomark Res 2015;3:23. [17] Azar PM, Kitagawa H, Fukunishi A, Yasuda T, Oki M, Saji H, et al. Uneventful transfusion of Jr (a+) red cells in the presence of anti-Jra. J Jpn Soc Blood Transfus 1988;34:406–10. [18] Watson WJ, Wax JR, Miller RC, Brost BC. Prevalence of new maternal alloantibodies after intrauterine transfusion for severe Rhesus disease. Am J Perinatol 2006;23:189–92. https://doi.org/10.1055/s-2006-934092. [19] Schonewille H, Klumper FJ, van de Watering LM, Kanhai HH, Brand A. High additional maternal red cell alloimmunization after Rhesus- and K-matched intrauterine intravascular transfusions for hemolytic disease of the fetus. Am J Obstet Gynecol 2007;196(143):e1–6. https://doi.org/10.1016/j.ajog.2006.10.895. [20] el-Azeem SA, Samuels P, Rose RL, Kennedy M, O’Shaughnessy RW. The effect of the source of transfused blood on the rate of consumption of transfused red blood cells in pregnancies affected by red blood cell alloimmunization. Am J Obstet Gynecol 1997;177:753–7. [21] Zelinski T, Coghlan G, Liu XQ, Reid ME. ABCG2 null alleles define the Jr(a-) blood group phenotype. Nat Genet 2012;44:131–2. https://doi.org/10.1038/ng.1075. [22] Lee SS, Jeong HE, Yi JM, Jung HJ, Jang JE, Kim EY, et al. Identification and functional assessment of BCRP polymorphisms in a Korean population. Drug Metab Dispos 2007;35:623–32. https://doi.org/10.1124/dmd.106.012302. [23] Kobayashi D, Ieiri I, Hirota T, Takane H, Maegawa S, Kigawa J, et al. Functional assessment of ABCG2 (BCRP) gene polymorphisms to protein expression in human placenta. Drug Metab Dispos 2005;33:94–101. https://doi.org/10.1124/dmd.104.
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M.-S. Kim, et al.
Invest 2010;69:81–3. https://doi.org/10.1159/000259724. [26] Kim H, Park MJ, Sung TJ, Choi JS, Hyun J, Park KU, et al. Hemolytic disease of the newborn associated with anti-Jra alloimmunization in a twin pregnancy: the first case report in Korea. Korean J Lab Med 2010;30:511–5. https://doi.org/10.3343/ kjlm.2010.30.5.511. [27] Toy P, Reid M, Lewis T, Ellisor S, Avoy DR. Does anti-Jra cause hemolytic disease of the newborn? Vox Sang 1981;41:40–4.
001628. [24] Hong YJ, Chung Y, Hwang SM, Park JS, Kwon JR, Choi YS, et al. Genotyping of 22 blood group antigen polymorphisms and establishing a national recipient registry in the Korean population. Ann Hematol 2016;95:985–91. https://doi.org/10.1007/ s00277-016-2645-7. [25] Masumoto A, Masuyama H, Sumida Y, Segawa T, Hiramatsu Y. Successful management of anti-Jra alloimmunization in pregnancy: a case report. Gynecol Obstet
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