The Rh blood group system: RHD update

Glenn Ramsey

doi:10.2478/immunohematology-2025-007

.blurhash-client-img { display: none !important; }

The Rh blood group system: RHD update

Immunohematology

Volume 41 (2025): Issue 2 (June 2025)

By: Glenn Ramsey

Paid access

|Jul 2025

Abstract

The Rh blood group system was last reviewed in Immunohematology in 2010 (Chou ST, Westhoff CM. The Rh and RhAG blood group systems. Immunohematology 2010;26:178–86). This update focuses on RHD, RhD structure, alterations in D expression, anti-D alloimmunization, and applications of RHD genotyping for weak and discrepant D phenotypes; identification of RHD genotypes that encode partial D phenotypes; and prevention and management of anti-D in pregnancy. Updates to the RHAG system and to RHCE and its encoded antigens are in recent or upcoming publications of Immunohematology, respectively.

References

Chou ST, Westhoff CM. The Rh and RhAG blood group systems. Immunohematology 2010;26:178–86.
Search in Google Scholar Back to article
Flegel WA. Molecular genetics of RH and its clinical application. Transfus Clin Biol 2006;13:4–12.
Search in Google Scholar Back to article
Li X, Jayachandran S, Nguyen HH, Chan MK. Structure of the Nitrosomonas europaea Rh protein. Proc Nat Acad Sci U S A 2007;104:19279–84.
Search in Google Scholar Back to article
Lupo D, Li X, Durand A, et al. The 1.3-Å resolution structure of Nitrosomonas europaea Rh50 and mechanistic implications for NH3 transport by Rhesus family proteins. Proc Nat Acad Sci U S A 2007;104:19303–8.
Search in Google Scholar Back to article
Gruswitz F, Chaudhury S, Ho JD, et al. Function of human Rh based on structure of RhCG at 2.1 Å. Proc Nat Acad Sci U S A 2010;9638–43.
Search in Google Scholar Back to article
Silvy M, Chapel-Hernandes S, Callebaut I, et al. Characterization of novel RHD alleles: relationship between phenotype, genotype, and trimeric architecture. Transfusion 2012;52:2020–9.
Search in Google Scholar Back to article
De Brevern AG, Floch A, Barrault A, et al. Alloimmunization risk associated with amino acid 223 substitution in the RhD protein: analysis in the light of molecular modeling. Transfusion 2018;58:2683–92.
Search in Google Scholar Back to article
Vallese F, Kim K, Yen LY, et al. Architecture of the human erythrocyte ankyrin-1 complex. Nat Struct Mol Biol 2022; 29:706–18.
Search in Google Scholar Back to article
Floch A, Galochkina T, Pirenne F, Tournamille C, de Brevern AG. Molecular dynamics of the human RhD and RhAG blood group proteins. Front Chem 2024;12:1360392.
Search in Google Scholar Back to article
Floch A, Pirenne F, Barrault A, et al. Insights into anti-D formation in carriers of RhD variants through studies of 3D intraprotein interactions. Transfusion 2021;61:1286–301.
Search in Google Scholar Back to article
Trueba-Gómez R, Rosenfeld-Mann F, Baptista-González HA, Domínguez-López ML, Estrada-Juárez H. Use of computational biology to compare the theoretical tertiary structures of the most common forms of RhCE and RhD. Vox Sang 2023;118:881–90.
Search in Google Scholar Back to article
Nicolas V, Mouro-Chanteloup I, Lopez C, et al. Functional interaction between Rh proteins and the spectrin-based skeleton in erythroid and epithelial cells. Transfus Clin Biol 2006;13:23–8.
Search in Google Scholar Back to article
Blanc M, David F, Abrami L, et al. SwissPalm: protein palmitoylation database. F1000Res 2015;4:261. Release 5, 2025. Available from https://swisspalm.org. Accessed 27 May 2025.
Search in Google Scholar Back to article
Daniels G. Human blood groups. 3rd ed. Oxford: Wiley-Blackwell, 2013:182–258.
Search in Google Scholar Back to article
Daniels G. Variants of RhD—current testing and clinical consequences. Br J Haematol 2013;161:461–70.
Search in Google Scholar Back to article
Mazières S, Condemi S, El Nemer W, Chiaroni J. Rapid change in red cell blood group systems after the main Out of Africa of Homo sapiens. Sci Rep 2025;15:1597.
Search in Google Scholar Back to article
Blancher A, Socha WW. The Rhesus system. In: Blancher A, Klein J, Socha WW, Eds. Molecular biology and evolution of blood group and MHC antigens in primates. Berlin: Springer-Verlag, 1997:147-218.
Search in Google Scholar Back to article
Anstee DJ. The relationship between blood groups and disease. Blood 2010;115:4635–43.
Search in Google Scholar Back to article
Flegr J, Toman J, Hůla M, Kaňková S. The role of balancing selection in maintaining human RhD blood group polymorphism: a preregistered cross-sectional study. J Evol Biol 2021;34:426–38.
Search in Google Scholar Back to article
Bruun-Rasmussen P, Dziegiel MH, Banasik K, Johansson PI, Brunak S. Associations of ABO and Rhesus D blood groups with phenome-wide disease incidence: a 41-year retrospective cohort study of 482,914 patients. eLife 2023;12:e83116.
Search in Google Scholar Back to article
International Society of Blood Transfusion. RHD blood group alleles. v6.4. Red cell immunogenetics and blood group terminology. Amsterdam: International Society of Blood Transfusion, 2023. Available from https://www.isbtweb.org/resource/004rhd.html. Accessed 26 May 2025.
Search in Google Scholar Back to article
Wagner FF, Flegel WA. The Rhesus site. Transfus Med Hemother 2014;41:357-63. Human RhesusBase version 2.5.2. 18 March 2020. Available from https://www.rhesusbase.info/. Accessed 26 May 2025.
Search in Google Scholar Back to article
Floch A, Téletchéa S, Tournamille C, de Brevern AG, Pirenne F. A review of the literature organized into a new database: RHeference. Transfus Med Rev 2021;35:70–7. Available from https://www.rheference.org. Accessed 26 May 2025.
Search in Google Scholar Back to article
Tippett P, Lomas-Francis C, Wallace M. The Rh antigen D: partial D antigens and associated low incidence antigens. Vox Sang 1996;70:123–31.
Search in Google Scholar Back to article
Sandler SG, Flegel WA, Westhoff CM, et al. It’s time to phase in RHD genotyping for patients with a serologic weak D phenotype. Transfusion 2015;55:680–9.
Search in Google Scholar Back to article
Flegel WA, Denomme GA, Queenan JT, et al. It’s time to phase out “serologic weak D phenotype” and resolve D types with RHD genotyping including weak D type 4. Transfusion 2020;60:855–9.
Search in Google Scholar Back to article
Ramsey G, Park YA, Eder AF, et al. Obstetric and newborn weak D-phenotype RBC testing and Rh immune globulin management recommendations: lessons from a blinded specimen-testing survey of 81 transfusion services. Arch Pathol Lab Med 2023;147:71-8.
Search in Google Scholar Back to article
Theiler C, Lomas-Francis C, Vege S, et al. Weak and partial D phenotyping: a comparison study between molecular and serologic results. Immunohematology 2024;40:159–65.
Search in Google Scholar Back to article
Denomme G, Dake LLR, Vilensky D, Ramyar L, Judd WJ. Rh discrepancies caused by variable reactivity of partial and weak D types with different serologic techniques. Transfusion 2008; 48:473–8.
Search in Google Scholar Back to article
Avent ND. New insight into the Rh system: structure and function. ISBT Sci Ser 2007;2:35–45.
Search in Google Scholar Back to article
Fennell K, Hoffman R, Yoshida K, et al. Effect on gene expression of three allelic variants in GATA motifs of ABO, RHD, and RHCE regulatory elements. Transfusion 2017;57:2804–8.
Search in Google Scholar Back to article
McGowan EC, Wu PC, Hellberg Å, Lopez GH, Hyland CA, Olsson ML. A bioinformatically initiated approach to evaluate GATA1 regulatory regions in samples with weak D, Del, or D-phenotypes despite normal RHD exons. Transfus Med Hemother 2024;51:252–64.
Search in Google Scholar Back to article
Li Q, Hou L, Guo Z, Ye L, Yue D, Zhu Z. Molecular basis of the RHD gene in blood donors with DEL phenotypes in Shanghai. Vox Sang 2009;97:139–46.
Search in Google Scholar Back to article
Christiansen M, Sørensen BS, Grunnet N. RHD positive among C/E+ and D- blood donors in Denmark. Transfusion 2010;50:1460–4.
Search in Google Scholar Back to article
Wagner FF, Gassner C, Müller TH, Schönitzer D, Schunter F, Flegel WA. Molecular basis of weak D phenotypes. Blood 1999;93:385–93.
Search in Google Scholar Back to article
Flegel WA, von Zabern I, Wagner FF. Six years’ experience performing RHD genotyping to confirm D– red blood cell units in Germany for preventing anti-D immunizations. Transfusion 2009;49:465-71.
Search in Google Scholar Back to article
Trueba-Gómez R, Rosenfeld-Mann F, Estrada-Juárez H. Prediction of the antigenic regions in eight RhD variants identified by computational biology. Vox Sang 2024;119:590–7.
Search in Google Scholar Back to article
Lejon Crottet S, Haer-Wigman L, Gowland P, Fontana S, Niederhauser C, Hustinx H. Serologic and molecular investigations of DARI (weak D type 4.2), DARI.2, DAR1.3, DAR2 (DARE), and DARA. Transfusion 2013;53:3000–8.
Search in Google Scholar Back to article
Srivastasa K, Polin H, Sheldon SL, et al. The DAU cluster: a comparative analysis of 18 RHD alleles, some forming partial D antigens. Transfusion 2016;56:2520–31.
Search in Google Scholar Back to article
Roussel M, Poupel S, Nataf J, et al. RHD*DOLl and RHD*DOL2 encode a partial D antigen and are in cis with the rare RHCE*ceBI allele in people of African descent. Transfusion 2013;53:363–72.
Search in Google Scholar Back to article
Wagner FF, Frohmajer A, Flegel WA. RHD positive haplotypes in D negative Europeans. BMC Genet 2001;2:10.
Search in Google Scholar Back to article
Fichou Y, Gehannin P, Corre M, et al. Extensive functional analyses of RHD splice site variants: insights into the potential role of splicing in the physiology of Rh. Transfusion 2015;55:1432–43.
Search in Google Scholar Back to article
Ogasawara K, Sasaki K, Isa K, et al. Weak D alleles in Japanese: a c.960G>A silent mutation in exon 7 of the RHD gene that affects D expression. Vox Sang 2016;110:179–84.
Search in Google Scholar Back to article
Raud L, Le Tertre M, Vigneron L, et al. Missense RHD single nucleotide variants induce weakened D antigen expression by altering splicing and/or protein expression. Transfusion 2021;61:2468–76.
Search in Google Scholar Back to article
Floch A, Vege S, Berardi P, et al. An intron c.149-2632T>A change in RHD is associated with aberrant transcription and very weak D phenotype. Transfusion 2022;62:E14–6.
Search in Google Scholar Back to article
Fichou Y. Hybrids and microconversions in RH genes: investigation and implication in transfusion therapy. Ann Blood 2023;8:7.
Search in Google Scholar Back to article
Flegel WA, Eicher NI, Doescher A, et al. In-frame triplet deletions in RHD alter the D antigen phenotype. Transfusion 2006;46:2156–61.
Search in Google Scholar Back to article
Flegel WA, Srivastava K. Frameshift variations in the RHD coding sequence: molecular mechanisms permitting protein expression. Transfusion 2020;60:2737–44.
Search in Google Scholar Back to article
Wagner FF. Serology and molecular biology of DEL: a narrative review. Ann Blood 2023;8:28.
Search in Google Scholar Back to article
Fichou Y, Parchure D, Gogri H, et al. Molecular basis of weak D expression in the Indian population and report of a novel, predominant variant RHD allele. Transfusion 2018;58: 1540–9.
Search in Google Scholar Back to article
Richard M, Perrault J, Constanzo-Yanez J, Khalifé S, St-Louis M. A new DEL variant caused by exon 8 deletion. Transfusion 2007;47:852–7.
Search in Google Scholar Back to article
Srivastava K, Stiles DA, Wagner FF, Flegel WA. Two large deletions extending beyond either end of the RHD gene and their red cell phenotypes. J Hum Genet 2018;63:27–35.
Search in Google Scholar Back to article
Tsunemaya H, Isa K, Ogasawara K, et al. Identification of a mutation in the RHAG gene of Japanese with weak D phenotype. Transfusion 2013;53(Suppl 2):167A.
Search in Google Scholar Back to article
Wen J, Verhagen OJHM, Jia S, et al. A variant RhAG protein encoded by the RHAG*572A allele causes serological weak D expression while maintaining normal RhCE phenotypes. Transfusion 2019;59:405–11.
Search in Google Scholar Back to article
Satchwell TJ, Bell AJ, Hawley BR, et al. Severe ankyrin-R deficiency results in impaired surface retention and lysosomal degradation of RhAG in human erythroblasts. Haematologica 2016;101:1018–27.
Search in Google Scholar Back to article
Shao CP, Maas JH, Su YQ, Köhler M, Legler TJ. Molecular background of Rh D-positive, D-negative, Del and weak D phenotypes in Chinese. Vox Sang 2002;83:156-61.
Search in Google Scholar Back to article
Tilley L. An update on the RHAG blood group system. Immunohematology 2025;41:1–3. DOI: 10.2478/immunohematology-2025-002.
Search in Google Scholar Back to article
Vege S, Floch A. An update on the Rh blood group system: RHCE. Immunohematology (in press).
Search in Google Scholar Back to article
Denomme GA, Wang D, Matheson KA, Titolo D. The proximal cis-regulatory region of the RHD/RHCE promoter is 105 bp and contains a 55-bp core devoid of known binding motifs but necessary for transcription. Transfusion 2009;49:1361–9.
Search in Google Scholar Back to article
Pham BN, Roussel M, Peyrard T, et al. Anti-D investigations in individuals expressing weak D type 1 or weak D type 2: alio- or autoantibodies? Transfusion 2011;51:2679–85.
Search in Google Scholar Back to article
Morin P, Perrault J, St-Louis M, Leiva-Torres GA, Robitaille N, Trépanier P. Weak D type 42: antigen density and risk of alloimmunization in the province of Québec. Vox Sang 2022;117:943–8.
Search in Google Scholar Back to article
Raud L, Ka C, Gourlaouen I, et al. Functional analysis of novel RHD variants: splicing disruption is likely to be a common mechanism of variant D phenotype. Transfusion 2019;59:1367–75.
Search in Google Scholar Back to article
Matzhold EM, Polin H, Körmöczi G, et al. RHD del28Phe (DMW) encoded by a novel in-frame deletion resulting in reduced D antigen expression. Transfusion 2019;59:3033–4.
Search in Google Scholar Back to article
Pereira J, Rodrigues M J, Tilley L, et al. RhD variant caused by an in-frame triplet duplication in the RHD gene. Transfusion 2011;51:570–3.
Search in Google Scholar Back to article
Tilley L, Rodrigues MJ, Malde R, et al. Two novel RhD variants caused by triplet deletions in the RhD gene. Transfusion Med 2007;17(Suppl 1):31.
Search in Google Scholar Back to article
Gassner C, Doescher A, Drnovsek TD, et al. Presence of RHD in serologically D-, C/E+ individuals: a European multicenter study. Transfusion 2005;45:527–38.
Search in Google Scholar Back to article
Nogues N, Tarrago M, Subirana L, et al. RHD null alleles in the Spanish population. Vox Sang 2007;93(Suppl 1):205.
Search in Google Scholar Back to article
Lopez GH, Turner RM, McGowan EC, et al. A DEL phenotype attributed to RHD exon 9 sequence deletion: slipped-strand mispairing and blood group polymorphisms. Transfusion 2018;58:685–91.
Search in Google Scholar Back to article
Fichou Y, Chen J, Le Maréchal C, et al. Weak D caused by a founder deletion in the RHD gene. Transfusion 2012;52: 2348–55.
Search in Google Scholar Back to article
International Society of Blood Transfusion. RHAG blood group alleles. v6.4. Red cell immunogenetics and blood group terminology. 2023. Available from https://www.isbtweb.org/resource/030rhag.html. Accessed 26 May 2025.
Search in Google Scholar Back to article
Hartel-Schenk S, Agre P. Mammalian red cell membrane Rh polypeptides are selectively palmitoylated subunits of a macromolecular complex. J Biol Chem 1992;267:5569–74.
Search in Google Scholar Back to article
Blaskovic S, Blanc M, Gisou van der Goot F. What does S-palmitoylation do to membrane proteins? FEBS J 2013; 280:2766–74.
Search in Google Scholar Back to article
Mesquita FS, Abrami L, Linder ME, Bamji SX, Dickinson BC, Gisou van der Goot F. Mechanisms and functions of protein S-acylation. Nat Rev Molec Cell Biol 2024;25:488–509.
Search in Google Scholar Back to article
Łach A, Gryzbek M, Heger E, et al. Palmitoylation of MPP1 (membrane-palmitoylated proteinl)/p55 is crucial for lateral membrane organization in erythroid cells. J Biol Chem 2012;287:18974–84.
Search in Google Scholar Back to article
Łach A, Gryzbek M, Heger E, et al. Withdrawal: palmitoylation of MPP1 (membrane-palmitoylated proteinl)/p55 is crucial for lateral membrane organization in erythroid cells. J Biol Chem 2018;293:2786.
Search in Google Scholar Back to article
Yazer MH, Triulzi DJ, Sperry JL, Seheult JN. Rate of RhD-alloimmunization after the transfusion of multiple RhD-positive primary red blood cell-containing products. Transfusion 2021;61(Suppl l):S150–8.
Search in Google Scholar Back to article
Seheult JN, Callum J, Delaney M, et al. Rate of D- alloimmunization in trauma does not depend on the number of RhD-positive units transfused: the BEST collaborative study. Transfusion 2022;62(Suppl l):S185–92.
Search in Google Scholar Back to article
Ji Y, Luo G, Fu Y. Incidence of anti-D alloimmunization in D-negative individuals receiving D-positive red blood cell transfusion: a systematic review and meta-analysis. Vox Sang 2022;117:633–40.
Search in Google Scholar Back to article
Hubert T, Kerkhoffs JL, Brand A, Schonewille H. Anti-D immunization after D positive platelet transfusions in D negative recipients: a systematic review and meta-analysis. Transfusion 2024;64:933–45.
Search in Google Scholar Back to article
Perez-Alvarez I, Hayes C, Hailemariam T, Shin E, Hutchinson T, Klapper E. RHD genotyping of serologic RhD-negative blood donors in a hospital-based blood donor center. Transfusion 2019;59:2422–8.
Search in Google Scholar Back to article
Pardi C, Hellberg Å, Isakson P. Single-exon fetal RHD genotyping: a 31-month follow up in the obstetric population of Western Sweden. Blood Transfus 2024;22:387–94.
Search in Google Scholar Back to article
Krog GR, Clausen FB, Berkowicz A, et al. Is current serologic RhD typing of blood donors sufficient for avoiding immunization of recipients? Transfusion 2011;51:2278–85.
Search in Google Scholar Back to article
Stegmann TC, Veldhuisen B, Bijman R, et al. Frequency and characterization of known and novel RHD variant alleles in 37 782 Dutch D-negative pregnant women. Br J Haematol 2016;173:469–79.
Search in Google Scholar Back to article
Crottet SL, Henny C, Meyer S, et al. Six years’ experience performing RHD genotyping to confirm D- red blood cell units in Germany for preventing anti-D immunizations. Transfus Apher Sci 2014;50:169–74.
Search in Google Scholar Back to article
Polin H, Danzer M, Gaszner W, et al. Identification of RHD alleles with the potential of anti-D immunization among seemingly D- blood donors in Upper Austria. Transfusion 2009;49:676-81.
Search in Google Scholar Back to article
Orzińska A, Guz K, Polin H, et al. RHD variants in Polish blood donors routinely typed as D negative. Transfusion 2013;53(Suppl 2):2945-53.
Search in Google Scholar Back to article
Vendrame TAP, Arnoni CP, Muniz JG, et al. Characterization of RHD alleles present in serologically R HD-negative donors determined by a sensitive microplate technique. Vox Sang 2019;114:869–75.
Search in Google Scholar Back to article
Trucco Boggione C, Luján Brajovich ME, Tarragó M, et al. Molecular structures identified in serologically D- samples of an admixed population. Transfusion 2014;54:2456–62.
Search in Google Scholar Back to article
Ye S, Wu D, Wang M, et al. A comprehensive investigation of RHD polymorphisms in the Chinese Han population in Xi'an. Blood Transfus 2014;12:396–404.
Search in Google Scholar Back to article
Thongbut J, Laengsri V, Raud L, et al. Nation-wide investigation of RHD variants in Thai blood donors: impact for molecular diagnostics. Transfusion 2021;61:931–8.
Search in Google Scholar Back to article
Kim JY, Kim SY, Kim C, Yon GS, Park SS. Molecular characterization of D- Korean persons: development of a diagnostic strategy. Transfusion 2005;45:345–52.
Search in Google Scholar Back to article
Ogasawara K, Suzuki Y, Sasaki K, et al. Molecular basis for D- Japanese: identification of novel DEL and D- alleles. Vox Sang 2015;109:359–65.
Search in Google Scholar Back to article
Flegel WA, Srivastava K. 40 Years of researching the Del phenotype results in a change of transfusion practice. Transfusion 2024;64:1187–90.
Search in Google Scholar Back to article
Hess JR. Safe transfusion in Asian-type DEL. Blood 2023:141:2044–6.
Search in Google Scholar Back to article
Bowman J. Thirty-five years of Rh prophylaxis. Transfusion 2003;43:1661–6.
Search in Google Scholar Back to article
Pegoraro V, Urbinati D, Visser GHA, et al. Hemolytic disease of the fetus and newborn due to Rh(D) incompatibility: a preventable disease that still produces significant morbidity and mortality in children. PLoS ONE 2020;15:e0235807.
Search in Google Scholar Back to article
Luo X, Keller M A, James I, et al. Strategies to identify candidates for D variant genotyping. Blood Transfus 2018;16:293–301.
Search in Google Scholar Back to article
Horn TN, Keller J, Keller MA, Klinger L. Identifying obstetrics patients in whom RHD genotyping can be used to assess risk of D alloimmunization. Immunohematology 2020;36:146–51.
Search in Google Scholar Back to article
Arnoni CA, Vendrame TA, Silva FS, et al. Serologic profiling of D variants in donor routine: unveiling the impact on false-negative results and alloimmunization. Immunohematology 2024;40:47–53.
Search in Google Scholar Back to article
Ramsey G, Barriteau CM. Estimating the serological under-recognition of patients with weak or partial RHD variants. Transfusion 2024;64:920–8.
Search in Google Scholar Back to article
Barriteau CM, Lindholm PL, Hartman K, Sumugod RD, Ramsey G. RHD genotyping to resolve weak and discrepant RhD patient phenotypes. Transfusion 2022;62:2194–9.
Search in Google Scholar Back to article
Londero D, Monge J, Hellberg A. A multi-centre study on the performance of the molecular genotyping platform ID RHD XT for resolving serological weak RhD phenotype in routine clinical practice. Vox Sang 2020;115:241–8.
Search in Google Scholar Back to article
Westhoff CM, Floch A. Blood group genotype matching for transfusion. Br J Haematol 2025;206:18–32.
Search in Google Scholar Back to article
Vege S, Sprogøe U, Lomas-Francis C, et al. Impact of RHD genotyping on transfusion practice in Denmark and the United States and identification of novel RHD alleles. Transfusion 2021;61:256–65.
Search in Google Scholar Back to article
Madgett TE, Tounsi WA, Halawani AJ, Avent ND. RHD molecular analysis: from discovery to next generation sequencing. Ann Blood 2023;8:36.
Search in Google Scholar Back to article
Khandelwal A, Zittermann S, Sierocinski T, Montemayor C. RH genotyping by next-generation sequencing. Ann Blood 2023;8:39.
Search in Google Scholar Back to article
Lane WJ, Westhoff CM, Gleadall NS, et al. Automated typing of red blood cell and platelet antigens; a whole-genome sequencing study. Lancet Haematol 2018;5:e241–51.
Search in Google Scholar Back to article
Halls JBL, Vege S, Simmons DP, et al. Overcoming the challenges of interpreting complex and uncommon RH alleles from whole genomes. Vox Sang 2020;115:790–801.
Search in Google Scholar Back to article
Chen S, Francioli LC, Goodrich JK, et al. A genomic mutational constraint map using variation in 76,156 human genomes. Nature 2024;625:92–100.
Search in Google Scholar Back to article
The All of Us Research Program Genomics Investigators. Genomic data in the All of Us research program. Nature 2024;627:340–6.
Search in Google Scholar Back to article
Fung-Kee-Fung K, Wong K, Walsh J, Hamel C, Clarke G. Guideline no. 448: prevention of Rh D alloimmunization. J Obstet Gynaecol Can 2024;46:102449.
Search in Google Scholar Back to article
Westhoff CM, Nance S, Lomas-Francis C, Keller M, Chou ST. Experience with RHD*weak D type 4.0 in the USA. Blood Transfus 2019;17:91–3.
Search in Google Scholar Back to article
Miranda MR, Delfino dos Santos T, Castilho L. Systematic RHD genotyping in Brazilians reveals a high frequency of partial D in transfused patients serologically typed as weak D. Transfus Apher Sci 2021;60:103235.
Search in Google Scholar Back to article
Jenkins CM, Johnson ST, Bellissimo DB, Gottschall JL. Incidence of weak D in blood donors typed as D positive by the Olympus PK 7200. Immunohematology 2005;21:152–4.
Search in Google Scholar Back to article
Haspel RL, Westhoff CM. How do I manage Rh typing in obstetric patients? Transfusion 2015;55:470–4.
Search in Google Scholar Back to article
Mamone L, James IL, Yoon EJ, Alsammak M. Clinical and cost efficacy of molecular RhD genotyping. Transfusion 2018;58(Suppl 2):178A.
Search in Google Scholar Back to article
Uzuni A, Wlosinski L, Lopez-Plaza I. Updated evaluation of RhD status among women of child-bearing age in Detroit, Michigan. Am J Clin Pathol 2021;156:1000–6.
Search in Google Scholar Back to article
Hudgins JP, Matsushita C, Tuma CW, O’Brien L, Shulman IA. Identification of RHD allelic variants discovered by atypical typing results on the NEO/Echo platforms. Immunohematology 2021;37:165–70.
Search in Google Scholar Back to article
Keller MA. RH genetic variation and the impact for typing and personalized transfusion strategies: a narrative review. Ann Blood 2023;8:18.
Search in Google Scholar Back to article
Denomme GA, Wagner FF, Fernandes BJ, Li W, Flegel WA. Partial D, weak D types, and novel RHD alleles among 33,864 multiethnic patients: implications for anti-D alloimmunization and prevention. Transfusion 2005;45:1554–60.
Search in Google Scholar Back to article
Clarke G, Hannon J, Berardi P, et al. Resolving variable maternal D typing using serology and genotyping in selected prenatal patients. Transfusion 2016;56:2980–5.
Search in Google Scholar Back to article
Leiva-Torres GA, Chevrier M, Constanzo-Yanez J, et al. High prevalence of weak D type 42 in a large-scale RHD genotyping program in the province of Quebec (Canada). Transfusion 2021;61:2727–35.
Search in Google Scholar Back to article
Polin H, Danzer M, Hofer K, Gassner W, Gabriel C. Effective molecular RHD typing strategy for blood donations. Transfusion 2007;47:1350–5.
Search in Google Scholar Back to article
Juhl D, Luckner K, Brockmann C, et al. RHD-negative red cells may be avoided for patients with ambiguous serologic typing for the RHD antigen. Transfusion 2024;64:281–8.
Search in Google Scholar Back to article
Müller TH, Wagner FF, Trockenbacher A, et al. PCR screening for common weak D types shows different distributions in three Central European populations. Transfusion 2001;41: 45–52.
Search in Google Scholar Back to article
Fichou Y, Le Maréchal C, Jamet D, et al. Establishment of a medium-throughput approach for the genotyping of RHD variants and report of nine novel rare alleles. Transfusion 2013;53:1821–8.
Search in Google Scholar Back to article
Van Sandt VST, Gassner C, Emonds M, Legler TJ, Mahieu S, Körmöczi GF. RHD variants in Flanders, Belgium. Transfusion 2015;55:1411–7.
Search in Google Scholar Back to article
Lucacevic Krstic J, Dajak S, Bingulac-Popovic J, Dogic V, Mratinovic-Mikulandra J. Anti-D reagents should be chosen accordingly to the prevalence of D variants in the obstetric population. J Clin Lab Anal 2018;32:e22285.
Search in Google Scholar Back to article
Safic Stanic H, Kruhonja Galic Z, Dogic V, Bingulac-Popovic J, Jukic I. Serological and molecular characterisation of the most prevalent weak D variants in Croatian population. Transfus Med 2023;33:132–6.
Search in Google Scholar Back to article
Xhetani M, Seferi I, Férec C, Zoraqi G, Fichou Y. Distribution of Rhesus blood group antigens and weak D alleles in the population of Albania. Blood Transfus 2014;12:565–9.
Search in Google Scholar Back to article
Koutsouri T, Chaikali A, Giannopoulos A, et al. Frequency distribution of RHD alleles among Greek donors with weak D phenotypes demonstrates a distinct pattern in central European countries. Transfus Med 2019;29:468–70.
Search in Google Scholar Back to article
Yanasik M, Oguz FS, Besisik SK, et al. Frequency of RHD variants in serologically weak D Turkish blood donors. Transfus Apher Sci 2021;60:103024.
Search in Google Scholar Back to article
Oodi A, Daneshvar Z, Goudarzi S, Amirizadeh N. RHD genotyping of serological weak D phenotypes in the Iranian blood donors and patients. Transfus Apher Sci 2020;59:102870.
Search in Google Scholar Back to article
El Housse H, El Wafi M, Ouabdelmoumene Z, et al. Comprehensive phenotypic and molecular investigation of RhD and RhCE variants in Moroccan blood donors. Blood Transfus 2019;17:151–6.
Search in Google Scholar Back to article
Ouchari M, Srivastava K, Romdhane H, Yacoub SJ, Flegel WA. Transfusion strategy for weak D type 4.0 based on RHD alleles and RH haplotypes in Thnisia. Transfusion 2018;58:306–12.
Search in Google Scholar Back to article
Hussein E, Teruya J. Weak D types in the Egyptian population. Am J Clin Pathol 2013;139:806–11.
Search in Google Scholar Back to article
Abdelrazik AM, Elshafie SM, Ahmed GME, Abdelaziz HM. Combining serology and molecular typing of weak D role in improving D typing strategy in Egypt. Transfusion 2013;53:2940–4.
Search in Google Scholar Back to article
Maryam DU, Mukhtar IG, Yusuf AA, Salisu AL High prevalence of serological weak D phenotype and preponderance of weak D type 4.0.1. genetic variant in a Nigerian population: implications for transfusion practice in a resource-limited setting. Hematol Transfus Cell Ther 2022;44:386–91.
Search in Google Scholar Back to article
Cruz BR, Chiba AK, Moritz E, Bordin JO. RHD alleles in Brazilian blood donors with weak D or D-negative phenotypes. Transfus Med 2012;22:84-9.
Search in Google Scholar Back to article
Dezan MR, Oliviera VB, Nunes Gomes Q, et al. High frequency of variant RHD genotypes among donors and patients of mixed origin with serologic weak-D phenotype. J Clin Lab Anal 2018;32:e22596.
Search in Google Scholar Back to article
Person RDM, Arnoni CP, Muniz JG, et al. Serologic strategy in detecting RHD altered alleles in Brazilian blood donors. Hematol Transfus Cell Ther 2020;42:365–72.
Search in Google Scholar Back to article
Rodrigues ES, Romagnoli AC, Santos FLS, et al. Frequency and characterization of RHD variant alleles in a population of blood donors from southeastern Brazil: comparison with other populations. Transfus Apher Sci 2021;60:103135.
Search in Google Scholar Back to article
Trucco Boggione C, Nogues N, Gonzalez-Santesteban C, et al. Characterization of RHD locus polymorphism in D negative and D variant donors from Northwestern Argentina. Transfusion 2019;59:3236-42.
Search in Google Scholar Back to article
Aburto A, Zapata D, Retamales E, et al. Genotype analysis to clarify RhD variants in discrepant samples of Chilean population. Front Immunol 2023;14:1299639.
Search in Google Scholar Back to article
Khetan D, Verma A, Chaudhary RK, Shukla JS. Molecular characterisation of RhD variants in North Indian blood donor population. Transfus Med 2020;30:295-303.
Search in Google Scholar Back to article
Mishra G, Sachan D, Krishna D, Parchure D, Madkaikar M, Kulkami S. Characterising Indian RhD variants by serological and molecular methods. Transfus Med 2020;30:324-6.
Search in Google Scholar Back to article
Zhang X, Li G, Zhou Z, et al. Molecular and computational analysis of 45 samples with a serologic weak D phenotype detected among 132,479 blood donors in northeast China. J Transl Med 2019:17:393.
Search in Google Scholar Back to article
Ye L, Li M, Yang Q, Zhu Z. RHD alleles contributing to serologically weak D phenotypes in China: a single-centre study over 10 years. Vox Sang 2022;117:949-57.
Search in Google Scholar Back to article
Chung YN, Kim TY, Yu H, Bae JC, Cho D. Molecular basis of serological weak D phenotypes and RhD typing discrepancies identified in the Korean population. Blood Transfus 2021; 19:327-34.
Search in Google Scholar Back to article
Isa K, Sasaki K, Ogasawara K, et al. Prevalence of RHD alleles in Japanese individuals with weak D phenotype: identification of 20 new RHD alleles. Vox Sang 2016;111:315-9.
Search in Google Scholar Back to article
McGowan EC, Lopez GH, Knauth CM, et al. Diverse and novel RHD variants in Australian blood donors with a weak D phenotype: implication for transfusion management. Vox Sang 2017;112:279–87.
Search in Google Scholar Back to article
Schoeman EM, Roulis EV, Perry MA, Flower RL, Hyland CA. Comprehensive blood group antigen profile predictions for Western Desert Indigenous Australians from whole exome sequence data. Transfusion 2019;59:768-78.
Search in Google Scholar Back to article
Jadhao S, Davison C, Roulis E, et al. Genomic characterisation of clinically significant blood group variants in Aboriginal Australians. Blood Transfus 2024;22:464-74.
Search in Google Scholar Back to article
Takasaki K, Friedman DF, Uter S, Vege S, Westhoff CM, Chou ST. Variant RHD alleles and Rh immunization in patients with sickle cell disease. Br J Haematol 2023;201:1220–8.
Search in Google Scholar Back to article
Chang T, Haupfear KM, Yu J, et al. A novel algorithm comprehensively characterizes human RH genes using whole- genome sequencing data. Blood Adv 2020;4:4347-57.
Search in Google Scholar Back to article
Silvy M, Tournamille C, Babinet J, et al. Red blood cell immunization in sickle cell disease: evidence of a large responder group and a low rate of anti-Rh linked to partial Rh phenotype. Haematologica 2014;99:ell6.
Search in Google Scholar Back to article
Hui YMT, Gurung K, Layton DM, Ibidapo M, Grimsley S, Regan F. Sickle cell disease patients in two London trusts: genotyping including RH variants. Transfus Med 2022;32:210-20.
Search in Google Scholar Back to article
Desay K, Hill O, Tovey S, Finning K. Red blood cell genotyping to reduce alloimmunization and improve blood selection for haemoglobinopathy patients. Transfus Med 2016;26(Suppl 2):21. Available from https://www.bbts.org.uk/downloads/bbts2016/presentations/09.00friqs3bbts2016karendesav.l.pdf. Accessed 26 May 2025.
Search in Google Scholar Back to article
Muniz JG, Arnoni C, Medeiros R, et al. Antigen matching for transfusion support in Brazilian female patients with sickle cell disease to reduce RBC alloimmunization. Transfusion 2021;61:2458-67.
Search in Google Scholar Back to article
Teles B, Santos T, Castilho L. Risk of clinically significant anti-D in sickle cell disease patients with partial D transfused with D-positive red blood cells. Vox Sang 2023;118(Suppl 1):263.
Search in Google Scholar Back to article
Shih AW, Yan MTS, Elahie AL, et al. Utilising red cell antigen genotyping and serological phenotyping in sickle cell disease patients to risk-stratify patients for alloimmunisation risk. Transfus Med 2020;30:263-74.
Search in Google Scholar Back to article
Leiva-Torres GA, Cigna M, Constanzo-Yanez J, et al. Transfusing children with sickle cell disease using blood group genotyping when the pool of Black donors is limited. Transfusion 2024;64:716-26.
Search in Google Scholar Back to article
Reid ME, Hipsky CH, Hue-Roye K, Hoppe C. Genomic analyses of RH alleles to improve transfusion therapy in patients with sickle cell disease. Blood Cell Mol Dis 2014;52:195-202.
Search in Google Scholar Back to article
Chou ST, Evans P, Vege S, et al. RH genotype matching for transfusion support in sickle cell disease. Blood 2018;132: 1198-207.
Search in Google Scholar Back to article
Wheeler MM, Lannert KW, Huston H, et al. Genomic characterization of the RH locus detects complex and novel structural variation in multi-ethnic cohorts. Genet Med 2019;21:477-86.
Search in Google Scholar Back to article
Israelyan N, Vege S, Friedman DF, et al. RH genotypes and red cell alloimmunization rates in chronically transfused patients with sickle cell disease: a multisite study in the USA. Transfusion 2024;64:526-35.
Search in Google Scholar Back to article
Macedo MD, Miranda MR, Santos TD, Leal I, Castilho L. Rh antibodies as a result of altered Rh epitopes on transfused red cells: a case series of seven Brazilian patients. Blood Transfus 2021;19:413-9.
Search in Google Scholar Back to article
Kirkegaard J, Rahorst L, Burgos A, et al. Evidence that donors with variant RH genotypes are associated with unexpected Rh antibodies. Transfusion 2023;63:1962-8.
Search in Google Scholar Back to article
Chou ST, Mewha J, Friedman DF, et al. Genotyped RhD+ red cells for D-positive patients with sickle cell disease with conventional RHD and unexpected anti-D. Blood 2024; 144:2045-9.
Search in Google Scholar Back to article
American College of Obstetricians and Gynecologists. Paternal and fetal genotyping in the management of alloimmunization in pregnancy. Obstet Gynecol 2024;144:e47-9.
Search in Google Scholar Back to article
Pirelli KJ, Pietz BC, Johnson ST, Pinder HL, Bellissimo DB. Molecular determination of RHD zygosity: predicting risk of hemolytic disease of the fetus and newborn related to anti-D. Prenat Diagn 2010;30:1207-12
Search in Google Scholar Back to article
Sillence KA, Halawani AJ, Tounsi WA, et al. Rapid RHD zygosity determination using digital PCR. Clin Chem 2017; 63:1388-97.
Search in Google Scholar Back to article
Stef M, Fennell K, Apraiz I, et al. RHgenotyping by nonspecific quantitative next-generation sequencing. Transfusion 2020; 60:2691-701.
Search in Google Scholar Back to article
Petch S, Crosby D. Updates in preimplantation genetic testing (PGT). Best Pract Res Clin Obstet Gynaecol 2024;96:102526.
Search in Google Scholar Back to article
Moise KJ, Abels EA. Management of red cell alloimmunization in pregnancy. Obstet Gynecol 2024;144:465-80.
Search in Google Scholar Back to article
Seeho SKM, Burton G, Leigh D, Marshall JT, Persson JW, Morris JM. The role of preimplantation genetic diagnosis in the management of severe rhesus alloimmunization: first unaffected pregnancy: case report. Hum Reprod 2005;20:697-701.
Search in Google Scholar Back to article
Verlinsky Y, Rechitsky S, Ozen S, Masciangelo C, Ayers J, Kuliev A. Preimplantation genetic diagnosis for the Kell genotype. Fertil Steril 2003;80:1047-51.
Search in Google Scholar Back to article
Altarescu G, Geva TE, Grisaru-Granovsky S, et al. Preimplantation genetic diagnosis for fetal neonatal alloimmune thrombocytopenia due to antihuman platelet antigen maternal antibodies. Obstet Gynecol 2012;119:338-43.
Search in Google Scholar Back to article
Clausen FB. Antenatal RHD screening to guide antenatal anti-D immunoprophylaxis in non-immunized D-pregnant women. Immunohematology 2024;40:15-27.
Search in Google Scholar Back to article
Mateus-Nino JF, Wynn J, Wiggins-Smith J, et al. Clinical performance of cell-free DNA for fetal RhD detection in RhD- negative pregnant individuals in the US. Obstet Gynecol 2025;145:402-8.
Search in Google Scholar Back to article
Thompson MG, Xu W, Moore B, et al. Clinical validation of a prenatal cell-free DNA screening test for fetal RHD in a large U.S. cohort. Obstet Gynecol 2025;145:211-6.
Search in Google Scholar Back to article
Moise KJ. The use of free DNA for fetal RHD genotyping in the Rh-negative pregnant patient: the time has come. Am J Obstet Gynecol 2025;232:188-93.
Search in Google Scholar Back to article
American College of Obstetricians and Gynecologists. Rho(D) immune globulin shortages. Practice advisory. March 2024. Available from https://www.acog.org/clinical/dinical-guidance/practice-advisorv/articles/2024/03/rhod-immune-globulin-shortages. Accessed 26 May 2025.
Search in Google Scholar Back to article
Association for the Advancement of Blood & Biotherapies. Association Bulletin #24-02. Use of Rh immune globulin and considerations in the setting of supply shortages and limited availability. 15 July 2024. Available from https://www.aabb.org/news-resources/resources/association-bulletins. Accessed 26 May 2025.
Search in Google Scholar Back to article
Levine P, Rosenfield RE, White J. The first example of the Rh phenotype r^Gr^G. Am J Hum Genet 1961;13:299-305.
Search in Google Scholar Back to article
Issitt PD. Serology and genetics of the Rhesus blood group system. Cincinnati, OH: Montgomery Scientific, 1979:1.
Search in Google Scholar Back to article
Pierce SR, Reid ME. Bloody brilliant: a history of blood groups and blood groupers. Bethesda, MD: AABB Press, 2016:253.
Search in Google Scholar Back to article