Have a personal or library account? Click to login

Kell and Kx blood group systems: an update

Paid access
|Oct 2025

References

  1. ISBT Blood Group Allele Database: 006 KEL and 019 KX Alleles. International Society of Blood Transfusion; 2021-2023. Available from https://www.isbtweb.org/isbt-working-parties/rcibgt.html. Accessed 31 January 2025.
  2. Lee S, Russo D, Redman CM. The Kell blood group system: Kell and XK membrane proteins. Semin Hematol 2000;37:113–21.
  3. Lee S, Zambas ED, Marsh WL, Redman CM. Molecular cloning and primary structure of Kell blood group protein. Proc Natl Acad Sci U S A 1991;88:6353–7.
  4. Lee S, Lin M, Mele A, et al. Proteolytic processing of big endothelin-3 by the Kell blood group protein. Blood 1999;94:1440–50.
  5. Lee S, Russo DCW, Reiner AP, et al. Molecular defects underlying the Kell null phenotype. J Biol Chem 2001;276:27281–9.
  6. Ho M, Chelly J, Carter N, Danek A, Crocker P, Monaco AP. Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein. Cell 1994;77:869–80.
  7. Allen FH Jr, Krabbe SM, Corcoran PA. A new phenotype (McLeod) in the Kell blood-group system. Vox Sang 1961; 6:555–60.
  8. Denomme GA. Kell and Kx blood group systems. Immunohematology 2015;31:14–9.
  9. Lee S. Molecular basis of Kell blood group phenotypes. Vox Sang 1997;73:1–11.
  10. Stanfield GM, Horvitz HR. The ced-8 gene controls the timing of programmed cell deaths in C elegans. Mol Cell 2000;5: 423–33.
  11. Lee S, Russo D, Redman C. Functional and structural aspects of the Kell blood group system. Transfus Med Rev 2000;14: 93–103.
  12. Camara-Clayette V, Rahuel C, Lopez C, et al. Transcriptional regulation of the KEL gene and Kell protein expression in erythroid and non-erythroid cells. Biochem J 2001;356: 171–80.
  13. Clapéron A, Rose C, Gane P, Collec E, Bertrand O, Ouimet T. The Kell protein of the common K2 phenotype is a catalytically active metalloprotease, whereas the rare Kell K1 antigen is inactive: identification of novel substrates for the Kell protein. J Biol Chem 2005;280:21272–83.
  14. Lee S, Debnath AK, Redman CM. Active amino acids of the Kell blood group protein and model of the ectodomain based on the structure of neutral endopeptidase 24.11. Blood 2003;102:3028–34.
  15. Azouzi S, Collec E, Mohandas N, An X, Colin Y, Le Van Kim C. The human Kell blood group binds the erythroid 4.1R protein: new insights into the 4.1R-dependent red cell membrane complex. Br J Haemotol 2015;17:862–71.
  16. New Zealand Blood Service. Policy for the provision of K negative red cells to females with child bearing potential (National Policy Document 111P01702). Available from https://www.nzblood.co.nz/assets/Transfusion-Medicine/PDFs/111P017.pdf. Accessed 7 February 2025.
  17. Goldman M, Lane D, Webert K, Fallis R. The prevalence of anti-K in Canadian prenatal patients. Transfusion 2015; 55:1486–91.
  18. Luken JS, Folman CC, Lukens MV, et al. Reduction of anti-K-mediated hemolytic disease of newborns after the introduction of a matched transfusion policy: a nation-wide policy change evaluation study in the Netherlands. Transfusion 2021;61: 713–21.
  19. Luken JS, Folman CC, Meekers JH, Lukens MV, van der Schoot CE, de Haas M. Major reduction in occurrence of anti-c and anti-E in pregnancy after more than 10 years of preventive matched transfusion with most benefit for c-matching. Br J Haematol 2024;205:1599–604.
  20. Regan F, Veale K, Robinson F, et al. Guideline for the investigation and management of red cell antibodies in pregnancy: a British Society for Haematology guideline. Transfus Med 2025;35:3–23.
  21. Australian and New Zealand Society of Blood Transfusion. Guidelines for transfusion and immunohaematology laboratory practice. Available from https://anzsbt.org.au/guidelines/guidelines-for-transfusion-and-immunohaematology-laboratory-practice/. Accessed 17 September 2025.
  22. Gleadall NS, Veldhuisen B, Gollub J, et al. Development and validation of a universal blood donor genotyping platform: a multinational prospective study. Blood Adv 2020;4:3495–506.
  23. Fasano RM, Chou ST. Red blood cell antigen genotyping for sickle cell disease, thalassemia, and other transfusion complications. Transfus Med Rev 2016;30:197–201.
  24. Flegel WA, Gottschall JL, Denomme GA. Implementing mass-scale red cell genotyping at a blood center. Transfusion 2015;55:2610–5; quiz 2609.
  25. Jacko G, Powley T, Daly J. Frequency of red blood cell phenotypes from genotyped Australian blood donors. Transfus Med 2024;34:219–22.
  26. Akinbolaji TJ. When and why is red blood cell genotyping applicable in transfusion medicine: a systematic review of the literature. Immunohematology 2024;40:58–64.
  27. Grey D, Poole J, Martin P, et al. P23: haemolytic disease of the newborn caused by a new Kell antigen. Transfus Med 2003;13(Suppl 1):30.
  28. Martin-Blanc S, Laget L, Babinet J, et al. Characterization of a novel high prevalence antigen in the KEL blood group system. Vox Sang 2022;117(Suppl 1):6–271.
  29. Hyland C, Buhariwala K, Lopez G, et al. Intertwining roles for genomics and international data sharing defines a novel low prevalence Kell antigen in a blood donor. Transfus Med 2022;32(Suppl 3):11.
  30. Lopez GH, Buhariwala KN, Condon JA, et al. KHOZ (KEL41): a novel low-prevalence antigen in the Kell blood group system antithetical to KHIZ (KEL40). Transfusion. 2025;65:E25–7.
  31. Karamatic-Crew V, Poole J, Watson T, Bullock T, Burton N, Daniels G. KASH (KEL34): a novel high incidence antigen in the Kell blood group system. Vox Sang 2010;99(Suppl 1):357.
  32. Karamatic-Crew V, Poole J, Bullock T, Malde R, Burton N, Daniels G. Abstracts - PO11: KELP (KEL35): a new high incidence antigen in the Kell blood group system defined by two homozygous missense mutations in KEL. Transfus Med 2010;20(Suppl 1):30.
  33. Karamatic-Crew V, Poole J, Bullock T, Regan P, Burton N, Daniels G. KETI, a novel high incidence antigen in the Kell blood group system: a serological and molecular study. Vox Sang 2011;101(Suppl 1):19.
  34. Reid ME, Lomas-Francis C, Olsson ML. The blood group antigen factsbook: Kell blood group system. 3rd ed. Academic Press, San Diego, CA, 2012.
  35. Allen FH Jr, Lewis SJ, Fudenberg H. Studies of anti-Kpb, a new antibody in the Kell blood group system. Vox Sang 1958;3: 1–13.
  36. Giollo M, Minervini G, Scalzotto M, Leonardi E, Ferrari C, Tosatto SC. BOOGIE: predicting blood groups from high throughput sequencing data. PLoS One. 2015;10:e0124579.
  37. Möller M, Jöud M, Storry JR, Olsson ML. Erythrogene: a database for in-depth analysis of the extensive variation in 36 blood group systems in the 1000 Genomes Project. Blood Adv 2016;1:240–9.
  38. Schoeman EM, Lopez GH, McGowan EC, et al. Evaluation of targeted exome sequencing for 28 protein-based blood group systems, including the homologous gene systems, for blood group genotyping. Transfusion 2017;57:1078–88.
  39. Lane WJ, Vege S, Mah HH, et al. Automated typing of red blood cell and platelet antigens from whole exome sequences. Transfusion 2019;59:3253–63.
  40. 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.
  41. Matosinho CGR, Silva CGR, Martins ML, Silva-Malta MCF. Next generation sequencing of red blood cell antigens in transfusion medicine: systematic review and meta-analysis. Transfus Med Rev 2024;38:150776.
  42. Redman CM, Lee S. A historical perspective on the discovery of the Kell blood group carriers. Transfusion 2013;53(11 Suppl 2):2831–3.
  43. Scharberg EA, Wieckhusen C, Luz B, et al. Fatal hemolytic disease of the newborn caused by an antibody to KEAL, a new low-prevalence Kell blood group antigen. Transfusion 2017;57:217–8.
  44. Lomas-Francis C, Vege S, Velliquette RW, et al. Expansion of the Kell blood group system: two new high-prevalence antigens and two novel K0 (Kell null ) phenotypes. Transfusion 2013;53(11 Suppl 2):2887–91.
  45. Deleers M, Guizani M, Jani J, Hulot M, El Kenz H. A case of severe foetal anaemia due to anti-Kell that could not be detected by the weekly assessment of middle cerebral artery peak systolic velocity. Transfus Apher Sci 2018;57:111–3.
  46. Savoia HF, Parakh A, Kane SC. How I manage pregnant patients who are alloimmunized to RBC antigens. Blood 2025;145:2275–82.
  47. Tormey CA, Stack G. Immunogenicity of blood group antigens: a mathematical model corrected for antibody evanescence with exclusion of naturally occurring and pregnancy-related antibodies. Blood 2009;114:4279–82.
  48. Pelc-Kłopotowska M, Płoski R, Szczałuba K, et al. A novel KEL c.1414-1G>T allele in a polish patient with anti-Ku antibody. Transfusion 2022;62:E43–4.
  49. Denomme GA, Anani WQ. Mass-scale red cell genotyping of blood donors: from data visualization to historical antigen labeling and donor recruitment. Transfusion 2019;59:2768–
  50. Moncharmont P, Barday G, Benamara H. Low incidence of post-transfusion Kell (KEL1) alloimmunisation in patients under 50 years old. Transfus Med 2020;30:70–2.
  51. Philips C, Scholes T. Making every unit count: the Kell conundrum. Transfus Med 2019;29(Suppl 2):35.
  52. Vaughan JI, Warwick R, Letsky E, Nicolini U, Rodeck CH, Fisk NM. Erythropoietic suppression in fetal anemia because of Kell alloimmunization. Am J Obstet Gynecol 1994;171:247–52.
  53. Vaughan JI, Manning M, Warwick RM, Letsky EA, Murray NA, Roberts IA. Inhibition of erythroid progenitor cells by anti-Kell antibodies in fetal alloimmune anemia. N Engl J Med 1998;338:798–803.
  54. Daniels G, Hadley A, Green CA. Causes of fetal anemia in hemolytic disease due to anti-K. Transfusion 2003;43:115–6.
  55. Jacobs JW, Sugrue RP, Federspiel JJ, et al. The utility of a critical antibody titer in anti-K alloimmunized pregnancies: a systematic review and meta-analysis of diagnostic test accuracy. Transfus Med Rev 2025;39:150895.
  56. Alshehri AA, Jackson DE. Non-invasive prenatal fetal blood group genotype and its application in the management of hemolytic disease of fetus and newborn: systematic review and meta-analysis. Transfus Med Rev 2021;35:85–94.
  57. Slootweg YM, Lindenburg IT, Koelewijn JM, Van Kamp IL, Oepkes D, De Haas M. Predicting anti-Kell-mediated hemolytic disease of the fetus and newborn: diagnostic accuracy of laboratory management. Am J Obstet Gynecol 2018;219:393. e391–3.e398.
  58. Ohto H, Denomme GA, Ito S, Ishida A, Nollet KE, Yasuda H. Three non-classical mechanisms for anemic disease of the fetus and newborn, based on maternal anti-Kell, anti-Ge3, anti-M, and anti-Jr(a) cases. Transfus Apher Sci 2020;59:102949.
  59. Lee E, De Silva M. Unlike anti-C, anti-K in pregnancy is more likely to have been induced by previous transfusion; this can be prevented. Transfusion 2004;44(Suppl):104A.
  60. Royal Australian and New Zealand College of Obstetricians and Gynaecologists. The management of women with red cell antibodies during pregnancy (green-top guideline no. 65). Available from https://ranzcog.edu.au/wp-content/uploads/RCOG-Red-Cell-Antibodies-During-Pregnancy.pdf. Accessed 7 February 2025.
  61. O’Brien H, Hyland C, Schoeman E, Flower R, Daly J, Gardener G. Non-invasive prenatal testing (NIPT) for fetal Kell, Duffy and Rh blood group antigen prediction in alloimmunised pregnant women: power of droplet digital PCR. Br J Haematol 2020;189:e90–4.
  62. Australian Red Cross Lifeblood. Fetal blood group testing: NIPA for clinically significant fetal blood group antigens. Available from https://www.lifeblood.com.au/health-professionals/red-cell-reference/fetal-blood-group-testing. Accessed 1 March 2025.
  63. Finning K, Martin P, Summers J, Daniels G. Fetal genotyping for the K (Kell) and Rh C, c, and E blood groups on cell-free fetal DNA in maternal plasma. Transfusion 2007;47:2126–33.
  64. Zaki-Dizaji M, Shafiee A, Kohandel Gargari O, Fathi H, Heidary Z. Maternal and fetal factors affecting cell-free fetal DNA (cffDNA) fraction: a systematic review. J Reprod Infertil 2023;24:219–31.
  65. Elsayed H, Ng M, Rutherford M, Gupta R. Bilateral cystic encephalomalacia follow ing multiple intrauterine transfusions for anti-Kell isoimmunisation. BMJ Case Rep 2015;2015:bcr2013202750.
  66. Phung TV, Houfflin-Debarge V, Ramdane N, et al. Maternal red blood cell alloimmunization requiring intrauterine transfusion: a comparative study on management and outcome depending on the type of antibody. Transfusion 2018;58:1199–205.
  67. Lydaki E, Nikoloudi I, Kaminopetros P, et al. Serial blood donations for intrauterine transfusions of severe hemolytic disease of the newborn with the use of recombinant erythropoietin in a pregnant woman alloimmunized with anti-Ku. Transfusion 2005;45:1791–5.
  68. Virk M, Papakonstantino K, Cai W, Oh D, Andrews J. Blood donation during pregnancy due to anti-Ku hemolytic disease of the fetus and newborn. Lab Med 2019;50:421–5.
  69. Mattaloni SM, Arnoni C, Céspedes R, et al. Clinical significance of an alloantibody against the Kell blood group glycoprotein. Transfus Med Hemother 2017;44:53–7.
  70. Vlachodimitropoulou E, Lo TK, Bambao C, et al. Intravenous immunoglobulin in the management of severe early onset red blood cell alloimmunisation. Br J Haematol 2023;200:100–6.
  71. Laurencin C, Sebbag L, Jousserand G, et al. Novel XK mutation in a McLeod patient diagnosed after heart transplant. Clin Neurol Neurosurg 2018;168:64–6.
  72. Wu PC, McGowan EC, Lee YQ, Ghosh S, Hansson J, Olsson ML. Epigenetic dissection of human blood group genes reveals regulatory elements and detailed characteristics of and four other loci. Transfusion 2024;64:1083–96.
  73. Fürst D, Tsamadou C, Neuchel C, Schrezenmeier H, Mytilineos J, Weinstock C. Next-generation sequencing technologies in blood group typing. Transfus Med Hemother 2020;47:4–13.
  74. Mayr G, Bublitz M, Steiert TA, et al. A structure-based in silico analysis of the Kell blood group system. Front Immunol 2024;15:1452637.
  75. De Franceschi L, Scardoni G, Tomelleri C, et al. Computational identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis. PLoS One 2012;7:e31015.
  76. Fikrig SM, Phillipp JC, Smithwick EM, Oyen R, Marsh WL. Chronic granulomatous disease and McLeod syndrome in a black child. Pediatrics 1980;66:403–4.
  77. Braun AA, Jung HH. Systematic review of phenotypes in McLeod syndrome and case report of a progressive supranuclear palsy in a female carrier. Orphanet J Rare Dis 2024;19:312.
  78. Walker RH, Barreto M, Bateman JR, et al. The protean presentations of XK disease (McLeod syndrome): a case series with new observations and updates on previously reported families. Front Neurosci 2024;18:1408105.
  79. Yu H, Li L, Li X, Liu H. Clinical features and novel pathogenic variants of Chinese patients with McLeod syndrome and choreaacanthocytosis. Mol Genet Genomic Med 2024;12: e70015.
  80. Blackstone WZ, Malaguit SE, Shwaish NS, Frandsen EL. Contiguous Xp21 deletion involving Duchenne muscular dystrophy and McLeod neuroacanthocytosis syndrome results in rapidly progressive and fatal cardiomyopathy. Cardiol Young 2025;35:358–60.
  81. Cloos AS, Ghodsi M, Stommen A, et al. Red blood cell lipid distribution in the pathophysiology and laboratory evaluation of chorea-acanthocytosis and McLeod syndrome patients. Front Physiol 2025;16:1543812.
  82. Fujimori K, Shimizu S, Ishikawa T, et al. Hematopoietic cell transplantation in a patient with X-linked chronic granulomatous disease with McLeod phenotype. Pediatr Transplant 2025;29:e70086.
  83. Roulis E, Hyland C, Flower R, Gassner C, Jung HH, Frey BM. Molecular basis and clinical overview of McLeod syndrome compared with other neuroacanthocy tosis syndromes: a review. JAMA Neurol 2018;75:1554–62.
  84. Dambietz CA, Doescher A, Heming M, et al. Case report: clinical, genetic and immunological characterization of a novel XK variant in a patient with McLeod syndrome. Front Genet 2024;15:1421952.
  85. Tian PC, Wang Y, Chen Z, Shi DD, Wang HL, Luo Q. The first case report of McLeod syndrome in an infant with a novel mutation (c.89C>A, p. Ser30X) in XK. Clin Neurol Neurosurg 2019;184:105421.
  86. Peikert K, Hermann A, Danek A. XK-associated McLeod syndrome: nonhematological manifestations and relation to VPS13A disease. Transfus Med Hemother 2022;49:4–12.
  87. Trakarnsanga K, Griffiths R, Wilson M, et al. An immortalized adult human erythroid line facilitates sustainable and scalable generation of functional red cells. Nature Commun 2017;8:1–5.
  88. Hawksworth J, Satchwell TJ, Meinders M, et al. Enhancement of red blood cell transfusion compatibility using CRISPR-mediated erythroblast gene editing. EMBO Mol Med 2018;10:e8454.
  89. An HH, Gagne AL, Maguire JA, et al. The use of pluripotent stem cells to generate diagnostic tools for transfusion medicine. Blood 2022;140:1723–34.
DOI: https://doi.org/10.2478/immunohematology-2025-014 | Journal eISSN: 1930-3955 | Journal ISSN: 0894-203X
Language: English
Page range: 90 - 99
Published on: Oct 31, 2025
Published by: American National Red Cross
In partnership with: Paradigm Publishing Services
Publication frequency: 4 issues per year
Keywords:

© 2025 Candice L. Davison, Gregory A. Denomme, published by American National Red Cross
This work is licensed under the Creative Commons License.