Rh-D Positive Variants
The blood group of an Individual is designated as its ABO and Rh-D status of that Individual. The ABO status of an individual depends on the presence or absence of A-antigen or B-antigen or both on the surface of Red Blood Cells. Similarly, the Positive and Negative blood group is decided by the D-antigen of the Rhesus (Rh) blood group, Although the Rh-blood group has four more antigens(C, c, E, e) besides D-antigens. Normally D-antigen can be confirmed by using commercial anti-D antisera. The presence of D-antigen is designated as D-Positive and absence is designated as Negative. For some Individuals D-antigens are altered due to mutation of genes or positioning of other Rh-antigens resulting in a decrease in the expression of D-antigens producing variants of Rh-D antigens. These variants are reacted variably with the commercial anti-D antisera. These are :
C in Trans to D
Weak D ( Dᵘ )
Partial-D or Mosaic-D
Del
C in Trans to D :
This type of variant is mostly due to the Positional effect. That means C-antigens are present in the opposite haplotype to the D-allele ( Dce / dCe). When C-antigen is inherited to the same haplotype then the position is called cis-variants (DCe/dce). The D-antigens are normal both genetically and structurally but expression of antigen is reduced due to the steric hindrance of C-antigen in relation to D-antigens. Serologically it can not be differentiated as the structurally D-antigen is complete. A molecular study is needed to differentiate the two variants. The individuals safely transfused the D-positive blood units without adverse effects.
Weak -D: ( Dᵘ)
The D-antigens expressed Completely with all epitopes but quantitative reduction of D-antigen. Individuals expressing weak variants of D-antigen had missense mutation(s) within the transmembrane or Cytoplasmic domain of Rh-D. There were several types of Weak-D variants. The quantitative reduction of D-antigen was noticed especially in Types 1,2 and 3, hence these individuals do not form anti-D in their sera. Recently, the International Society of Blood Transfusion (ISBT) has included a new variant " Weak-Partial variant" which describes the weak-D variant with qualitative changes in D-epitopes making them prone to anti-D formation. These include weak-D type 4.2, 11, 15, and 21 (McGOWEN EC et.al). The prevalence of serological weak -D prevalence worldwide has been estimated to range from 0 to 3% ( Sandler SG et.al). In India, the prevalence of weak D ranges from 0.0075 to 0.2% ( Gupta A et.al) in the total blood donor population in different geographical regions. A study by Fichou Y et.al found that Weak-D types 3, 8, and 25 are commonly seen in Indian Populations.
Weak-D is difficult to define serologically because a negative reaction with a particular monoclonal anti-sera or by a specific method could result due to weak expression of antigen rather than its absence. So all D-negative blood donors and D-negative mothers are needed to screen for weak-D testing by Indirect antiglobulin Testing (IAT) procedure using a blend of monoclonal IgM and IgG or Monoclonal IgM and Polyclonal (Human) IgG anti-D reagents. The IAT-positive blood donors are marked as D-positive and IAT-negative as D-negative. Genetic testing to detect D-variants using Polymerase Chain reaction (PCR) has a better sensitivity than serological methods. It has been common practice that weak-D individuals should be transfused with D-positive blood to conserve D-negative blood as weak-D variants do not form anti-D. Weak-D-positive mothers are not a candidate for Rh-immunoglobulin prophylaxis.
Reference :
1. McGowan, E.C., Lopez, G.H., Knauth, C.M., Liew, Y.-.-W., Condon, J.A., Ramadi, L., Parsons, K., Turner, E.M., Flower, R.L. and Hyland, C.A. (2017), Diverse and novel RHD variants in Australian blood donors with a weak D phenotype (https://pubmed.ncbi.nlm.nih.gov/28220510/)
2.Sandler, S.G., Chen, L.N. and Flegel, W.A. (2017), Serological weak D phenotypes: a review and guidance for interpreting the RhD blood type using the RHD genotype. Br J Haematol, 179: 10-19.https://doi.org/10.1111/bjh.14757
3.Fichou, Y., Parchure, D., Gogri, H., Gopalkrishnan, V., Le Maréchal, C., Chen, J.-M., Férec, C., Madkaikar, M., Ghosh, K. and Kulkarni, S. (2018), Molecular basis of weak D expression in the Indian population and report of a novel, predominant variant RHD allele. Transfusion, 58: 1540-1549. https://doi.org/10.1111/trf.14552
Partial / Mosaic -D:
In Partial D-type individuals, D-epitopes are missing or altered within RH-D protein. The D-antigen is not complete due to missing epitopes. Partial-D -D cause may be due to missense mutation affecting the exofacial protein segment or by the hybrid protein. Molecular genetics determine the partial -D types: DII, DIII, DIV, DV, DVI, DVII, DAU, DBT, DFR, DHMi, DHMii, DNB, DHAR (Rh33). Phenotypic changes due to missense mutation are limited, low alloimmunization risk, and difficult serological detection. DNB and DVII are the two most important partial-D types in these individuals. Hybrid genes result when a portion of the RHD gene is replaced by the RHCE gene: RHD-RHCE-RHD (Normally: RHD-RHCE). The incidence of Partial-D in the Indian population was 0.15% and the most common variant was DFR (Kulkarni, S. et.al).
Serological Characteristics: The serological detection by commercially used monoclonal anti-D can not define all the variants of partial-D. Some Partial-D antigens show weaker reactions and others show normal reactions. The anti-D are formed mostly with hybrid protein individuals and against the portion of the RH-D protein that is missing on exposure to normal Rh-D protein RBCs. The anti-D is an alloantibody and does not react with the patient's own cell.
Transfusion Protocol: The transfusion recipients should receive D-negative blood. Pregnant women with the DVI type of partial-D -D make anti-D but rarely cause a clinical problem in D-positive fetus (Lacey, P.A., et.al). So recommendations have been made to the administration of anti-D to partial-D (DVI and DNB) phenotype mothers following the birth of D-positive babies (Tippett et al.).
References:
1. Kulkarni, S., Colah, R., Gorakshakar, A., Gupte, S. and Mohanty, D. (2005), Molecular Characterization of Partial D Variants in India. Transfusion Medicine, 15: 69-82. https://doi.org/10.1111/j.1365-3148.2005.00554am.x
2.Rizzo C, Castiglia L, Arena E, Gangi S, Mazzola G, Caruso C, Vasto S. Weak D and partial D: our experience in daily activity. Blood Transfus. 2012 Apr;10(2):235-6. doi: 10.2450/2012.0060-11. Epub 2012Feb13.PMID:22337276;PMCID:PMC3320789.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320789/
3.Lacey, P.A., Caskey, C.R., Werner, D.J. and Moulds, J.J. (1983), Fatal hemolytic disease of a newborn due to anti-D in an Rh-positive Du variant mother. Transfusion, 23: 91-94. https://doi.org/10.1046/j.1537-2995.1983.23283172867.x
4.Tippett P, Lomas-Francis C, Wallace M. The Rh antigen D: partial D antigens and associated low incidence antigens. Vox Sang. 1996;70(3):123-31. doi: 10.1111/j.1423-0410.1996.tb01309.x. PMID: 8740002. https://pubmed.ncbi.nlm.nih.gov/8740002/
Del :
Del Phenotype is a D-positive variant in which D-antigen can be demonstrated only by the Adsorption-Elution methods with anti-D.This phenotype was first described by Okuba et.al in 1984. Molecular study showed that there was variability in mutation in Del phenotype alleles. These mutations are : Missense, Splice Site, hybrid structure, Frameshift,Premature termination codon. The most common Asian type was Del allele RHD*01EL.01 carrying substitution c.1227G>A. The high frequency of Del phenotype was observed in Japanese D-negative people compared to other Asian countries ( Okubo et.al). The frequency of Del phenotype was 0.079% among 0.27% of D-Negative populations. In contrast, the European population is 0.03% in Poland to 0.28% in Croatia. In India, the frequency of Del phenotype was observed 1.5% among D-Negative Individuals (Samir S et. al.). The prevalence of Del phenotypes in Han Chinese populations were 0.3-0.5% among 30% of D-negative phenotypes in native China and 32% those living in Taiwan.
Serological Characteristics: The Del phenotypes are mostly D-negative in routine serological testing as well as weak-D testing. Anti-D is unlikely in these individuals with RHD✶01EL.01 alleles. Some studies showed formation of anti-D occur in Del phenotype and most of the anti-D was observed in pregnant women (Kormoczi et al.) . The D-antigens can only be elicited by Adsorption and Elution methods.
Transfusion Protocol: Several studies reported the formation of D-alloimmunization when Del phenotype blood units transfused to D-negative phenotype individuals.
References:
1.https://aob.amegroups.org/article/view/7557/html#B151
2.Okubo Y, Yamaguchi H, Tomita T, Nagao N. A D variant, Del? Transfusion. 1984 Nov-Dec;24(6):542. doi:10.1046/j.1537-2995.1984.24685066827.x.PMID:6438843.https://pubmed.ncbi.nlm.nih.gov/6438843
3..https://www.sciencedirect.com/science/article/abs/pii/S1473050215000464
4..Gu J, Wang XD, Shao CP, Wang J, Sun AY, Huang LH, Pan ZL. Molecular basis of DEL phenotype in the Chinese population. BMC Med Genet. 2014 May 5;15:54. doi: 10.1186/1471-2350-15-54. PMID: 24884404; PMCID: PMC4024116.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024116/
5..Körmöczi GF, Gassner C, Shao CP, Uchikawa M, Legler TJ. A comprehensive analysis of DEL types: partial DEL individuals are prone to anti-D alloimmunization. Transfusion. 2005 Oct;45(10):1561-7. doi: 10.1111/j.1537-2995.2005.00584.x. PMID: 16181205.https://pubmed.ncbi.nlm.nih.gov/16181205/
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