It's time to phase out “serologic weak D phenotype” and resolve D types with <i>RHD</i> genotyping including weak D type 4

Flegel, Willy A.; Denomme, Gregory A.; Queenan, John T.; Johnson, Susan T.; Keller, Margaret; Westhoff, Connie M.; Katz, Louis M.; Delaney, Meghan; Vassallo, Ralph R.; Simon, Clayton D.; Sandler, S. Gerald

doi:10.1111/trf.15741

Cited by 35 publications

(53 citation statements)

References 48 publications

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“…Anti‐D in patients with weak partial D 4.0 has been the subject of much discussion 44,45 . RHD*weak partial D 4.0 has an allele frequency of 0.02 to 0.049 in African Americans, 46,47 and although anti‐D has not been reported to be associated with weak D 4.0 in Europe, where the allele is uncommon, or in Tunisia where the allele is frequent, 48 anti‐D was identified in three of 16 children with sickle cell disease.…”

Section: Discussionmentioning

confidence: 99%

Impact of RHD genotyping on transfusion practice in Denmark and the United States and identification of novel RHD alleles

et al. 2020

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Background Reduced D antigen on red blood cells (RBCs) may be due to “partial” D phenotypes associated with loss of epitope(s) and risk for alloimmunization or “weak” D phenotypes that do not lack major epitopes with absence of clinical complications. Genotyping of samples with weak and discrepant D typing is recommended to guide transfusion and RhIG prophylaxis. The goal was to compare the impact of RHD genotyping on transfusion practice in two centers serving different populations. Study Design and Methods Fifty‐seven samples from Denmark and 353 from the United States with weak or discrepant D typing were genotyped. RBC typing was by multiple methods and reagents. DNA isolated from white blood cells was tested with RBC‐Ready Gene D weak or CDE in Denmark or RHD BeadChip in the United States. RHD was sequenced for those unresolved. Results Of Caucasian samples from Denmark, 90% (n = 51) had weak D types 1, 2, or 3; two had other weak D, two partial D, and two new alleles. In diverse ethnic U.S. samples, 44% (n = 155) had weak D types 1, 2, or 3 and 56% (n = 198) had other alleles: uncommon weak D (n = 13), weak 4.0 (n = 62), partial D (n = 107), no RHD (n = 9), and new alleles (n = 7). Conclusion Most samples with weak or variable D typing from Denmark had alleles without risk for anti‐D. In U.S. samples, 48% could safely be treated as D+, 18% may require consideration if pregnancy possible, and 34% could potentially benefit from being treated as D–. Black and multiracial ethnicities were overrepresented relative to population.

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Section: Discussionmentioning

confidence: 99%

Impact of RHD genotyping on transfusion practice in Denmark and the United States and identification of novel RHD alleles

et al. 2020

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“…6 In immunohematology, molecular typing has been increasingly used to complement, and even replace to some extent, serological testing. 7,8 An efficient diagnostic strategy consists typically in the genotyping of the most common alleles on a population-specific basis to guide physicians for transfusion practice, as well as for the management of pregnant women. To this aim, the global knowledge of the molecular determinants driving variant antigen expression, which are known to be populationdependent, is critical.…”

Section: Introductionmentioning

confidence: 99%

Nation‐wide investigation ofRHDvariants in Thai blood donors: Impact for molecular diagnostics

et al. 2020

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Background: Knowledge of the molecular determinants driving antigen expression is critical to design, optimize, and implement a genotyping approach on a population-specific basis. Although RHD gene variability has been extensively reported in Caucasians, Africans, and East-Asians, it remains to be explored in Southeast Asia. Thus the molecular basis of non-D+ blood donors was investigated in Thailand. Study Design and Methods: First, 1176 blood samples exhibiting an inconclusive or negative result by automated serological testing were collected in the 12 Regional Blood Centres of the Thai Red Cross located throughout Thailand. Second, the RHD gene was analyzed in all samples by 1) quantitative multiplex PCR of short fluorescent fragments, and 2) direct sequencing, when necessary, for identifying structural variants and single nucleotide variants, respectively. Results: Additional serological typing yielded 51 and 1125 samples with weak/partial D and D-negative (D-) phenotype, respectively. In the first subset, partial RHD*06.03 was the most common variant allele (allele frequency: 18.6%). In the second subset, the whole deletion of the gene is largely the most frequent (allele frequency: 84.9%), followed by the Asian DEL allele found in 15.6% of the samples. Eight novel alleles with various mutational mechanisms were identified. Conclusion: We report, for the first time at the national level, the molecular basis of weak/partial D and serologically D-phenotypes in Thai blood donors. The design and implementation of a dedicated diagnostic strategy in blood donors and patients are the very next steps for optimizing the management and supply of RBC units in Thailand.

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“…Compared to its high prevalence in individuals of North African descent, very few cases of anti-D production have been described for this variant, mostly not consistent with alloanti-D, 27,43,45 and autoadsorption studies are lacking. 2 Only a few alloanti-D have been described in patients with SCD. 44 No cases of hemolytic transfusion reaction or hemolytic disease of the newborn have been reported, and the risk of anti-D production and hemolytic complications seems to be low.…”

Section: Discussionmentioning

confidence: 99%

“…1 In current practice, weak D antigen expression is often considered to indicate the presence of an RhD variant, and molecular analysis is recommended for interpretation. 2 Hundreds of RHD alleles have been described. 3 For many of these RhD variants, the risk of anti-D formation is unknown and can, at best, be estimated by combining the available data: serological testing with monoclonal anti-D, prediction of the position of the substitution (extracellular or not), exposure of carriers to standard RhD through transfusion or pregnancy, and similarity with other RhD variants (with the same substitutions or substitutions affecting nearby residues).…”

Section: Introductionmentioning

confidence: 99%

“…Anti‐D alloimmunization can occur during transfusion or pregnancy and leads to hemolytic transfusion reactions or hemolytic disease of the newborn 1 . In current practice, weak D antigen expression is often considered to indicate the presence of an RhD variant, and molecular analysis is recommended for interpretation 2 . Hundreds of RHD alleles have been described 3 .…”

Section: Introductionmentioning

confidence: 99%

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Insights intoanti‐Dformation in carriers ofRhDvariants through studies of3Dintraprotein interactions

et al. 2021

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Background Many RhD variants associated with anti‐D formation (partial D) in carriers exposed to the conventional D antigen carry mutations affecting extracellular loop residues. Surprisingly, some carry mutations affecting transmembrane or intracellular domains, positions not thought likely to have a major impact on D epitopes. Study Design and Methods A wild‐type Rh trimer (RhD1RhAG2) was modeled by comparative modeling with the human RhCG structure. Taking trimer conformation, residue accessibility, and position relative to the lipid bilayer into account, we redefine the domains of the RhD protein. We generated models for RhD variants carrying one or two amino acid substitutions associated with anti‐D formation in published articles (25 variants) or abstracts (12 variants) and for RHD*weak D type 38. We determined the extracellular substitutions and compared the interactions of the variants with those of the standard RhD. Results The findings of the three‐dimensional (3D) analysis were correlated with anti‐D formation for 76% of RhD variants: 15 substitutions associated with anti‐D formation concerned extracellular residues, and structural differences in intraprotein interactions relative to standard RhD were observed in the others. We discuss the mechanisms by which D epitopes may be modified in variants in which the extracellular residues are identical to those of standard RhD and provide arguments for the benignity of p.T379M (RHD*DAU0) and p.G278D (RHD*weak D type 38) in transfusion medicine. Conclusion The study of RhD intraprotein interactions and the precise redefinition of residue accessibility provide insight into the mechanisms through which RhD point mutations may lead to anti‐D formation in carriers.

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It's time to phase out “serologic weak D phenotype” and resolve D types with RHD genotyping including weak D type 4

Cited by 35 publications

References 48 publications

Impact of RHD genotyping on transfusion practice in Denmark and the United States and identification of novel RHD alleles

Impact of RHD genotyping on transfusion practice in Denmark and the United States and identification of novel RHD alleles

Nation‐wide investigation ofRHDvariants in Thai blood donors: Impact for molecular diagnostics

Insights intoanti‐Dformation in carriers ofRhDvariants through studies of3Dintraprotein interactions

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