Weak D alleles express distinct phenotypes

Abstract

The weak D phenotype is caused by many different RHD alleles encoding aberrant RhD proteins, raising the possibility of distinct serologic phenotypes and of anti-D immunizations in weak D. We reported 6 new RHD alleles, D category III type IV, DIM, and the weak D types 4.1, 4.2.1, 4.2.2, and 17. The immunohematologic features of 18 weak D types were examined by agglutination and flow cytometry with more than 50 monoclonal anti-D. The agglutination patterns of the partial D phenotypes DIM, DIII type IV, and DIVtype III correlated well with the D epitope models, those of the weak D types showed no correlation. In flow cytometry, the weak D types displayed type-specific antigen densities between 70 and 4000 RhD antigens per cell and qualitatively distinct D antigens. A Rhesus D similarity index was devised to characterize the extent of qualitative changes in aberrant D antigens and discriminated normal D from all tested partial D, including D category III. In some rare weak D types, the extent of the alterations was comparable to that found in partial Ds that were prone to anti-D immunization. Four of 6 case reports with anti-D in weak D represented auto-anti-D. We concluded that, in contrast to previous assumptions, most weak D types, including prevalent ones, carry altered D antigens. These observations are suggestive of a clinically relevant potential for anti-D immunizations in some, but not in the prevalent weak D types, and were used to derive an improved transfusion strategy in weak D patients.

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

“…Patient and donor samples from the region of southern Denmark and the U.S. encountered over approximately 1 year (7‐12 months, respectively), with weaker than expected or discrepant D serologic typing were genotyped for RHD to determine if the patient could be treated as D+ or would be better treated as D– and to begin to estimate the overall impact of RHD genotyping on clinical practice. Individuals with weak D types 1, 2, and 3 can safely be treated as D+ and are more frequent in the Caucasian population 5,11,12,29,30 . In addition, although anti‐D has occasionally been reported, no clinically significant HDFN or transfusion reactions have been reported in individuals with other uncommon weak D types.…”

Insights intoanti‐Dformation in carriers ofRhDvariants through studies of3Dintraprotein interactions

“…We did not include the records of patients with RHD*weak partial D 4.0, as they have been discussed elsewhere, 24 or those of patients with RHD*weak D types 1, 2, and 3 and RHD*DAU0 alleles because of their high prevalence and the high likelihood of anti-D being autoantibodies. 5,27,43,51,68,70 Many patient records were not sufficiently detailed to establish whether the anti-D were alloantibodies or not, 6 but the available data were collected: direct antiglobulin test (DAT), autologous control, elution, autoadsorption results, other antibodies detected, patient transfusion and pregnancy history, and presence of sickle cell disease (SCD). A perfectly characterized alloanti-D 6 would be associated with negative results for autocontrol, DAT, elution, and autoadsorption, with both anti-LW 22 and anti-G excluded.…”

“…RHD*weak partial types 11, 15 and 21) have since been shown to be associated with anti-D formation. [3][4][5][6][7][8] It is unlikely that any single approach will ever be able to classify all RhD variants definitively. Assessments based on a combination of different elements are, therefore, the best solution.…”

“…However, this approach is often inadequate, and several alleles initially thought to encode weak D antigens (e.g. RHD*weak partial types 11, 15 and 21 ) have since been shown to be associated with anti‐D formation 3–8 . It is unlikely that any single approach will ever be able to classify all RhD variants definitively.…”

Red cell genotyping precision medicine: a conference summary

“…Single-nucleotide polymorphisms in the RHD gene were known prior to the 1999 paper to occur in several partial D phenotypes [Avent et al 1996; Legler et al 1998], but the scale of mutations in RHD were laid bare by this landmark publication. We have over 150 defined weak D type alleles [Wagner et al 2014] and we are still gaining detailed knowledge of their clinical significance [Sandler et al 2015]; some are capable of eliciting anti-D when individuals are exposed to D-positive blood [Wagner et al 2000; Sandler et al 2015].…”