Serological weak D phenotypes: a review and guidance for interpreting the RhD blood type using the RHD genotype

Abstract

Approximately 0·2-1% of routine RhD blood typings result in a "serological weak D phenotype." For more than 50 years, serological weak D phenotypes have been managed by policies to protect RhD-negative women of child-bearing potential from exposure to weak D antigens. Typically, blood donors with a serological weak D phenotype have been managed as RhD-positive, in contrast to transfusion recipients and pregnant women, who have been managed as RhD-negative. Most serological weak D phenotypes in Caucasians express molecularly defined weak D types 1, 2 or 3 and can be managed safely as RhD-positive, eliminating unnecessary injections of Rh immune globulin and conserving limited supplies of RhD-negative RBCs. If laboratories in the UK, Ireland and other European countries validated the use of potent anti-D reagents to result in weak D types 1, 2 and 3 typing initially as RhD-positive, such laboratory results would not require further testing. When serological weak D phenotypes are detected, laboratories should complete RhD testing by determining RHD genotypes (internally or by referral). Individuals with a serological weak D phenotype should be managed as RhD-positive or RhD-negative, according to their RHD genotype.

Keywords: RHD gene; RhD blood group; blood transfusion; partial D phenotype; serological weak D phenotype.

Figure 1

The D antigen in the red cell membrane. The RhD protein consists of 417 amino acids (circles). All amino acid positions involved in the known, molecularly-defined weak D types are marked: weak D type 1, 2 and 3 (red), weak D type 4 cluster (yellow) and the additional 11 weak D types (orange) of the original description by Wagner et al (1999). Many more amino acid substitutions have since been identified in one (grey) or several weak D types (blue) causing a serological weak D phenotype. Also, five rare subtypes of weak D type 1, 2 or 3 have been characterized that carry one additional amino acid substitution each (red ring). There are nine exon boundaries in the RHD cDNA (black bars), as reflected in the amino acid sequence (Flegel 2011). Amino acid no. 1 is lacking from the mature protein in the red cell membrane, and the arch depicts the Rh protein vestibule (modified from Flegel 2006).

Figure 2

Flow diagram for managing a laboratory result of a “serological weak D phenotype.” If the report of routine RhD typing is “RhD-negative,” the individual should be managed as RhD-negative; and if “RhD-positive,” the individual should be managed as RhD-positive. If the result of RhD typing is a “serological weak D phenotype,” the laboratory should retest the blood sample or refer it to a reference laboratory for RHD genotyping. If a weak D type 1, 2 or 3 is detected, the individual should be managed as RhD-negative. If a weak D type 1, 2 or 3 is detected, the individual can be managed safely as RhD-positive. (Reproduced from Sandler, S.G., Flegel, W.A., Westhoff, C.M., Denomme, G.A., Delaney, M., Keller, M.A., Johnson, S.T., Katz, L., Queenan, J.T., Vassallo, R.R. & Simon, C.D. (2015) It’s time to phase in RHD genotyping for patients with a serologic weak D phenotype. Transfusion, 55, 680–689, with permission of Wiley Periodicals, Inc.)