The above letter was also sent to Dr Flegel: Dr Flegel offered the following reply

Because of the work cited by Dr Kumpel,¹ the question posed in her letter, whether weak D RBCs are really immunogenic, can be answered with a “yes.” This answer had been disputed for many years,² and it is worth noting that this often academic dispute may abate now. Neither had it been equivocal nor is it surprising that the immunization index for weak D and DEL RBCs was confirmed to be much lower than for regular D+ RBCs.

Proof for primary immune responses in humans is often circumstantial, and multiple observations need to be collated before a conclusive answer may be given. Among the three anti-D immunizations attributed to weak D RBCs so far, two were reported as primary,^3,4 and Dr Kumpel conceded a primary immune response by at least one of them.⁴ One primary immunization is possible in the two DEL RBCs transfusion events researched,⁵ although final evidence is missing. The antigen density must not correlate well with the rate of immunization, because the patient’s immunologic response may be a factor whose characteristics we do not know.⁶

In any East Asian population, less than 3 percent are D− people, but among them approximately 15 to 30 percent carry the DEL phenotype encoded by the RHD(K409K) allele, which renders it the most frequent DEL variant worldwide. Very many DEL+ RBC transfusions must have occurred in D− recipients. I propose to refrain from any affirmative answer, that causing primary anti-D immunizations by weak D and DEL RBCs is “extremely unlikely,”¹ until more of these transfusion recipients will have been examined carefully.

Because up to one-third of the supposedly D− recipients in East Asia are actually DEL+, they are of course unlikely to become immunized by DEL+ blood. They might not even develop anti-D after exposure to regular D+ RBCs: Because of the sheer number of patients and of blood units involved, this topic could considerably affect—and might ease—transfusion practice in East Asian populations.

I concur with Dr Garratty’s balanced statements⁷ that we need to be more concerned about weak D antigens and that detection of the RHD gene or parts thereof does not always mean that D antigen will be expressed.^6,7 Molecular screening of donors for RHD would allow elimination of the indirect antiglobulin test for D antigen and, efficiently organized, must not be more expensive than the antiglobulin testing currently mandated in many countries. Neither should the estimation of cost and benefit be limited to weak D, DEL, and donors.⁸ Pregnant women carrying certain weak D types can be spared from receiving unnecessary RhIg shots, which could lower their overall healthcare bill. Donors with D chimerism would also be detected who are prone to cause primary immunizations with any of their RBCs units.⁶

Dr Brooks concluded in a recent AABB Administrative Think Tank report⁹ that for whatever incremental margin of safety we might be able to squeeze out of further testing, the costs will be disproportionately high. This statement referred to testing including NAT of the currently known infectious diseases, and who would disagree? Molecular testing of blood groups has not been implemented in earnest at most of our institutions. Lessons from other industries should let us ponder the possibility that a good deal of safety could be attained at low incremental cost for quite some time to come.

The stipulation in the British guidelines cited by Dr Kumpel¹ testifies the older serologists’ prudence, who mandated very useful surrogate markers long before the molecular bases could be anticipated. Perhaps they realized the importance of weak D, the perception of which has since been withered away. Current knowledge will enable us to drop the use of these surrogate markers and to base the transfusion strategy on the established clinical relevance of distinct alleles. Some, but not all, alleles lack such relevance;^6,7 only these alleles may be disregarded safely and specifically. The decision to label or utilize RBC units as D+ or D− must not rely on surrogate markers and on arbitrary serologic cutoffs anymore that have hitherto been subject to, for instance, idiosyncrasies of monoclonal anti-D.

Blood group genotyping may equip transfusion medicine to provide individualized medication at reasonable cost: we should seize this opportunity.