In my July post, “Blood Bank Case Study: What’s Your Type?” I discussed some of the dilemmas when dealing with a weak D phenotype and the fact that there is no standard or general consensus as to the testing performed or terminology to be used in resulting a weak D patient. Results obtained on patient testing also vary depending on the method used, and the anti-D reagent and enhancement used in testing. This can be confusing to medical technologists, physicians and to patients.
For anyone who has not been in the Blood bank for a while, the Du variant was first recognized in 1946 and renamed weak D in 1992. To review last month’s blog, serologic studies have distinguished three broad categories of D variants, weak D, partial D, and DEL, from conventional D. A serologic weak D phenotype is one that has no or weak reactivity (≤2+) of RBCs with an anti‐D reagent at immediate spin, but does agglutinate with antihuman globulin. Since there is no general consensus on how labs perform and report patient testing for weak D, it is left up to individual interpretation as to what type blood these patients should receive, and, if pregnant, if they should receive Rh D immune globulin (Rhogam). Last month I focused on testing, resulting, donors and blood administration. In this blog I will focus on issues concerning weak D in the obstetric population and how labs can move forward now and in the future towards the best patient care and blood management.
About 15% of Caucasians are RhD negative. About 3% are weak D phenotypes.In the genral population, this means that about 0.2% to 1.0% inherit RHD genes that code for serologic weak D phenotypes.2 In Europe and the US, weak D phenotypes are the most common D variants found, but we also know that the prevalence of weak D phenotypes varies by race and ethnicity. Today we have much more information about D antigen expression than we had in the past, because we have the availability to genotype these weak D RBCs. We know that more than 84 weak D types have been identified, but types 1, 2, and 3 account for more than 90% of these in people of European ethnicity.1 Currently, with the mixed ethnicity population in the US, about 80% of people who inherit RHD genes for serologic weak D phenotypes are found to be weak D type 1, 2, or 3.3 We also know that types 1, 2 and 3 are unlikely to become alloimmunized to anti-D, so they can safely be treated as RhD positive and receive RhD positive units.
The introduction of RhD immune globulin in 1968 is one of the great success stories in obstetrics. Rhogam has been used very successfully in developed countries in the prevention and treatment of hemolytic disease of the fetus and newborn due to RhD alloimmunization. The routine recommendation is that women who are candidates for Rhogam receive one dose at approximately 28 weeks’ gestation and a second dose after the delivery of an Rh pos baby. Additional recommendations are for administration of Rhogam after threatened miscarriage, abdominal trauma during pregnancy and before invasive diagnostic procedures.
But, who is a candidate? Any unsensitized woman who is RhD negative and who may be carrying or who delivers an RhD positive baby is a candidate for Rhogam. And, that brings us back to the problem that we have no standardization for the reporting of serological weak D phenotypes.
As an example, let’s look at a patient who has 3 children. Many labs do not do weak D testing on patients and report anyone who is RhD negative at immediate spin as RhD negative. This patient was typed at such a lab (Lab #1) as RhD negative, and received Rhogam for her first pregnancy. During her 2nd pregnancy, she had moved to a different state, and went to another lab (Lab #2) for prenatal testing. This lab performed serologic weak D testing and found this patient to be weak D positive and reported her type as RhD positive. Rhogam was not further discussed during this pregnancy and the patient did not receive Rhogam. The patient had blood drawn during her 3rd pregnancy at yet a third hospital (Lab #3). Some labs distinguish women who are pregnant or of childbearing age from the general population, and have different procedures on the reporting of RhD type on these women. This hospital’s procedure was to do weak D testing on all patients, but, in women of childbearing age, if weak D positive, they report these women as RhD negative. The patient was told she was RhD negative and would be a candidate for Rhogam. At this time the woman thought she remembered that she didn’t get Rhogam with her second pregnancy and was a little confused, but with 2 young children and pregnant with her 3rd, she simply followed the doctor’s recommendation and didn’t question further. When her 3rd child was 4 months old, she attended a Red Cross blood drive at work and donated a unit of blood. Soon she received a blood donor card in the mail that said she was RhD positive. At this point she was thoroughly confused and questioned all the lab results she had had done over the past 6 years. On her next visit to the doctor she questioned her obstetrician. The obstetrician recommended RhD genotyping. The woman was found to be weak D type 2. The doctor explained to her that all blood donors who are weak D are treated as RhD positive, but, that as a patient, policies and procedures vary. However, he also informed her that now that they had her genotype, she would be considered RhD positive. He explained that the genotype was DNA testing, would not need to be repeated, she would not need Rhogam for any future pregnancies and she could safely receive RhD positive blood products.
The American College of Obstetricians and Gynecologists (ACOG) guidance practice bulletin of 1981 recommended that recommended that RhD‐negative women “whether Du positive or Du negative” were candidates for Rhogam. Shortly afterwards, that recommendation was reversed and revised to read “[a] woman who is genetically Du‐positive is Rh‐positive and administration of Rh immune globulin is unnecessary.1 This remained the recommendation of the group until the latest version of this publication in 2017. The 2017 ACOG guidelines recommend giving Rhogam to weak D positive patients, “in appropriate clinical situations, until further studies are available.”3 Another comparative study published in 2018 reported inconsistency between national groups over how to treat weak D phenotypes and recommended the creation of international guidelines.4
Thus, the controversy over whether a pregnant woman who is weak D positive is RHD positive or RHD negative continues. The latest recommendations, and those of ACOG, are for a move to genotyping patients with a serological weak D phenotype. There are several benefits to this. As we can see from my case study example, genotyping put this woman at ease and gave her definitive answers about her blood type. It also can do the same thing for medical technologists and physicians. RHD genotyping only needs to be performed once on a patient. If performed at the first prenatal appointment, this would alleviate much confusion as to procedures and how to report the results. I have in blood bank, that whenever we have a weak D on a prenatal patient, there are questions about how to result them, and we refer to the SOPs. We also occasionally get a patient who had previously been typed elsewhere where the reporting procedures were different and there is therefore an apparent discrepancy between the current and historical typing. This causes frequent phone calls from physicians and nurses asking for clarifications on weak D types, and questions about Rhogam. Lastly, RHD genotyping could avoid confusion which could lead to transcription and computer entry errors when entering types on these patients. RHD genotyping would solve all of these problems and eliminate confusion.
Additional benefits of RHD genotyping are, if RHD genotyping was performed on all weak D transfusion recipients, we could save as many as 47,700 units of RHD negative RBCs annually.3 With the availabilityof molecular testing, there is no reason to administer RhD negative units to patients who can use RhD positive units. This could help alleviate the constant shortage of RHD negative units. With RHD molecular testing, these critical units could be reserved for patients who are truly RhD negative.
It may not be feasible for all laboratories to perform molecular testing for RHD genotypes, but reference laboratories should offer affordable testing for the most prevalent and clinically relevant RHD genotypes. From a study done of over 3100 laboratories, it was found that, at this time in the US, most labs are managing weak D phenotypes as RhD negative. Laboratories not performing weak D testing are essentially avoiding their detection. Clinical laboratories should instead increase the detection of serological weak D and interpret these with the use of RHD genotyping. Rhogam shortages exists, and RHD genotyping could save thousands of injections of Rhogam annually in the US alone, and at the same time, avoid the unnecessary administration of products to patients. The work group study calculated that annually, approximately 24,700 doses of unnecessary Rhogam could be avoided.1 It is time to move forwards to molecular testing for the best patient care and blood management.
- Sandler SG, Flegel, WA, Westhoff CM, et al. It’s time to phase in RHD genotyping for patients with a serologic weak D phenotype. Transfusion 2015;55:680‐9
- Garratty G. Do we need to be more concerned about weak D antigens? Transfusion 2005;45:1547‐1551.
- Practice Bulletin No. 181: Prevention of Rh D AlloimmunizationObstetrics & Gynecology: August 2017 – Volume 130 – Issue 2 – p e57-e70 doi: 10.1097/AOG.0000000000002232
- Sperling, JD et al. Prevention of RhD Alloimmunization: A Comparison of Four National Guidelines. Am J Perinatol. 35(2):110-119. doi: 10.1055/s-0037-1606609. Epub 2017 Sep 14.
-Becky Socha, MS, MLS(ASCP)CM BB CM graduated from Merrimack College in N. Andover, Massachusetts with a BS in Medical Technology and completed her MS in Clinical Laboratory Sciences at the University of Massachusetts, Lowell. She has worked as a Medical Technologist for over 30 years. She’s worked in all areas of the clinical laboratory, but has a special interest in Hematology and Blood Banking. When she’s not busy being a mad scientist, she can be found outside riding her bicycle.