Mother O Blood Type Baby a Blood Type Weak D

Br J Haematol. Author manuscript; bachelor in PMC 2018 Oct 1.

Published in last edited class as:

PMCID: PMC5612847

NIHMSID: NIHMS870563

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

Due south. Gerald Sandler

^aneDepartment of Pathology and Laboratory Medicine, MedStar Georgetown University Infirmary, Washington, DC

Leonard Chen

^oneDepartment of Pathology and Laboratory Medicine, MedStar Georgetown University Hospital, Washington, DC

Willy A. Flegel

²Department of Transfusion Medicine, NIH Clinical Center, National Institutes of Wellness, Bethesda, MD, United states

Summary

Approximately 0.two% to 1% of routine RhD blood typings result in a "serological weak D phenotype." For more than than 50 years, serological weak D phenotypes take 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 every bit RhD-positive, in contrast to transfusion recipients and pregnant women, who take been managed equally RhD-negative. Most serological weak D phenotypes in Caucasians limited molecularly divers weak D types ane, two or 3 and can be managed safely as RhD-positive, eliminating unnecessary injections of Rh allowed globulin and conserving limited supplies of RhD-negative RBCs. If laboratories in the UK, Ireland and other European countries validated the utilize of potent anti-D reagents to outcome in weak D types 1, ii and iii typing initially as RhD-positive, such laboratory results would non crave further testing. When serological weak D phenotypes are detected, laboratories should consummate RhD testing past 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: Serological weak D phenotype, fractional D phenotype, RhD blood group, RHD gene, blood transfusion

Since the identification of the Rh factor more vii decades ago (Levine & Stetson, 1939; Landsteiner & Weiner, 1940), recipients of blood transfusions and blood donors have been categorized as either RhD-positive (D+ ruddy blood cells [RBCs]) or RhD-negative (D- RBCs). In 1946, the first D variant antigen was reported, that is, RBCs that did not agglutinate when RhD typed by certain anti-D sera, just did agglutinate when typed with other anti-D sera (Stratton, 1946). Stratton named these D variants D^U. Subsequently, case reports revealed that some women with a D^U phenotype who had been exposed to D+ RBCs past transfusion or pregnancy formed anti-D (Argall et al, 1953; Simmons &Krieger, 1960; Ostgard et al, 1986; Mayne et al, 1991; Domen & Hoetge, 1997). Additional pregnancies were reported that were complicated past RhD haemolytic disease of the fetus and newborn (Colina et al, 1974; White et al, 1983; Lacey et al, 1983; Cannon et al, 2003). To protect RhD-negative women from exposure to the D antigen and forming anti-D (RhD alloimmunization) by transfusion of RBCs from a donor with a D^U variant antigen, policies were developed in the United States requiring RBCs from blood donors who tested initially negative by anti-D to exist retested with anti-human globulin (a "weak D examination") (Scientific Committee of the Joint Blood Quango & Standards Committee of the American Clan of Blood Banks, 1958). If RBCs agglutinated later on addition of antihuman globulin to anti-D typing, the RBCs were interpreted to be D+. If RBCs did not agglutinate afterwards addition of anti-homo globulin, they were interpreted to be D−. Of the five Blood Establishments in the Uk and Ireland, only the Northern Ireland Blood Transfusion Service uses a weak D exam for blood donors. The Irish Blood Transfusion Service does perform a weak D examination on RhD-negative blood donors who are C+/Eastward+. In the U.s., a weak D test was not required for pregnant women or transfusion recipients. If RBCs from a significant woman or transfusion recipient typed negative past initial anti-D testing and a weak D examination was not performed, the individual's RhD type was interpreted to be RhD-negative to ensure that the private was not inadvertently exposed to D+ or D variant RBCs. In recent years, molecular laboratory methods have been developed that dissever D variant antigens into 3 groups, namely, molecularly defined weak D phenotypes, fractional D phenotypes and DEL phenotypes. The following review is intended as a guide for managing blood transfusions and Rh immunoprophylaxis for significant women whose RhD type has been reported by the laboratory as a serological weak D phenotype. Our intent is to review the molecular scientific discipline determining D variant RBC antigens and to provide guidance for managing patients with a serological weak D phenotype based on the individual's RHD genotype.

Clinical importance of the RhD blood grouping antigen

From a clinical perspective, the Rh claret group system is the about important of the 36 blood grouping systems (Storry et al, 2016) afterwards ABO. Among the 54 blood group antigens in the Rh organisation, the RhD antigen is the virtually immunogenic and important in clinical practise (Gunson, et al, 1976; Urbaniak & Robertson, 1981; Storry et al, 2014). The consequence of an RhD-negative adult female forming anti-D is that any subsequent pregnancy involving an RhD-positive fetus is at hazard for morbidity and bloodshed associated with Rh haemolytic illness of the fetus and newborn. The effect of any RhD-negative individual forming anti-D is that the selection of transfusing D+ RBCs in an emergency is eliminated and there is now an absolute lifetime requirement for transfusing only D- RBCs.

Report of the first D variant antigen (D^U) and subsequent changes in terminology

Stratton (1946) reported that RBCs from a blood donor at the Manchester Majestic Infirmary failed to agglutinate with 20 anti-D sera, simply agglutinated variably with 12 other anti-D sera. Stratton determined that the donor had inherited a D variant antigen from his father, equally did his two brothers. He reported the D variant as a "new Rh allelomorph" and named it "D^U." As more sensitive RhD typing methods were adult, it became apparent that an individual's RBCs that typed as D^U by a relatively insensitive transmission tube method may be typed as a straightforward D+ (RhD-positive) if retested by a potent monoclonal anti-D reagent, or past a more sensitive manual or an automated RhD typing method (Agre et al, 1992).

In 1992, Ortho Diagnostics (Raritan, NJ) convened a meeting of immunohaematologists to consider the impact of these more sensitive RhD typing methods on the terminology for D^u RBCs. The participants cited "D negative," "D^U positive," "Rh negative, D^U positive," "D negative, D^U positive," "D^U phenotype," "Rh positive D^U" and others as examples of different names used to describe a serological weak D phenotype. The outcome of the meeting was a Letter to the Editor of Transfusion, recommending elimination of the term D^U and "wider utilize of the designation 'weak D' for all weak expressions of the D antigen [to] eliminate much of the defoliation caused by inconsistent and sometimes erroneous terminology" (Agre et al, 1992). Inside a decade, new laboratory methods were developed capable of determining RHD genotypes that were expressed as a serological weak D phenotype (Flegel et al, 1998; Wagner et al, 1999). Molecular scientists began to study RHD genotypes as "weak D type i," "weak D type 2," and so forth, introducing terminology for RHD genotyping that could be confused easily with the "weak D" designation intended by Agre et al (1992) for serologically-adamant weak expression of the D antigen.

In 2015, the AABB (formerly, American Association of Blood Banks) and the College of American Pathologists (CAP) convened a Piece of work Group on RHD Genotyping and charged it with developing recommendations to clarify clinical issues related to RhD typing (Sandler et al, 2015). The Work Group published its recommendations using the term "serologic weak D phenotype" to distinguish the effect of serological weak D testing using anti-homo globulin in clinical laboratories versus the results of RHD genotyping for weak D types based on molecular methods.

A laboratory report of a serological weak D phenotype reflects sensitivity of the laboratory's method, too as the molecular basis for the weak D antigen

In the United States, a serological weak D phenotype is normally defined every bit reactivity of RBCs with an anti-D reagent giving no or weak (≤2+) reactivity in initial testing, but agglutinating moderately or strongly with anti-human globulin (a weak D test) (Jenkins et al, 2005; Daniels, 2013; Sandler et al, 2015). In Europe, such a "weak D test" is oft understood to exist what a reference laboratory does to resolve equivocal serological reactivity, whether past serological or molecular methods. Grading a serological reaction every bit ≤two+ is often subjective and at that place is a lack of consensus for the definition. In the UK and Republic of ireland, about clinical laboratories use potent anti-D reagents and few utilize indirect antiglobulin-reactive anti-D reagents. Any serological reaction of ≤ 2+ is likely to be referred to a Cherry Cell Immunohaematology (RCI) Laboratory. Typically, RCI Laboratories employ the Caliber Advanced Partial RhD Typing Kit (Quotient/Alba Bioscience Limited, Edinburgh, Scotland), comprising of 12 ten IgG anti-D reagents, to place serological weak D phenotypes. RCI Laboratories in the UK practise not currently perform RHD genotyping for these patients' samples. In Republic of ireland, RHD genotyping for serological weak D phenotypes commenced in 2016. The observed prevalence of serological weak D phenotypes increases when the laboratory method of detection is relatively insensitive, for example, manual tube testing. In this state of affairs, the showtime phase of anti-D detection may be too insensitive to agglutinate RBCs with a D variant antigen, just the RBCs will be agglutinated by the second weak D test phase and, therefore, the sample is interpreted to be a serological weak D phenotype. In contrast, the observed prevalence of serological weak D phenotypes decreases when the method of detection is more than sensitive, for example, an automated gel cavalcade or solid-phase analyser using a blend of potent recombinant monoclonal anti-D reagents. In this situation, the highly sensitive first phase of D antigen testing by anti-D volition agglutinate RBCs expressing a weak D antigen and the sample is interpreted to exist a conventional RhD-positive. Thus, a blood sample from a patient or claret donor with a weak D variant antigen may exist interpreted to exist RhD-positive when tested by a laboratory using a sensitive RhD typing method. However, the same sample may be interpreted to express a serological weak D phenotype if tested past the same or a unlike laboratory using a less stiff anti-D reagent. The prevalence of serological weak D phenotypes besides varies by race and ethnicity (Tabular array I). An estimated 0.2 – 1.0% of Caucasians inherit an RHD genotype that codes for a serological weak D phenotype (Garratty, 2005). In North London, the prevalence of weak D phenotypes was estimated to be 0.three% for white and 1.7% for black blood donors (Contreras & Knight, 1991).

Tabular array I

Prevalence of serological weak D phenotypes in different populations and by different laboratory methods

Population	n	Prevalence	Method	Reference
Donors (France)	203,240	0.56%	Groupamatic	Garretta et al, (1974)
Donors (The states)	23,000	3.0%	Transmission tube	Stroup Walters, (1988)
Donors (D-C+ and/or E+) (England)	16,484	0.3%	Groupamatic	Contreras & Knight, (1989)
Donors (D-C−Eastward−) (England)	xv,000	0.0%	Groupamatic	Contreras & Knight, (1989)
Donors (Netherlands)	13,500	0.23%	Transmission tube	Van Rhenen et al, (1989)
Patients (D−) (Canada)	5,672	0.96%	Transmission tube	Denomme et al, (2005)
Donors (U.s.)	one,005	0.iv%	Olympus PK7200	Jenkins et al, (2005)
Prenatal (United States)	501	2.two%	Transmission tube	Wang et al, (2010)
Pregnant women (Croatia)	102,982	0.47%	Manual tube Monoclonal anti-D	Lukacevic Krstic et al, (2016)

A serological weak D phenotype is the expression of an amino acid substitution in the RhD poly peptide or an RHD-RHCE-D gene conversion causing a D variant antigen

The molecular ground for a serological weak D phenotype tin can exist determined by retesting the claret sample past one of several molecular methods to identify the underlying mutation or recombination (Monteiro et al, 2011; Tilley & Grimsley, 2014). The most common D variant antigen identified when a serological weak D phenotype is detected in a Caucasian is a molecularly defined weak D type. Less commonly, a serological weak D phenotype is associated with a fractional D phenotype, which is a D variant most oftentimes expressed as D+, simply may occasionally present equally a serological weak D phenotype. A third category of D variants, DEL phenotypes, is included in this review for the purpose of a comprehensive overview of D variants, simply the expression of the D antigen in DEL phenotypes is too weak to be detected equally a serological weak D phenotype. Molecular studies of D antigens in different populations reveal a pregnant number of D variant alleles amidst individuals who blazon equally RhD-negative by routine serological methods. A written report of 33,864 hospital patients in Toronto, Canada revealed that at to the lowest degree 0.96% of RhD-negative patients expressed an RHD variant allele (Denomme et al, 2005). A study of 37,782 RhD-negative meaning Dutch women detected 0.96% with a D variant allele (Stegmann et al, 2016). The prevalences of RHD alleles in studies conducted among RhD-negative donors in Europe, E Asia, South America and North Africa are summarized in a review (Denomme, 2013).

Weak D types

A molecularly divers weak D type is a variant of the RhD protein with an amino acrid exchange in the trans-membranous or intracellular segment and expresses a decreased quantity of D antigen (Wagner et al, 1999; Flegel et al, 2007) (Figure i). Most serological weak D phenotypes (>95% in Northern Europeans) are the expression of weak D types 1, ii, 3 or 4.0/4.i (Flegel, 2011). To engagement, 147 weak D types take been listed on the Rhesus database (http://www.rhesusbase.info/) (Table II.)

The D antigen in the cherry 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 blazon one, 2 and 3 (blood-red), weak D type 4 cluster (yellow) and the additional eleven weak D types (orange) of the original clarification by Wagner et al (1999). Many more amino acrid substitutions have since been identified in i (grey) or several weak D types (blue) causing a serological weak D phenotype. Also, 5 rare subtypes of weak D type i, 2 or 3 take been characterized that carry one additional amino acid commutation each (cherry-red ring). In that location are 9 exon boundaries in the RHD cDNA (black bars), as reflected in the amino acrid sequence (Flegel 2011). Amino acrid no. one is lacking from the mature protein in the cerise cell membrane, and the arch depicts the Rh protein antechamber (modified from Flegel 2006).

Tabular array II

Interpreting results of RHD genotyping for clinical do

Weak D type	Prevalence among serological weak D phenotypes in diverse populations			Clinical practice per AABB-CAP Work Group*			Reference
	Caucasians	Africans	Asians	Recommendation	Anti-D reports	Evidence
Type 1, ii, iii	> 90%	rare	rare	RhD positive	no reports	strong	Wagner et al (2000); Flegel (2006)
Blazon 4.0, four.ane, four.3	< 2%	common	not reported	RhD negative	under investigation	precautionary	Wagner et al (2000); Polin et al (2007); Sandler et al (2015)
Type iv.2 (DAR)	rare	common	rare	RhD negative	many reports	stiff	Hemker et al (1999); Wagner et al (2000)
Type 11	< 1%	not reported	not reported	RhD negative	single report	precautionary	Flegel (2006)
Blazon 15	< 1%	not reported	mutual	RhD negative	single report	precautionary	Wagner et al (2000); Luettringhaus et al (2006)
Type 21	3 reports	non reported	not reported	RhD negative	single written report	precautionary	Müller et al (2001); Polin et al (2007); McGann & Wenk (2010)
Type 57	i report	non reported	non reported	RhD negative	single report	precautionary	Le Marechal et al (2007)
All other weak D types combined	< 5%	rare	rare	RhD negative	not reported	precautionary	Flegel (2006)

Partial D phenotypes

Partial D phenotypes were initially described as "blood factors" (Unger et al, 1959), then every bit "mosaics" (Tippett & Sanger, 1962; Wiener & Unger, 1962). Salmon et al (1984) introduced the term "partial D" (Issitt & Telen,1996). Molecular studies take determined that RBCs expressing a partial D phenotype have an amino acid substitution in at least one of the extracellular or RBC membrane surface loops (Wagner et al, 1999; Flegel et al, 2007) (Effigy i). Most RBCs express a fractional D phenotype as D+ by routine serological methods and are not detected every bit serological weak D phenotypes. They are not detected by routine RhD typing unless the individual has been exposed to D+ RBCs and formed anti-D (Westhoff, 2005). Occasionally, partial D RBCs have decreased expression of the D antigen and are detected equally a serological weak D phenotype by routine RhD typing (Westhoff, 2005; Stegmann et al, 2016). Approximately v – 10% of weak D phenotypes in the Us are estimated to be fractional D phenotypes (Garratty, 2005). There are 105 partial D types listed by the Rhesus database (http://www.rhesusbase.info/). Partial D types are also separated into D categories, of which DVI is the most common and about likely to be associated with germination of anti-D in Caucasian populations. The prevalence of DVI in South-western Germany amongst more than 70,000 blood donors was 0.02% (Wagner et al, 1995). In Southward-western England, 5.0% of blood donors classified equally D^u were constitute to take the category DVI phenotype (Leader et al, 1990). In the United States, monoclonal anti-D blood typing reagents are selected to avert detection of DVI RBCs (Wagner et al, 1995; Judd et al, 2005). The upshot is that transfusion recipients with a partial DVI phenotype, who would otherwise exist routinely typed as RhD-positive, volition be typed every bit RhD-negative. While this strategy protects DVI transfusion recipients from receiving transfusions of potentially immunogenic D+ RBCs, the exercise does not protect transfusions recipients with other partial D types from alloimmunization by transfusion of random (wild-type) D+ RBCs (von Zabern et al, 2013). For example, transfusion recipients who have inherited a DIV partial D phenotype are probable to be typed as RhD-positive and are at risk of alloimmunization by random D+ RBCs (von Zabern et al, 2013).

DEL phenotypes

DEL variant antigens (formerly, D_el ) express a D antigen that is also weak to exist detected by routine serological methods as D+ or equally a serological weak D phenotype. DEL variant antigens were first detected by adsorption of anti-D and elution (Okubo et al, 1984; Okubo et al, 1991). DEL variant RBCs from claret donors routinely blazon as D- (anti-D and weak D test negative), but transfusion of DEL variant RBCs to RhD-negative recipients has been reported to stimulate formation of anti-D (Yasuda et al, 2005; Kim et al, 2009; Shao, 2010; Yang et al, 2015). Transfusion recipients with a complete DEL phenotype and an RHD (1227G>A) allele (Asian-type DEL) are not at run a risk of forming anti-D following transfusion of D+ RBCs (Wang et al, 2014).

Pregnant women with a complete DEL phenotype who deliver an RhD-positive newborn are not at gamble for forming anti-D, but pregnant women with sure partial or hybrid DEL alleles are at risk for forming anti-D. At that place are significant differences in the prevalence of DEL phenotypes and the RHD (1227G>A) allele (Wagner et al, 2001) amidst RhD-negative individuals in different racial and ethnic populations. Less than 1% of Chinese Han are RhD-negative (Gu et al, 2014; Yang et al, 2007) and of these, as many equally xxx% express the DEL phenotype (Shao et al, 2002, Wagner et al, 2005). In Japanese, 0.5% are RhD-negative (Okubo et al, 1991) and 28% of these express a DEL phenotype (Fukumori et al, 1997). In Koreans, 0.xv% are RhD-negative and of these, 17% limited a DEL phenotype (Kim et al, 2005, Lüttringhaus et al, 2006). The prevalence of DEL phenotypes is significantly less in Caucasians, of whom approximately 15% are RhD- negative and just 0.1% of these limited a DEL phenotype (Flegel et al, 2009). Amid the iii – 5% of African Americans who are RhD-negative, in that location are no reports of DEL phenotypes (Daniels, 2002).

When are serological weak D phenotypes detected?

Near serological weak D phenotypes are detected when a pregnant adult female, potential transfusion recipient or blood donor has a blood sample routinely typed for RhD and the grade of RBC agglutination is weaker (≤2+) than expected for RhD typing using potent anti-D reagents (iii+ to 4+). Also, serological weak D phenotypes are detected when a clinical laboratory types a claret sample as D+, simply the laboratory's record of a prior RhD type is D−. The discrepancy may reverberate an mistake in patient or sample identification. Alternatively, the discrepancy may reverberate the increased potency of new monoclonal RhD typing reagents in the laboratory compared to previously used plasma-derived anti-D reagents that were less effective for detecting weakly expressed D variant antigens.

Applying RHD genotyping results in clinical practice

In the United States, the longstanding laboratory practice of non performing a weak D test for transfusion recipients and pregnant women – and/or managing serological weak D phenotypes as RhD-negative – has proven to be a prophylactic strategy in that it protects susceptible individuals from RhD alloimmunization and forming anti-D. Still, that practice results in unnecessary transfusion of difficult-to-obtain D- RBCs for many transfusion recipients and unnecessary injections of Rh immune globulin for many pregnant women (Sandler et al, 2015). The following section describes how RHD genotyping transfusion recipients with a serological weak D phenotype can conserve inventories of RhD-negative RBCs without compromising transfusion prophylactic. Also, RHD genotyping meaning women when a serological weak D is detected can avoid unnecessary injections of Rh immune globulin without compromising the safe of their pregnancy or the fetus.

Blood donors and transfusion recipients

Post-obit recognition that RhD haemolytic disease of the fetus and newborn was the result of RhD-negative mothers forming anti-D, clinical practice guidelines required that RhD-negative transfusion recipients, particularly women of childbearing potential, receive only D− RBCs when transfused. In 1958, the offset guideline for managing transfusion recipients or blood donors with a serological weak D phenotype was published in the first edition of AABB Standards (Scientific Committee of the Joint Blood Quango & Standards Committee of the American Association of Claret Banks, 1958). That initial guidance for transfusion do required a weak D test if a claret donor's RBCs typed as D− by direct agglutination using an anti-D reagent, but regarded a directly agglutination method to be sufficient for RhD typing of transfusion recipients' RBCs. That guidance has remained unchanged for more than 50 years. The current 30^th edition of Standards requires a weak D examination for claret donors, thereby protecting RhD-negative transfusion recipients from inadvertent exposure by transfusion to potentially immunogenic RBCs with a serological weak D phenotype (Ooley et al, 2015). In dissimilarity, the current thirty^th edition of Standards considers a weak D examination for transfusion recipients to be "optional," resulting in most recipients with a serological weak D phenotype beingness categorized every bit RhD-negative, protecting them from inadvertent exposure to RBCs that are either D+ or express a serological weak D phenotype (Ooley et al, 2015).

In 2014, CAP conducted a survey of policies and practices for testing serological weak D phenotypes and administration of Rh immune globulin involving more than than 3100 laboratories in the United states (Sandler et al, 2014a). This survey revealed that there was a lack of standard practice for interpreting the RhD blazon when a serological weak D phenotype was detected. Observational studies in central Europe betoken that transfusion recipients with a weak D type 1, 2 or iii in the homozygous or hemizygous state are not at risk for forming alloanti-D when exposed to D+ RBCs (Wagner et al, 2000, Flegel, 2006). Approximately ninety% of Caucasians in central Europe with a serological weak D phenotype have a weak D type 1, 2 or iii and can be managed safely as RhD-positive (Flegel, 2007). The AABB-CAP Piece of work Group recommended that RHD genotyping be performed for transfusion recipients when a serological weak D phenotype is detected by routine RhD typing. Those patients whose serological weak D phenotype is associated with a molecularly defined weak D type 1, ii or three may be transfused safely with D+ RBCs (Figure 2). Although an automated DNA extraction system tin extract DNA from whole blood in less than ane hour, turnaround times increment if the laboratory uses manual methods for the extraction. Currently, in the U.s., most RHD genotyping is performed in reference laboratories and, therefore, the turnaround time is more than 1 day, excluding the procedure for patients requiring an urgent transfusion. For patients requiring chronic transfusions, for instance, sickle cell disease, thalassaemia and myelodysplastic syndrome, the results of once-in-a-lifetime RHD genotyping may not exist available in time for the current transfusion, but would be available for hereafter transfusions (Fasano & Chou, 2016; Chou et al, 2013; ). New methods for blood group genotyping, for example, direct polymerase chain reaction (PCR) distension without DNA extraction, offer the promise of reducing the time for RHD genotyping to minutes, making RHD genotyping feasible for existent-time application in the infirmary (Wagner et al, 2017). Patients with sickle prison cell illness do good from RHD genotyping, non only considering about have a requirement for chronic transfusion, but besides because they are at increased risk of alloimmunization to certain Rh and other blood group antigens considering of the differences that they inherit from their African ancestry compared to those inherited by the predominately Caucasian donors in Western countries (Vichinsky et al, 1990).

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 every bit 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 iii is detected, the individual tin be managed safely every bit RhD-positive. (Reproduced from Sandler, S.G., Flegel, W.A., Westhoff, C.M., Denomme, 1000.A., Delaney, Thou., Keller, M.A., Johnson, Southward.T., Katz, L., Queenan, J.T., Vassallo, R.R. & Simon, C.D. (2015) It'due south time to phase in RHD genotyping for patients with a serologic weak D phenotype. Transfusion, 55, 680–689, with permission of Wiley Periodicals, Inc.)

Meaning women

In the United States, guidelines for managing pregnant women with a serological weak D phenotype were first introduced in 1981 (Oberman, 1981). The American Association of Blood Banks issued a standard that a adult female's candidacy for Rh allowed globulin should be adamant by the same laboratory method every bit that for RhD typing of claret donors (Oberman, 1981). Thus, women with a serological weak D phenotype were categorized equally RhD-positive and non considered candidates for Rh immunoprophylaxis with Rh immune globulin. Within a few years, in that location were reports of women with a serological weak D who delivered an RhD-positive newborn, did not receive Rh immune globulin, and who formed anti-D (White et al, 1983; Ostgard et al, 1986; Mayne et al, 1991; Domen & Hoetge, 1997). Currently, in the UK and Ireland, women with a serological weak D phenotype are ofttimes managed equally RhD-positive. Although most of these women would be determined to be RhD-positive if RHD genotyped, a minority will have an RHD type other than 1, two or three that would qualify them as candidates for Rh immune globulin.

The AABB standard was revised in the current thirty^th edition of AABB'southward Standards which determines a pregnant woman'southward candidacy for Rh immune globulin using the same RhD typing method for as that for a transfusion recipient, that is, the adult female'southward anti-D typing of RBCs is negative and the examination for weak D is optional (Ooley, 2015). A survey of hospital practice in the United States past CAP in 2014 revealed that only nineteen.8% of responding laboratories performed a weak D test when a patient'southward RBCs typed negative by the initial anti-D test (Sandler et al, 2014a). Thus, about pregnant women in the Usa with a serological weak D phenotype are managed without a weak D examination as RhD-negative for purposes of Rh immunoprophylaxis with Rh allowed globulin. While this strategy is safe and prevents Rh alloimmunization of RhD-negative pregnant women, the practice results in many significant women receiving unnecessary injections of Rh allowed globulin. The AABB-CAP Work Group reviewed data pertaining to the prophylactic of managing pregnant women and women of childbearing potential with a serological weak D phenotype. The Work Grouping determined that significant women with a weak D type i, two or 3 in the homozygous or hemizygous state are not at risk of forming alloanti-D when exposed to conventional D+ RBCs (Sandler et al, 2015). The Work Group recommended that RHD genotyping be performed when routine RhD typing resulted in a serological weak D phenotype for a pregnant women or a woman of childbearing potential. If the result was a weak D type 1, two or 3, the adult female can be managed safely as RhD-positive, considering she is not at risk of forming anti-D (Figure 2). The Piece of work Grouping's recommendation for pregnant women and other females of childbearing potential was accepted. In 2015, a Joint Statement on Phasing-in RHD Genotyping for Pregnant Women and Other Females of Childbearing Potential With a Serologic Weak D Phenotype was issued by the AABB, America'south Blood Centers, the American Cherry-red Cross, the American College of Obstetricians and Gynecologists, CAP and the Military Claret Programme (http://www.aabb.org/advocacy/statements/Pages/statement150722.aspx?PF=ane).

Toll effectiveness of RHD genotyping pregnant women with a serological weak D phenotype

A study using a Markov-based model evaluated the costs of options for managing the administration of Rh immune globulin in pregnant women in the Usa whose RhD type was reported to be a serological weak D phenotype (Kacker et al, 2015). The study determined that there would be cost saving when the cost of RHD genotyping was less than 256 USD. Genotyping would decrease net cost amid non-Hispanic Caucasian females, but would increase cost among non-Hispanic African Americans, not-Hispanic American Indian/Alaskans and Hispanic women (Kacker et al, 2015). The differences in cost for RHD genotyping unlike populations are a reflection of the higher prevalence of serological weak D phenotypes associated with weak D types 1, 2 or three in Caucasians compared to other racial and indigenous populations.

It's time for a image shift: Clinical laboratories should implement policies to increment detection of serological weak D phenotypes and resolve their estimation by RHD genotyping, not avoid their detection or make detection optional

Prior to the availability of molecular methods capable of distinguishing unlike D variant antigens that are expressed equally serological weak D phenotypes, laboratory practice in the Usa was abstention of the effect. Serological weak D phenotypes were interpreted as RhD-negative for meaning women and transfusion recipients, and as RhD-positive for blood donors (Sandler et al, 2014a). For the past 50 years, laboratories have used RhD typing policies and procedures selected for their avoidance of detecting D variant antigens. It'due south time to change the paradigm and select RhD typing reagents that will not but find normal ("wild type") RhD antigens, only as well detect D variant antigens. Such a scenario has been proposed and is feasible by RhD typing using 2 monoclonal anti-D reagents, one recognizing DVI and other clinically important partial D variants, and another not recognizing clinically important partial D variants. (Garratty, 2005: Denomme et al, 2005; Denomme & Flegel, 2008; von Zabern et al, 2013). Discrepant results using the 2-reagent protocol would prompt identification of the variant D allele by molecular methods.

Laboratories and transfusion services should discontinue reporting "serological weak D phenotype" as a test effect in response to a request to perform an RhD blood type

Traditionally, clinical practice for Rh immunoprophylaxis with Rh immune globulin, every bit well equally transfusion of RBCs, has been based on interpreting the results of RhD typing as RhD-positive or RhD-negative. Advances in molecular science take identified 147 weak D alleles of the RHD gene, simply the long-continuing do of managing meaning women and patients as either RhD-positive or RhD-negative continues to exist safe and adequate. As the science of RhD typing increasingly relies on RHD genotyping to guide the estimation of serological weak D phenotypes, molecular laboratories accept the responsibility of providing reports that are readily interpreted for managing patients as either RhD-positive or RhD-negative. Information technology's time for laboratories to discontinue the practice of reporting "serological weak D phenotype" in response to a asking to perform an RhD type. Today, given the laboratory resources for resolving a serological weak D phenotype, a laboratory offering RhD typing for clinical services should accept an internal procedure for resolving the occasional serological weak D result by "reflexively" (automatically) performing RHD genotyping or referring the claret sample to a molecular reference laboratory for resolution.

Should in-hospital clinical laboratories or regional reference laboratories perform the molecular testing required to resolve serological weak D phenotypes?

Many models exist that demonstrate the cost savings and opportunities for increased quality when low book tests are centralized in a reference laboratory. As clinicians increasingly recognize the benefit of applying RHD genotyping to resolve serological weak D phenotype results, laboratories will have options for providing the new service. Calculation an in-hospital molecular service for blood groups volition require the purchase of an automated extractor for Deoxyribonucleic acid, PCR work stations, centrifuges, a thermal cycler, hybridization oven, imaging system and a figurer (Sapatnekar & Figueroa, 2014). The initial uppercase expense and the ongoing cost of maintaining technical expertise for a relatively low-volume service are not realistic for most hospitals. For hospitals, an culling model, i.eastward., centralizing the required molecular services in a customs-based regional blood group reference laboratory, is more realistic. In our opinion, the second option -- hospitals refer blood samples for RHD genotyping to reference laboratories -- has the advantages of cost-constructive loftier-volume operations which can fund highly skilled molecular scientists and acquire upwardly-to-date technology (analysers) as this new laboratory scientific discipline evolves (Hillyer et al, 2008; Sandler et al, 2014b).

Acknowledgments

The authors thank Mouna Ouchari for updating Figure 1. This work was supported past the Intramural Enquiry Program (project ID Z99 CL999999) of the NIH Clinical Centre.

Footnotes

Publisher's Disclaimer: Disclaimers: The recommendations and opinions expressed are those of the authors, non their institutions or organizations. The views expressed do not necessarily represent the view of the National Institutes of Health, the Department of Health and Homo Services, or the U.Due south. Federal Regime.

Disharmonize of involvement: WAF receives royalties for RHD genotyping. SGS and LD declare having no conflicts of interest relevant to this commodity.

Author contributions

S. Gerald Sandler: Wrote the showtime draft and reviewed subsequent drafts. Leonard Chen: Fact-checker and formatted references. Willy A Flegel: Wrote all sections pertaining to molecular scientific discipline, edited all drafts, prepared Effigy 1 and Table II.

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