Abstract
Approximately 0Á2-1% 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. Since the identification of the Rh factor more than 7 decades ago (Levine & Stetson, 1939; Landsteiner & Weiner, 1940) , recipients of blood transfusions and blood donors have been categorized as either RhD-positive [D+ red blood cells (RBCs)] or RhD-negative (DÀ) 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, but 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 by 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 by RhD haemolytic disease of the fetus and newborn (Hill et al, 1974; Lacey et al, 1983; White 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 be retested with antiglobulin (a "weak D test") (Scientific Committee of the Joint Blood Council & Standards Committee of the American Association of Blood Banks, 1958) . If RBCs agglutinated after addition of antiglobulin to anti-D typing, the RBCs were interpreted to be D+. If RBCs did not agglutinate after addition of antiglobulin, they were interpreted to be DÀ. Of the five Blood Establishments in the UK and Ireland, only the Northern Ireland Blood Transfusion Service uses a weak D test for blood donors. The Irish Blood Transfusion Service does perform a weak D test on RhD-negative blood donors who are C+/E+. In the United States, a weak D test was not required for pregnant women or transfusion recipients. If RBCs from a pregnant woman or transfusion recipient typed negative by initial anti-D testing and a weak D test was not performed, the individual's RhD type was interpreted to be RhD-negative to ensure that the individual was not inadvertently exposed to D+ or D variant RBCs. In recent years, molecular laboratory methods have been developed that separate D variant antigens into three groups, namely, molecularly defined weak D phenotypes, partial D phenotypes and DEL phenotypes. The following review is intended as a guide for managing blood transfusions and Rh immunoprophylaxis for pregnant women whose RhD type has been reported by the laboratory as a serological weak D phenotype. Our intent is to review the molecular science 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.
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