Mathematics and transfusion medicine - Blood Transfusion

REVIEWThe genetics of the Rhesus blood group system*Willy A. FlegelInstitut für Klinische Transfusionsmedizin und Immungenetik Ulm und Institut für Transfusionsmedizin,Universitätsklinikum Ulm, GermanyThe Rhesus factor is clinically the most importantprotein-based blood group system. With 49 antigens sofar described, it is the largest of all 29 blood group systems.The unusually large number of Rhesus antigens isattributable to its complex genetic basis. The antigens arelocated on two Rhesus proteins - RhD and RhCE - and areproduced by differences in their protein sequences. In CDnomenclature, they are termed CD240D and CD240CE.Unlike proteins of other blood groups, Rhesus proteinsare expressed only in the membranes of red blood cells andtheir immediate precursors 1 .Rhesus is second in its clinical importance only to theABO blood group. Since the introduction of postpartumanti-D prophylaxis in the late 1960s, and combined preandpostpartum anti-D prophylaxis in the early 1990s, theincidence of haemolytic disease in newborns due toalloimmunization has been reduced by more than 90%. Upto 1% of all pregnant women have clinically significantanti-erythrocyte antibodies 2,3 .Anti-D remains the main indication for phototherapyor exchange transfusions in newborns 2,4 , and pregnantwomen who are D negative show an above averageincidence.The five most important Rhesus antigens are the causeof most alloimmunizations following blood transfusion.According to the German haemotherapy guidelines[Richtlinien zur Gewinnung von Blut undBlutbestandteilen und zur Anwendung vonBlutprodukten] 5 , D negative transfusion recipients mustalways be given D negative erythrocyte products.Since 2000, women of reproductive age and girls havealso received transfusions compatible for further Rhesusantigens such as C, c, E and e in addition to the K antigenof the Kell blood group 5 .This procedure also applies to patients who receiveregular transfusions or have immunohaematological50problems, like anti-erythrocyte allo- and autoantibodies.In the case of autoantibodies, their exact specificity is notusually determined. Although one thirds of suchautoantibodies are directed at Rhesus proteins, this hasvirtually no practical consequences for treatment 1 .The D antigen, discovered in 1939, was the first Rhesusantigen to be described. D positive patients were termedRhesus-positive. In 1946, a quantitative variant with aweakly expressed D antigen was discovered and termed"D u ". This variant, now called "weak D", is of clinical anddiagnostic importance.Since 1953, is has been clear that there are alsoqualitative variants of the D antigen. Although patientswith this partial D variant are positive for the D antigen,they can also form anti-D.The genetic basisIn order to understand the genetic basis of diseases, itis important to understand individual differences in geneticvariability, as well as their frequency and distribution inthe population 6 . There is usually a close correlation betweenthe genotype and the expressed phenotype. Thus, takinga change in the RHD gene as an example, it is possible tomake inferences about the expression of the RhD proteinin the erythrocyte membrane. As is the case with many Dvariants, modified RhD protein can have importantimplications for transfusion related antigenicity.The molecular basis of the RH allelesThe first Rhesus gene, the RHCE gene, was discoveredin 1990. The RHD gene was found two years later, and thetotal deletion of this gene ascertained as the cause of theEuropean D negative phenotype.*Part of this review was presented by the Author during the XXXIX SIMTI Congress(Paestum, SA, 4-7 October, 2006)Blood Transfus 2007; 5: 50-57© SIMTI Servizi Srl050-57_flegel.p65 5005/07/2007, 10.34