When an RH-negative woman is ABO- compatible with her husband, as Mr. and Mrs Waymarsh are, the risk of Rh alloimmunization is 16 percent. When they are ABO incompatible the risk falls to 7 percent. How do you explain this difference? 248Case 44: Hemolytic Disease of the NewbornFig. 44.1 Hemagglutination is usedto type blood and match compatibledonors and recipients for bloodtransfusion. Common gut bacteria bearantigens that are similar or identical toblood group antigens, and these stimulatethe formation of antibodies againstthese antigens in individuals who do notbear the corresponding antigen on theirown red blood cells (left column); thus,type O individuals, who lack A and Bantigens, have both anti-A and anti-Bantibodies, whereas type AB individualshave neither. The pattern of agglutinationof the red blood cells of a transfusiondonor or recipient with anti-A and anti-Bantibodies reveals the individual's ABOblood group. Before transfusion, theserum of the recipient is also tested forantibodies that agglutinate the red bloodcells of the donor, and vice versa, aprocedure called a cross-match, whichmay detect potentially harmful antibodiesagainst other blood groups that are notpart of the ABO system.30.5 weeks: hematocrit up to16.3% Further transfusionrequested.Serum fromindividuals of typeAnti-A and anti-BantibodiesAnti-B antibodiesBAnti-A antibodiesABNo antibodiesagainst A or BR-GlcNAc-GalFueno agglutinationno agglutinationno agglutinationno agglutinationRed blood cells from individuals of typeExpress the carbohydrate structuresR-GlcNAc-Gal-GalNAc R-GlcNAc-Gal-GalFúcRicagglutinationno agglutinationagglutinationno agglutinationagglutinationagglutinationno agglutinationno agglutinationR-GlcNAc-Gal-GaNAC3-2.3-2R-GNA-Gal-Galagglutinationagglutinationagglutinationno agglutinationThe Rh antigenic determinants are spaced very far apart on the red cell surface. Asa consequence, IgG antibodies against the Rh antigen do not fix complement andtherefore do not hemolyze red blood cells in vitro. For reasons that are less wellunderstood, IgG antibodies against the Rh antigen do not agglutinate Rh-positivered blood cells. Because of this it was very difficult to detect Rh antibodies untilRobin Coombs at the University of Cambridge devised a solution to the prob-lem by developing antibodies against human immunoglobulin. He showed thatRh-positive red blood cells coated with IgG anti-Rh antibodies could be taken froma fetus and agglutinated by antibodies against IgG. Furthermore, he showed thatwhen the serum of an alloimmunized woman was incubated with Rh-positive redblood cells, these red blood cells could then be agglutinated by antibody againstIgG (Fig. 44.2). The former is called the direct Coombs test and the latter the indi-rect Coombs test. This application of immunology to a vexing clinical problem ledultimately to treatment and prevention of the problem.The case of Cynthia Waymarsh: a fetus inimmunological distress.Mrs Waymarsh was 31 years old when she became pregnant for the third time. Shewas known to have blood group A, Rh-negative red cells. Her husband was alsotype A but Rh-positive. Their first-born child, a male, was healthy. During her secondpregnancy Mrs Waymarsh was noted to have an indirect Coombs titer at a 1:16 dilu-tion of her serum. The fetus was followed closely, and the delivery of a healthy babygirl was induced at 36 weeks of gestation.Five years later, Mrs Waymarsh became pregnant again. At 14 weeks of gestationher indirect Coombs titer was 1:8, and at 18 weeks it was 1:16. Amniotic fluid wasobtained at 22, 24, 27, and 29 weeks of gestation and was found to have increasing Case 44: Hemolytic Disease of the NewbornFig. 44.2 The Coombs direct and indirect anti-globulin tests forantibody to red blood cell antigens. An Rh-negative (Rh-) mother of anRh-positive (Rh+) fetus can become immunized to fetal red blood cellsthat enter the maternal circulation at the time of delivery. In a subsequentpregnancy with an Rh+ fetus, IgG anti-Rh antibodies can cross theplacenta and damage the fetal red blood cells. In contrast to anti-Rhantibodies, anti-ABO antibodies are of the IgM isotype; they cannotcross the placenta, and so do not cause harm. Anti-Rh antibodies do notagglutinate red blood cells, but their presence can be shown by washingthe fetal red blood cells and then adding antibody against humanimmunoglobulin, which agglutinates the antibody-coated cells. Thewashing removes unrelated immunoglobulins that would otherwise reactwith the anti-human immunoglobulin antibody. Anti-Rh antibodies can bedetected in the mother's serum in an indirect Coombs test; the serum isincubated with Rh+ red blood cells, and once the antibody has bound,the red cells are treated as in the direct Coombs test.amounts of bilirubin (a pigment derived from the breakdown of heme, indicatingthat the fetus's red blood cells were being hemolyzed). At 29 weeks of gestation ablood sample was obtained from the umbilical vein and found to have a hematocritof 6.2% (normal 45%). (The hematocrit is the proportion of blood that is composedof red cells, and because the volume of white cells is comparatively negligible, thisis simply ascertained by centrifuging whole unclotted blood in a tube.) On findingthat the fetus was profoundly anemic, 85 ml of type 0, Rh-negative packed red bloodcells were transfused into the umbilical vein. At 30.5 weeks of gestation anothersample of blood from the umbilical vein was obtained; the hematocrit was 16.3%.The etus was transfused with 75 ml of type 0, Rh-negative packed red blood cells.The fetus was examined at weekly intervals for the appearance of hydrops (seebelow), and none was observed. At 33.5 weeks of gestation, the hematocrit of ablood sample from the umbilical vein was 21%, so 80 ml of type 0, Rh-negativepacked red blood cells were again transfused into the umbilical vein. At 34.5 weeksof gestation it was determined that the fetus was sufficiently mature to sustainextrauterine life without difficulty; labor was induced and a normal female infantwas born. The hematocrit in the umbilical vein blood was 29%. The baby did welland no further therapeutic measures were undertaken.Hemolytic disease of the newborn.Although hemolytic disease of the newborn is most commonly the result of alloim-munization with Rh antigen, other red blood cell alloantigens, such as Lewis, Kell,Duffy, Kidd, and Lutheran, may cause alloimmunization. In each case, the mater-nal IgG antibodies cross the placenta in increasing amounts during the second tri-mester of pregnancy and hemolyze the fetal red blood cells. The resulting anemiamay become so severe that, if untreated, the fetus goes into heart failure and devel-ops massive edema; this is called hydrops fetalis and results in fetal death. The riskof fetal development of hydrops rises from 10% when the indirect Coombs titer ofthe mother is 1:16 to 75% when the maternal titer is 1:128. If the anemia is not sosevere as to cause hydrops, the affected infant at birth is still massively hemolyz-ing red blood cells. The newborn must dispose of the heme breakdown pigmentsrapidly, because an excessive accumulation of bilirubin results in the deposition ofthis pigment in the brain and severe neurological impairments. In response to theprofound anemia, the number of red blood cell precursors (erythroblasts) in thespleen, liver, and bone marrow expands rapidly; for this reason, hemolytic diseaseof the newborn has also been called erythroblastosis fetalis.As we have seen in this case, the extent of hemolysis can be determined easilyby obtaining amniotic fluid, into which the fetus begins to urinate by 20 weeks ofDirectCoombs testIndirectCoombs testRh- mother pregnant with Rh+ child(Rh*Washed fetal redcells coated withmaternal antibodyAdd rabbitanti-human antibodyRhMaternalserumAdd Rh+ red cellsand wash outunbound antibodyAgglutinationAdd rabbitanti-human antibody33.5 weeks: hematocrit upto 21%. Further transfusionrequested.249

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ABO and Rh are two separate blood type systems used to classify blood types. ABO blood type is…