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The Introduction into Clinical Practice of ABO Blood Group Test – The Discovery of Rh Factor

The introduction into clinical practice of the ABO blood grouping test for selecting donors made safe transfusion possible. As early as 1921, Unger reported intragroup transfusion reactions and recommended that, after the appropriate ABO donor had been identied, additional tests should be carried out to exclude the possibility of a recipient serum agglutinating the donor’s red cells (Unger, 1921). After blood banks were established in the 1940s, thousands of transfusions were given daily and the incidence of intragroup haemolytic reactions increased (Wiener, 1969). 

Often, patients who had received previous blood transfusions without reactions became immunized against agglutinogens present in the donor’s red cells but absent from their own. In 1939, Levine, with whom Landsteiner discovered the MN types, reported an unusual case of intragroup agglutination (Levine & Stetson, 1939). This woman, who had been admitted to the Bellevue hospital in NewYork, had a stillbirth. Her fetus was macerated and she needed a transfusion. She had not previously received any blood transfusions and was given whole blood from her husband who was also group O. Within 10 min, she developed severe symptoms and more bleeding. A crossmatch revealed that her serum agglutinated her husband’s cells. Of a total of 104 group O blood samples tested against her serum only 21 were compatible. Levine suggested that there had been an isosensitization in this woman caused by ‘products’ from the fetus. 
The discovery of the Rh factor by Landsteiner and Alexander Wiener in 1940 provided the pathophysiological basis for erythroblastosis and possibly explained the Levine case as having been caused by isosensitization to Rh antigen (Wiener, 1969). Alexander Wiener did not work at the Rockefeller Institute, where Landsteiner had his laboratory at the time, but in the serological laboratory at the chief medical examiner’s ofce in New York City. Wiener was interested in studying the evolution of agglutinogens M and N in anthropoid apes and monkeys. He obtained a series of anti-M and anti-N sera from rabbits, allowing him to study the inheritance of MN types (Wiener, 1938). Although all the anti-M sera reacted with human red cells, some strongly agglutinated rhesus monkey red cells and some did not. Absorption of the antisera with human M cells completely removed the antibody specicity for monkey red cells. Rabbits immunized with red cells of rhesus monkeys gave strong anti-M reactions after absorbing the sera with human N cells. 
When the anti-M agglutinin from the anti-rhesus rabbit sera was absorbed, red cells from 85% of Caucasians were agglutinated. The new blood factor identied by this reagent was different from all factors discovered previously and was named Rh factor. Although this nding was made in 1937, publication was delayed until 1940 to allow the methods for production of anti-rhesus sera to be improved (Landsteiner & Wiener, 1940). Initially, it was believed that animal and human antibodies identied a common antigen, Rh, on the surface of both rhesus and human red blood cells, but this was not the case. The original terms ‘Rh factor’ and ‘anti-Rh’, introduced by Landsteiner and Wiener, have persisted. The heteroantibody was re-named ‘anti-LW’ (after Landsteiner and Wiener) and the human alloantibody was re-named ‘anti-D’ (Avent & Reid, 2000). The Rh blood group system is the most polymorphic of all human blood groups and is composed of at least 45 antigens. The D antigen is highly immunogenic and induces an immune response in 80% of D-negative people when transfused with 200 ml of D-positive blood. Therefore, in most countries, D-typing is routine for blood donors and recipients. 
Alloantibodies directed against Rh antigens are usually immunoglobulin (Ig)G and cause destruction of transfused red cells or fetal red blood cells in haemolytic disease of the newborn (HDN). This disease is caused by maternal IgG antibody passing through the placenta, binding the fetal antigen-positive red blood cells and destroying them, leading to anaemia (Avent & Reid, 2000). BeforetheprophylacticuseofRhimmunoglobulins(anti-D globulin) was introduced, maternal anti-D antibodies frequently caused fetal brain damage, as a result of the increased levels of bilirubin (Kern icterus), and death. The mechanism underlying the prevention of maternal anti-D production after receipt of prophylactic Rh immunoglobulin could be due to antigen blocking or a central inhibition of the immune response. Prophylactic Rh immunoglobulins are usually given by intramuscular injection. Rh immunoglobulins are also used for treating idiopathic thrombocytopenia, when they are given intravenously. 
The primary mechanism of action for this indication is believed to be an immunological blockade of Fc receptors within the reticuloendothelial system, preventing entrapment of antibodycoated platelets with a subsequent rise in the circulating platelet count (Ware & Zimmerman, 1998). Today’s methods for obtaining Rh immunoglobulin for a therapeutic hyperimmunoglobulin preparation follow Wiener’s original 1943 procedures for obtaining anti-Rh antibodies for diagnostic purposes. In his search, Wiener found the most convenient source of anti-Rh sera were people already sensitized by pregnancy or transfusion. During World War II, Wiener prepared anti-Rh serum for the armed forces by injecting small Rh-positive red cells into people who were already sensitized and could induce a very strong anamnestic response. The best source of anti-Rh serum came from male Rh-negative volunteers immunized with a small dose of Rh-positive red cells. At least two injections, 4 months apart, for the production of specic high-titre anti-Rh antibodies were required (Wiener, 1969).

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