rh blood group system rh blood group system the rh blood group system is a human blood group system. it contains proteins on the surface of red blood cells. after the abo blood group system, it is the most likely to be involved in transfusion reactions. the rh blood group system consisted of 49 defined blood group antigens in 2005. as of 2023, there are over 50 antigens among which the five antigens d, c, c, e, and e are the most important. there is no d antigen. rh(d) status of an individual is normally described with a positive (+) or negative (−) suffix after the abo type (e.g., someone who is a+ has the a antigen and rh(d) antigen, whereas someone who is a− has the a antigen but lacks the rh(d) antigen). the terms rh factor, rh positive, and rh negative refer to the rh(d) antigen only. antibodies to rh antigens can be involved in hemolytic transfusion reactions and antibodies to the rh(d) and rh antigens confer significant risk of hemolytic disease of the fetus and newborn. the name rhesus factor (rh) goes back to the use of erythrocytes extracted from the blood of rhesus monkeys for obtaining the first blood serum. nomenclature rh haplotype notation fisher–racewiener dcer0 dcer1 dcer2 dcerz dcer dcer' dcer″ dcery the rh blood group system has two sets of nomenclatures: one developed by ronald fisher and r. r. race, the other by wiener. both systems reflected alternative theories of inheritance. the fisher–race system, which is more commonly in use today, uses the cde nomenclature. this system was based on the theory that a separate gene controls the product of each corresponding antigen (e.g., a "d gene" produces d antigen, and so on). however, the d gene was hypothetical, not actual. the wiener system used the rh–hr nomenclature. this system was based on the theory that there was one gene at a single locus on each of the 2 copies of chromosome 1, each contributing to production of multiple antigens. in this theory, a gene r1 is supposed to give rise to the "blood factors" rh0, rh′, and rh″ (corresponding to modern nomenclature of the d, c, and e antigens) and the gene r to produce hr′ and hr″ (corresponding to modern nomenclature of the c and e antigens). notations of the two theories are used interchangeably in blood banking (e.g., rho(d) meaning rhd positive). wiener's notation is more complex and cumbersome for routine use. because it is simpler to explain, the fisher–race theory has become more widely used. dna testing has shown that both are partially correct: there are in fact two linked genes, the rhd gene which produces a single immune specificity (anti-d) and the rhce gene with multiple specificities (anti-c, anti-c, anti-e, anti-e). thus, wiener's postulate that a gene could have multiple specificities (something many did not give credence to originally) has been proved to be correct. on the other hand, wiener's theory that there is only one gene has proved to be incorrect, as has the fisher–race theory that there are three genes, rather than the 2. the cde notation used in the fisher–race nomenclature is sometimes rearranged to dce to more accurately represent the co-location of the c and e encoding on the rhce gene, and to make interpretation easier. antigens the proteins which carry the rh antigens are transmembrane proteins, whose structure suggest that they are ion channels. the main antigens are d, c, e, c and e, which are encoded by two adjacent gene loci, the rhd gene which encodes the rhd protein with the d antigen (and variants) and the rhce gene which encodes the rhce protein with the c, e, c and e antigens (and variants). there is no d antigen. lowercase "d" indicates the absence of the d antigen (the gene is usually deleted or otherwise nonfunctional). 1. this is the rh-positive blood cell.2. this is the rh-negative blood cell.3. these are the antigens on the rh-positive blood cell that make it positive. the antigens allow the positive blood cell to attach to specific antibodies. rh phenotypes are readily identified through the presence or absence of the rh surface antigens. as can be seen in the table below, most of the rh phenotypes can be produced by several different rh genotypes. the exact genotype of any individual can only be identified by dna analysis. regarding patient treatment, only the phenotype is usually of any clinical significance to ensure a patient is not exposed to an antigen they are likely to develop antibodies against. a probable genotype may be speculated on, based upon the statistical distributions of genotypes in the patient's place of origin. r0 (cde or dce) is today most common in africa. the allele was thus often assumed in early blood group analyses to have been typical of populations on the continent; particularly in areas below the sahara. ottensooser et al. (1963) suggested that high r0 frequencies were likely characteristic of the ancient judea jews, who had emigrated from egypt prior to their dispersal throughout the mediterranean basin and europe on the basis of high r0 percentages among sephardi and ashkenazi jews compared to native european populations and the relative genetic isolation of ashkenazim. however, more recent studies have found r0 frequencies as low as 24.3% among some afroasiatic-speaking groups in the horn of africa, as well as higher r0 frequencies among certain other afroasiatic speakers in north africa (37.3%) and among some palestinians in the levant (30.4%). on the contrary, at a frequency of 47.2% of the population of basque country having the lack of the d antigen, these people display the highest frequency of the rh negative phenotype. rh phenotypes and genotypes (uk, 1948) phenotype expressed on cell genotype expressed in dna prevalence(%) fisher–race notationwiener notation d+ c+ e+ c+ e+ (rhd+)dce/dcer0rz 0.0125 dce/dcer0ry 0.0003 dce/dcer1r2 11.8648 dce/dcer1r″ 0.9992 dce/dcer2r′ 0.2775 dce/dcerzr 0.1893 d+ c+ e+ c+ e− (rhd+)dce/dcer2rz 0.0687 dce/dcer2ry 0.0014 dce/dcerzr″ 0.0058 d+ c+ e+ c− e+ (rhd+)dce/dcer1ry 0.0042 dce/dcerzr′ 0.0048 dce/dcer1rz 0.2048 d+ c+ e+ c− e− (rhd+)dce/dcerzrz 0.0006 dce/dcerzry < 0.0001 d+ c+ e− c+ e+ (rhd+)dce/dcer0r′ 0.0505 dce/dcer1r 32.6808 dce/dcer1r0 2.1586 d+ c+ e− c− e+ (rhd+)dce/dcer1r1 17.6803 dce/dcer1r′ 0.8270 d+ c− e+ c+ e+ (rhd+)dce/dcer2r0 0.7243 dce/dcer0r″ 0.0610 dce/dcer2r 10.9657 d+ c− e+ c+ e− (rhd+)dce/dcer2r2 1.9906 dce/dcer2r″ 0.3353 d+ c− e− c+ e+ (rhd+)dce/dcer0r0 0.0659 dce/dcer0r 1.9950 d− c+ e+ c+ e+ (rhd−)dce/dcerry 0.0039 dce/dcer′r″ 0.0234 d− c+ e+ c+ e− (rhd−)dce/dcer″ry 0.0001 d− c+ e+ c− e+ (rhd−)dce/dcer′ry 0.0001 d− c+ e+ c− e− (rhd−)dce/dceryry < 0.0001 d− c+ e− c+ e+ (rhd−)dce/dcerr′ 0.7644 d− c+ e− c− e+ (rhd−)dce/dcer′r′ 0.0097 d− c− e+ c+ e+ (rhd−)dce/dcerr″ 0.9235 d− c− e+ c+ e− (rhd−)dce/dcer″r″ 0.0141 d− c− e− c+ e+ (rhd−)dce/dcerr 15.1020 • figures taken from a study performed in 1948 on a sample of 2000 people in the united kingdom. rh phenotypes in patients and donors in turkey rh phenotypecdepatients (%)donors (%) r1rccde37.433.0 r1r2ccdee35.730.5 r1r1cde5.721.8 rrce10.311.6 r2rcdee6.610.4 r0r0cde2.82.7 r2r2cde2.82.4 rr″cee–0.98 rzrzcde–0.03 rr′cce0.8– rh antibodies rh antibodies are immunoglobulin g (igg) antibodies which are acquired through exposure to rh-positive blood (generally either through pregnancy or transfusion of blood products). the d antigen is the most immunogenic of all the non-abo antigens. approximately 80% of individuals who are d-negative and exposed to a single d-positive unit will produce an anti-d antibody. the percentage of alloimmunization is significantly reduced in patients who are actively exsanguinating. all rh antibodies except d display dosage (antibody reacts more strongly with red cells homozygous for an antigen than cells heterozygous for the antigen (ee stronger reaction vs ee). if anti-e is detected, the presence of anti-c should be strongly suspected (due to combined genetic inheritance). it is therefore common to select c-negative and e-negative blood for transfusion patients who have an anti-e and lack the c antigen (in general, a patient will not produce antibodies against their own antigens). anti-c is a common cause of delayed hemolytic transfusion reactions. hemolytic disease of the newborn main article: hemolytic disease of the newborn the hemolytic condition occurs when there is an incompatibility between the blood types of the mother and fetus. there is also potential incompatibility if the mother is rh negative and the father is positive. when any incompatibility is detected, the mother often receives an injection at 28 weeks gestation and at birth to avoid the development of antibodies towards the fetus. these terms do not indicate which specific antigen-antibody incompatibility is implicated. the disorder in the fetus due to rh d incompatibility is known as erythroblastosis fetalis. hemolytic comes from two words: "hema" (blood) and "lysis" (solution) or breaking down of red blood cells erythroblastosis refers to the making of immature red blood cells fetalis refers to the fetus. when the condition is caused by the rh d antigen-antibody incompatibility, it is called rh d hemolytic disease of the newborn or rh disease. here, sensitization to rh d antigens (usually by feto-maternal transfusion during pregnancy) may lead to the production of maternal igg anti-d antibodies which can pass through the placenta. this is of particular importance to d negative females at or below childbearing age, because any subsequent pregnancy may be affected by the rh d hemolytic disease of the newborn if the baby is d positive. the vast majority of rh disease is preventable in modern antenatal care by injections of igg anti-d antibodies (rho(d) immune globulin). the incidence of rh disease is mathematically related to the frequency of d negative individuals in a population, so rh disease is rare in old-stock populations of africa and the eastern half of asia, and the indigenous peoples of oceania and the americas, but more common in other genetic groups, most especially western europeans, but also other west eurasians, and to a lesser degree, native siberians, as well as those of mixed-race with a significant or dominant descent from those (e.g. the vast majority of latin americans and central asians). symptoms and signs in the fetus: enlarged liver, spleen, or heart and fluid buildup in the fetus' abdomen seen via ultrasound. symptoms and signs in the newborn: anemia that creates the newborn's pallor (pale appearance). jaundice or yellow discoloration of the newborn's skin, sclera or mucous membrane. this may be evident right after birth or after 24–48 hours after birth. this is caused by bilirubin (one of the end products of red blood cell destruction). enlargement of the newborn's liver and spleen. the newborn may have severe edema of the entire body. dyspnea (difficulty breathing) other animals with rh-like antigens causing hemolytic disease of the newborn rh disease only occurs in human fetuses however a similar disease called neonatal isoerythrolysis (ni) can be observed in animal species of newborn horses, mules, pigs, cats, cattle, and dogs. what differs between rh disease and ni is the pathogenesis of hemolysis between human fetuses and the animal species. with human mothers, the maternal antibodies are formed from the sensitization of foreign antigens of her unborn fetus’s red blood cells passing through the placenta causing hemolysis before birth, with other animals however, these maternal antibodies are not passed through the placenta but through colostrum. the newborn animal is without ni but soon develops hemolytic anemia after initial ingestion of its mother’s colostrum that contain antibodies that can be absorbed through the newborn’s intestines and are incompatible to its red blood cell antigen. after 48 hours of birth, the newborn may be allowed to nurse from its mother as her antibodies can no longer be absorbed through the neonate’s intestines. because the most active newborn animals consume the most colostrum, they may be the ones who are most affected by the blood incompatibility of antigen and antibody. rh proteins outside of human species rh molecules can be found in many different living organisms from worms, bacteria, algae, and other vertebrates. these rh molecules from different animals have the same biochemical function-differing slightly in their amino acid sequences. the rh proteins in other species, however, do not correspond with the rh blood group or antigens found on human red blood cells. one such example would be the nematode caenorhabditis elegans. because this worm does not have red blood cells, it cannot have rh antigens, excluding it from having a rh blood type. these rh