Rhesus blood group system

The term Rhesus (Rh) blood group system refers to the five main Rhesus antigens (C, c, D, E and e) as well as the many other less frequent Rhesus antigens. The terms Rhesus factor and Rh factor are equivalent and refer to the Rh D antigen only.

Rhesus factor
Individuals either have, or do not have, the Rhesus factor (or Rh D antigen) on the surface of their red blood cells. This is usually indicated by 'RhD positive' (does have the RhD antigen) or 'RhD negative' (does not have the antigen) suffix to the ABO blood type. Unlike the ABO antigens, the only ways antibodies are developed against the Rh factor are through placental sensitization or translation. That is, if a person who is RhD-negative has never been exposed to the RhD antigen, they do not possess the RhD antibody. The 'RhD-' suffix is often shortened to 'D pos'/'D neg', 'RhD pos'/RhD neg', or +/-. The latter is generally not preferred in research or medical situations, because it can be altered or obscured accidentally.

There may be prenatal danger to the fetus when a pregnant woman is RhD-negative and the biological father is RhD-positive. But, as discussed below, the situation is considerably more complex than that.

History of discoveries
The Rhesus system is named after the Rhesus Macaque, following experiments by Karl Landsteiner and Alexander S. Wiener, which showed that rabbits, when immunized with rhesus monkey red cells, produce an antibody that also agglutinates the red blood cells of many humans. Landsteiner and Alexander S. Wiener discovered this factor in 1937 (publishing in 1940). The significance of the Rh factor was soon realized. Dr. Phillip Levine working at the Newark Beth Israel Hospital made a connection between the Rh factor and the incidence of erythroblastosis fetalis, and Wiener realized adverse reactions from transfusions were also resulting from the Rh factor. Wiener then pioneered the exchange transfusion to combat erythroblastosis fetalis in newborn infants. This transfusion technique saved the lives of many thousands of infants before intrauterine transfusion was invented which enabled much more severely affected fetuses to be successfully treated. Drs. Neva Abelson and L.K. Diamond co-discovered a simple test for the Rh factor which was widely applied.

Rh nomenclature
The Rhesus system has two sets of nomenclatures, one developed by Doctors Fisher and Race and one by Dr. Wiener. Both systems reflected alternate theories of inheritance. The Fisher-Race system, which is more commonly in use today, utilizes the CDE nomenclature. This system originally postulated that there are three closely linked genes on each chromosome. The genes were designated as D and its hypothetical allele d; C and its allele c, E and its allele e. Each gene was supposed to control the product of the corresponding antigen (i.e., D gene produces D antigen, etc.)  However, the d gene was hypothetical, not actual.

The Wiener system used the Rh-Hr nomenclature. This system theorized that there was one gene at a single locus on each chromosome of the pair which controls production of multiple antigens. This concept postulated that a gene R gives rise to the “blood factors” Rho, rh’, and hr” and the gene r will produce hr’ and hr”.

Notations of the two theories are used interchangeably in blood banking (e.g., Rho(D)). Wiener’s notation is more complex and cumbersome for routine use. Because it is simpler to explain, the Fisher-Race theory is more widely used.

DNA testing has shown that both theories are partially correct. There are in fact two linked genes, one with multiple specificities and one with a single specificity. Thus, Wiener's postulate that a gene could have multiple specificities (something many did not give credence to originally) has been proven correct. On the other hand, Wiener's theory that there is one gene has proven incorrect, as has the Fischer-Race theory that there are three genes.

The Rhesus system antigens
The proteins which carry the Rhesus antigens are transmembrane proteins, whose structure suggest that they are ion channels. The main antigens are C, D, E, c and e, which are encoded by two gene loci, the D locus and the CE locus. There is no d antigen. Lowercase "d" indicates the absence of the D antigen (the gene is either deleted or nonfunctional).

Hemolytic disease of the newborn
Hemolytic disease of the newborn is also called Erythroblastosis Fetalis. This condition occurs when there is an incompatibility between the blood types of the mother and the baby. These terms do not indicate which specific antigen-antibody incompatibility is implicated.


 * hemolytic comes from two words: hemo (blood) and lysis (destruction) 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 RhD antigen-antibody incompatibility, it is called RhD Hemolytic disease of the newborn (often called Rhesus disease or Rh disease for brevity). Here, sensitization to Rh D antigens (usually by feto-maternal transfusion during pregnancy) may lead to the production of maternal IgG anti-RhD antibodies which can pass through the placenta. This is of particular importance to RhD negative females of or below childbearing age, because any subsequent pregnancy may be affected by the Rhesus D hemolytic disease of the newborn if the baby is Rh 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 Rhesus disease is mathematically related to the frequency of RhD negative individuals in a population, so Rhesus disease is rare in East Asians and Africans, but more common in Caucasians.


 * 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 which 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 or difficulty breathing.

Population data
The frequency of Rh factor blood types and the RhD neg allele gene differs in various populations.

Inheritance
The Rh(D) antigen is inherited on one locus (on the short arm of the first chromosome, 1p36.13-p34.3) with two alleles, of which Rh+ is dominant and Rh− recessive. The gene codes for a polypeptide on the red cell membrane. Rh− individuals (dd genotype) do not produce this antigen, and may be sensitized to Rh+ blood.

The Rhesus system is much more complex than the ABO blood type system because there are more than 30 combinations possible.

Two very similar epitopes, Cc and Ee, appear to be closely related to Rh.

Weak D
In testing, D positive blood is easily identified. Units which are negative for D are often retested to rule out a weaker reaction. This was previously referred to as Du, which has fallen out of favor. In some cases, this phenotype occurs because of an altered surface protein that is more common in people of African descent. The testing is difficult, since using different anti-D reagents, especially the older polyclonal reagents, may give different results.

The practical implication of this is that people with this sub-phenotype will have a product labeled as "D positive" when donating blood. When receiving blood, they are sometimes typed as a "D negative", though this is the subject of some debate. Most "Weak D" patients can receive "D positive" blood without complications. This is important, since most blood banks have a limited supply of "D negative" blood. Patients who test as "D negative" and whose "D positive" status is detectable with an IAT are commonly given "D negative" blood, but this is also debated.

This may lead to the unusual situation where a person is "D positive" as a donor but receives "D negative" blood. Since autologous donations are labeled with the blood type and matching the blood type is part of routine pre-transfusion clerical checks, this can easily lead to confusion.

Other Rh group antigens
43 other Rh group antigens have been described, but they are either much less frequently encountered or are rarely clinically significant. Each is given a number, though the highest assigned number (Rh56 or CENR) is not an accurate reflection of the antigens encountered since many (e.g. Rh38) have been combined, reassigned to other groups, or otherwise removed.