Everything about Rhesus Blood Group System totally explained
The term
Rhesus (Rh) blood group system refers to the 5 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 don't 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 don't 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 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 (for example, 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 (for example, Rho(D)). Wiener’s notation is more complex and cumbersome for routine use. Because it's 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 didn't give credence to originally) has been proven correct. On the other hand, Wiener's theory that there's 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're
ion channels
(External Link
). The main antigens are C, D, E, c and e, which are encoded by two adjacent gene loci, the RHD gene which encodes the D antigen
(External Link)) and the RHCE gene which encodes both the C and E antigens
(External Link). There is no d antigen. Lowercase "d" indicates the absence of the D antigen (the gene is usually deleted or otherwise nonfunctional).
Rhesus genotypes>
| Genotype |
symbol |
Rh(D) status
|
| cde/cde |
rr |
Negative |
| CDe/cde |
R1r |
Positive |
| CDe/CDe |
R1R1 |
Positive |
| cDE/cde |
R2r |
Positive |
| CDe/cDE |
R1R2 |
Positive |
| cDE/cDE |
R2R2 |
Positive |
Hemolytic disease of the newborn
This condition occurs when there's an incompatibility between the blood types of the mother and the baby. These terms don't indicate which specific antigen-antibody incompatibility is implicated. The disorder in the fetus due to rhesus-D incompatibility is known as erythroblastosis fetalis.
- 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's 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.
Population data for the Rh D factor and the RhD neg allele>
| Population |
Rh(D) Neg |
Rh(D) Pos |
Rh(D) Neg alleles |
| European Basque |
approx 35% |
65% |
approx 60% |
| Caucasian |
16% |
84% |
40% |
| American Blacks |
approx 7% |
93% |
approx 26% |
| Native Americans |
approx 1% |
99% |
approx 10% |
| African descent |
less 1% |
over 99% |
3% |
| Asian |
less 1% |
over 99% |
1% |
Inheritance
The Rh(D) antigen is inherited as one gene (RHD) (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 the RhD polypeptide on the red cell membrane. Rh− individuals lack a functional RHD gene (dd genotype) don't produce the D antigen, and may be sensitized to Rh+ blood.
Two very similar epitopes are encoded on the same protein on the adjacent related RHCE gene, Cc and Ee. It is believed that the RHD gene arose by duplication of the RHCE gene during primate evolution. Mice have just one RH gene (External Link).
The Rhesus system is much more complex than the ABO blood type system because there are more than 30 combinations possible.
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's 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're 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're either much less frequently encountered or are rarely clinically significant. Each is given a number, though the highest assigned number (Rh56 or CENR) isn't an accurate reflection of the antigens encountered since many (for example Rh38) have been combined, reassigned to other groups, or otherwise removed.
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