blood group

n.
Any of several immunologically distinct, genetically determined classes of human blood that are based on the presence or absence of certain antigens and are clinically identified by characteristic agglutination reactions. Also called blood type.

Genetically determined markers on the surface of cellular blood elements (red and white blood cells, platelets). In medicine, the matching of ABO and Rh groups of recipients and donors before blood transfusion is of paramount importance; other blood groups also can be implicated in incompatibility. Markers on white cells (histocompatibility antigens) are shared by a number of body tissue cells; these markers are important to the survival of transplanted organs and bone marrow. In law, the recognition of identity between bloodstains found at the scene of a crime and those on clothing of a suspect has resulted in many convictions, and blood typing has served to resolve paternity disputes. From an anthropologic standpoint, some blood groups are unique to specific populations and can be a reflection of tribal origin or migration patterns. Blood groups are also valuable markers in gene linkage analysis, and their study has contributed enormously to the mapping of the human genome.

Antibodies

Human blood can be classified into different groups based on the reactions of red blood cells with blood group antibodies (Table 1). Naturally acquired antibodies, such as anti-A and anti-B antibodies, are normally found in serum from persons whose red blood cells lack the corresponding antigen. It is thought that they are stimulated by antigens present in the environment, and are acquired by infants within months of birth. Because anti-A and anti-B antibodies can cause rapid, life-threatening destruction of incompatible red blood cells, blood for transfusion is always selected to be compatible with the plasma of the recipient. See also Antibody; Antigen.

ABO blood group system

Blood group	RBC antigens	Possible genotypes	Plasma antibody
A	A	A/A or A/O	anti-B
B	B	B/B or B/O	anti-A
O	—	O/O	Anti-A and anti-B
AB	A and B	A/B	—

Most blood group antibodies, including Rh antibodies, are immune in origin and do not appear in serum or plasma unless the host is exposed directly to foreign red blood cell antigens. The most common stimulating event is blood transfusion or pregnancy. Because of the large number of different blood group antigens, it is impossible, when selecting blood for transfusion, to avoid transfusing antigens that the recipient lacks. However, these foreign antigens may or may not be immunogenic. A single-unit transfusion of Rh D-positive to an Rh D-negative recipient causes production of anti-D in about 85% of cases. Consequently, in addition to matching for ABO types, Rh D-negative blood is almost always given to Rh D-negative recipients. In pregnancy, fetal red blood cells cross the placenta and enter the maternal circulation, particularly at delivery. The fetal red blood cells may carry paternally derived antigens that are foreign to the mother and stimulate antibody production. These antibodies may affect subsequent pregnancies by destroying the fetal red blood cells and causing a disease known as erythroblastosis fetalis.

Antigens, genes, and blood group systems

Approximately 700 distinct blood group antigens have been identified on human red blood cells. Biochemical analysis has revealed that most antigen structures are either protein or lipid in nature; in some instances, blood group specificity is determined by the presence of attached carbohydrate moieties. The human A and B antigens, for example, can be either glycoprotein or glycolipid, with the same attached carbohydrate structure. With few exceptions, blood group antigens are an integral part of the cell membrane.

A number of different concepts have been put forth to explain the genetics of the human blood groups. The presence of a gene in the host is normally reflected by the presence of the corresponding antigen on the red blood cells. Usually, a single locus determines antigen expression, and there are two or more forms of a gene or alleles (for example, a and b) that can occupy a locus. Each individual inherits one allele from each parent. For a given blood group, when the same allele (for example, allele a) is inherited from both parents, the offspring is homozygous for a and only the antigen structure defined by a will be present on the red blood cells. When different alleles are inherited (that is, a and b), the individual is heterozygous for a (and b), and both a and b antigens will be found on the red blood cells. In some blood group systems, several loci govern the expression of multiple blood group antigens within that system. These loci are usually closely linked, located adjacent to each other on the chromosome. Such complex loci may contain multiple alleles and are referred to as haplotypes.

Some 200 antigens have been assigned to 25 different blood group systems. Eight such systems are shown in the Table 2. For a system to be established, the genes involved must be distinct from other blood group system genes, and either they must be polymorphic (that is, two or more alleles, each with an appreciable frequency in a population) or the chromosome location must be known. Antigens that do not meet the criteria for assignment to a specific blood group system have been placed into collections, based primarily on biochemical data or phenotypic association, or into a series of either high- or low-frequency antigens.

Human blood group systems

System name	ISBT* symbol	System number	Antigens in system	Chromosome location†	Gene products
ABO	ABO	001	4	9q34.1-q34.2	A = α-N-acetylgalactosaminyl transferase B = α-galactosyl transferase
MNS	MNS	002	43	4q28-q31	GYPA = glycophorin A; 43-kDa single-pass glycoprotein GYPB = glycophorin B; 25-kDa single-pass glycoprotein
Rh	RH	004	45	1p36.13-p34	RHD and RHCE, 30–32-kDa multipass polypeptides
Lutheran	LU	005	18	19q13.2	78- and 85-kDa single-pass glycoproteins
Kell	KEL	006	23	7q33	93-KDa single-pass glycoprotein
Duffy	FY	008	6	1q22-q23	38.5-kDa multipass glycoprotein
Diego	DI	010	18	17q12-q21	95–105-kDa multipass glycoprotein
Xg	XG	012	1	Xp22.32	22–29-kDa single-pass glycoprotein

*International Society of Blood Transfusion.

^†Chromosome locations of genes/loci are identified by the arm (p = short; q = long), followed by the region, then by the band within the region, in both cases numbered from the centromere; ter = end.

ABO was the first human blood group system to be described. Three major alleles at the ABO locus on chromosome 9 govern the expression of A and B antigens. Gene A encodes for a protein (α-N-acetylgalactosaminyl transferase) that attaches a blood group–specific carbohydrate (α-N-acetyl-D-galactosamine) and confers blood group A activity to a preformed carbohydrate structure called H antigen. Gene B encodes for an α-galactosyl transferase that attaches α-D-galactose and confers blood group B activity to H antigen. In both instances, some H remains unchanged. The O gene has no detectable product; H antigen remains unchanged and is strongly expressed on red blood cells. These three genes account for the inheritance of four common phenotypes: A, B, AB, and O. A and O blood types are the most common, and AB the least common. The A and B genes are codominant; that is, when the gene is present the antigen can be detected. The O gene is considered an amorph since its product cannot be detected. When either A or B antigens are present on red blood cells, the corresponding antibody or antibodies should not be present in the serum or plasma. In adults, when A or B or both are absent from the red blood cells, the corresponding naturally acquired antibody is present in the serum. This reciprocal relationship between antigens on the red blood cells and antibodies in the serum is known as Landsteiner's law. Other ABO phenotypes do exist, but these are quite rare. Further, the A blood type can be subdivided, based on strength of antigen expression, with A₁ red blood cells having the most A antigen.

Currently 45 antigens are assigned to the Rh blood group system, although D is the most important. Red blood cells that carry D are called Rh-positive; red blood cells lacking D are called Rh-negative. Other important Rh antigens are C, c, E, and e. Rh antigen expression is controlled by two adjacent homologous structural genes on chromosome 1 that are inherited as a pair or haplotype. The RhD gene encodes D antigen and is absent on both chromosomes of most Rh-negative subjects. The RhCE gene encodes CE protein. Nucleotide substitutions account for amino acid differences at two positions on the CE protein, and result in the Cc and Ee polymorphisms.

Biological role

The function of blood group antigens has been increasingly apparent. Single-pass proteins such as the LU and XG proteins are thought to serve as adhesion molecules that interact with integrins on the surface of white blood cells. Multipass proteins such as band 3, which carries the DI system antigens, are involved in the transportation of ions through the red blood cell membrane bilipid layer. Some blood group antigens are essential to the integrity of the red blood cell membrane, for their absence results in abnormal surface shape; for example, absence of KEL protein leads to the formation of acanthocytes, and absence of RH protein results in stomatocytosis and hemolytic anemia. Many membrane structures serve as receptors for bacteria and other microorganisms. For example, the FY or Duffy protein is the receptor on red blood cells for invasion by Plasmodium vivax, the cause of benign tertian malaria. Particularly significant is the fact that Fy(a-b-) phenotype is virtually nonexistent among Caucasians but has an incidence of around 70% among African-Americans. Presumably, the Fy(a-b-) phenotype evolved as a selective advantage in areas where P. vivax is endemic. Similarly, the S-s-U-red blood cell phenotype in the MNS blood group system affords protection against P. falciparum, or malignant tertian malaria. Yet other blood group antigens can be altered in disease states; A, B, and H antigens are sometimes weakened in leukemia or may be modified by bacterial enzymes in patients with septicemia. See also Blood; Immunology.

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The giving of blood and its subsequent safe transfusion into a patient is now commonplace. Successful transfusion would not, however, be possible without the realization that the cells and tissues of individuals are distinct and that introduction of blood of one individual into another may cause an adverse reaction with subsequent destruction of the donated cells. Such reactions come about because there are substances — so-called blood group antigens — on the surface of the cells of the blood, especially on the red cells, or erythrocytes, which may interact with antibodies in another person's blood, leading to red cell destruction. Fortunately, although there are many different antigens on cells, only a small number of them limit transfusion compatibility. These have been designated into major groups, the so-called blood groups. The most well known is the ABO system. If, for example, a donor's cells have the A antigen, that blood cannot be given to a person whose blood contains Anti-A antibodies, because the red cells would be destroyed. Incompatibility of blood groups, usually in this instance of the Rhesus system, is also important in the condition of haemolytic disease of the new-born (HDN).

In the ABO system, the surface antigens of the red cells are determined by three genes, A, B, and O. (The genes are referred to by an italicized character, e.g. A, whilst the gene product (phenotype) and hence the blood groups are referred to by simple uppercase letter, e.g. group A.) All red cells have on their surface a glycolipid substance called H substance. The A gene and the B gene convert H substance into substance A and B, giving rise to cells of the A and B groups respectively. The O gene has no effect on H substance and thus group O cells have only H substance on their surface. These three genes combine in pairs to give six possible genotypes, AA, AO, BB, BO, AB, and OO. Since A and B are dominant over O, this results in four phenotypes: A, B, AB and O (see table). Eighty per cent of individuals also have A, B, and H substances in secretions such as tears and saliva.

Since, under normal circumstances, individuals do not form antibodies against their own proteins and since all red cells have H substance, no naturally occurring antibodies against H substance are found. Likewise individuals with group A cells (genotypes AA, AO, or AB), do not have antibodies against A substance in their plasma and individuals with group B cells (genotype BB, BO, or AB) do not have antibodies against B substance. However, substances closely related to A and B are widely distributed in nature and absorption of these from the gut, presumably shortly after birth, is thought to give rise to antibodies against A and/or B if that individual does not possess A and/or B antigens on their red cells. Thus, individuals who are group A have antibodies against B substance and those who are group B have antibodies against A substance.

Thus, an individual who is group AB should be able to receive cells of any group, since he would not have antibodies against any blood group substance and the transfused cells would not be destroyed. Likewise, it should be possible to transfuse group O blood into any individual, since the transfused cells will contain neither A nor B substance, but only O, and any antibodies against either A or B substance in the recipient plasma will be without effect. As group O cells do not react with anti-A or anti-B antibodies, people of group O became known as universal donors. But it is not quite as simple as that.

Genotype	Red cell antigen	Phenotype	Antibodies in	Frequency, UK,
			blood plasma	%
OO	None	O	Anti-A, B	46
AA or AO	A	A	Anti-B	42
BB or BO	B	B	Anti-A	9
AB	AB	AB	None	3

Although the ABO blood group system is the one which is of greatest concern in blood transfusion, approximately 400 blood group antigens have been described and, before blood transfusion is attempted, it is essential that the blood of the recipient and the blood of the donor are directly matched by a laboratory test to avoid incompatibility. The other blood grouping which is a common cause of transfusion incompatibility is the Rhesus system, and occasional reactions are encountered as a result of incompatibility in other systems.

The Rhesus (Rh) system is the usual cause of the so-called haemolytic disease of the new-born, although, rarely, the other grouping systems can be responsible. The Rh system derives its name from the discovery by Landsteiner and Wiener in 1940 that injection of red cells from a Rhesus monkey into a rabbit caused the production of antibodies, and that these antibodies reacted with the red cells of some humans (so-called Rh-positive individuals), but not others (Rh-negative individuals). Similar antibodies were found in the plasma of mothers who had given birth to children with HDN. The development of jaundice and anaemia soon after birth, and the occasional death of such infants was previously a mystery. The definition of the Rh group of an individual depends on the presence of a substance D; those whose cells have the D antigen are Rh positive, and their cells are attacked by D antibodies in blood of a person who is Rh negative. Clinically, only the D antigen and the anti-D antibody are important, although other (C and E) substances also differ between the groups.

Haemolytic disease of the new-born is the result of the passage of antibodies from the maternal circulation across the placenta into the fetal circulation, where they damage the red cells. The condition arises where the mother is Rh-negative but the fetus, and the father, are Rh-positive. At the time of birth in a first pregnancy in these circumstances, there is no damage to the infant, but fetal red cells leak into the maternal circulation, immunizing the mother and causing the production of antibodies. These antibodies are small enough in size to cross the placenta and enter the fetal circulation during subsequent pregnancies, causing HDN if the fetus is again Rh-positive. Often this is confined to mild anaemia, but in more serious cases the baby is severely anaemic and jaundiced because of the accumulation of bilirubin released from damaged red cells. In the 1940s complete ‘exchange transfusion’ — replacing the whole of the infant's blood via the umbilical cord soon after birth — started to be employed as a life saving measure. Fortunately, the risk of HDN caused by Rhesus incompatibility is now reduced enormously by the administration of an anti-D antibody to the mother at the time of the birth of the first and any subsequent Rh-positive child, thus removing fetal red cells from the maternal circulation before they can stimulate permanent production of antibody.

— D. E. Bowyer

n.pl

The division of blood into types on the basis of the compatibility of the erythrocytes and serum of one individual with the erythrocytes and serum of another individual. The groups are immunologically and genetically distinct.

See blood type.

The phenotype of erythrocytes defined by one or more cellular antigenic structural groupings under the control of allelic genes. The identification of specific blood groups is little used in veterinary medicine, except for the identification of parents, usually in horses and farm animals, and for purposes of selecting blood donors. For blood transfusions the usual practice is to carry out direct matching tests to avoid problems created by incompatibility. For blood group systems,