Blood groups

blood groups, differentiation of blood by type, classified according to immunological (antigenic) properties, which are determined by specific substances on the surface of red blood cells. Blood groups are genetically determined and each is characterized by the presence of a specific complex carbohydrate. About 200 different blood group substances have been identified and placed within 19 known blood group systems. The most commonly encountered blood group system is the ABO, or Landsteiner, system. Individuals may contain the A, B, or both A and B antigenic substances, or else lack these substances (type O). In the ABO system an individual who lacks one or more of these antigens will spontaneously develop the corresponding antibodies (agglutinins) shortly after birth. Thus a person with A type blood will naturally produce anti-B agglutinins, a person with B blood will produce anti-A agglutinins, and a person with O blood will produce anti-A and anti-B agglutinins; but a person with AB blood will not produce any agglutinins in this blood group system. Since these agglutinins are always present in the blood, in blood transfusion the donor blood must be compatible with the recipient's blood, i.e., the donor's blood must not contain antigen corresponding to the recipient's antibody. Other blood group systems, such as the MNSs, Lewis, Lutheran, and P systems, are not as important in transfusion because they act like true antigen-antibody systems, i.e., antibodies do not appear in blood plasma until the individual has been immunized by exposure to the other blood group antigens as in previous transfusions. In general, blood group substances are weak antigens, and antibody formation after transfusion occurs less than 3% of the time. Immunization can occur by pregnancy as well as by transfusion. Thus, in the Rh factor blood group system, an Rh-negative mother carrying an Rh-positive fetus produces anti-Rh antibodies against fetal red blood cells that cross the placenta. Since blood type is a genetic trait that is easy to test and the blood type of an individual is related to his or her parent's blood types by the laws of Mendelism (see under Mendel, Gregor), blood group typing is used legally to establish paternity. Anthropologists use the frequency of occurrence of various blood groups as tools to study racial or tribal origins.

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Blood groups

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 Antibody, Antigen

1 

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 glyco-lipid, 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.

2 

Human blood group systems

	System	ISBT*	System	Antigens	Chromosome
	name	symbol	number	in system	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 Blood, Immunology