INTRODUCTION Blood can be divided into two main parts, the blood plasma and the blood cells,

and both will be discussed later in this chapter. Many medical terms contain hemo- or hemato as a prex, derived from the Greek word haima (blood). Blood is distributed throughout an organism by a circulatory system and there exist three types of circulatory systems:. No circulatory system exists for instance in atworms (Platyhelminthes).. An open circulatory system is present in many invertebrates like molluscs and arthropods. The circulatory uid is called hemolymph and there is no distinction between blood and the interstitial uid. The closed circulatory system is present in all vertebrates. The blood never leaves the blood vessels system, or cardiovascular system, which is composed of arteries, veins and capillaries. SHORT HISTORY Already in ancient times people realized that blood was a special liquid with special but somehow obscure and unexplainable properties. The Greeks had already realized the importance of blood and Hippocrates of Kos (ca. 460BCca. 370 BC), often referred to as The Father of Medicine, proposed that diseases are based on an imbalance of the four humors, blood, phlegm, yellow bile and black bile, implying a physical cause of diseases and not a divine origin. He also introduced the Hippocratic Oath, a prescription of practices for physicians, which remains in use today. The Greek physician Galen (129ca. 200), working in Rome, knew that the blood vessels carry blood and he identied venous (dark red) and arterial (brighter and thinner) blood and assigned them distinct and separate functions. Galens observations, hypotheses and ideas and his triadic plan of physiology had a great inuence on medicine for more than a thousand years until the Renaissance. Ibn-el-Nas (12081288), born near Damascus, is thought to have been the rst to describe accurately the blood circulation in the human body. The famous Italian Leonardo da Vinci (14521519), a genius of extraordinary originality, despite of his own extensive and thoroughly executed studies and observations, was not in the position to develop a new comprehensive theory of the circulatory system and remained with the principles of the Galenic school. The English physician William Harvey (15781657) is credited to have been the rst to describe correctly and in great detail blood being pumped by the heart through the blood circulatory system. Already in ancient timesrst experiments dealing with blood transfusion have been described, but with little success. Blood coagulation and brinolysis were unknown processes and in consequence substances with anticoagulant properties were not available. The rst well-documented and successful blood transfusion was performed by the French physician Jean-Baptiste Denys (16251704) in 1667 using sheep blood and administering it to a 15 year old boy. At the beginning of the nineteenth century initial blood transfusion experiments from men to men were performed and the English physician James Blundell (17911878) was the rst to administer a successful human-to-human transfusion (in 1818) by extracting blood from the patients husband and then transfusing it to his wife. It took until the end of the

nineteenth century before the rst successful blood transfusions from vena to vena were carried out. The observation of blood group substances and the description of the ABO blood group system (described later in this chapter) at the beginning of the twentieth century by the Austrian biologist and physician Karl Landsteiner (18681943) was a great step in blood research and in blood transfusion. Landsteiner was rewarded with the Nobel Prise in Physiology and Medicine in 1930 for his achievements. In addition, together with theAmerican physician Alexander S.Wiener (19071976), Landsteiner was also the rst to identify the Rhesus factor in 1937. The description of the anticoagulant properties of sodium citrate in 1914 led in 1915 to the rst blood transfusions with conserved blood, which eventually saved many lives during the First World War. BLOOD COMPONENTS Blood is a very complex mixture of many types of components with very diverse properties and is often referred to as liquid organ. Its distribution via the vascular system throughout the whole body is essential for the existence of the organism. Blood exhibits a wide variety of functions and the description of one type of component, the blood plasma proteins, is the topic of this book. The main functions of blood are the following: Transport system of many types of components: Blood cells, e.g. erythrocytes to transport oxygen Low molecular weight compounds, e.g. salts and ions High molecular weight compounds, e.g. proteins Defence system against hostile pathogens such as bacteria, virus and fungi, thus maintaining a balance between the organism and the environment: Specialised cells, e.g. lymphocytes, monocytes and granulocytes Antibodies, e.g. IgG Components of the complement system The wound sealing and wound healing system, life-saving precautions in the case of injuries: Blood cells, e.g. blood platelets Blood coagulation and brinolysis The balance of heat distribution throughout the body, thus guaranteeing a constant body temperature. Blood can be separated by sedimentation into two main parts:

1. The blood cells, which are primarily synthesised in the bone marrow, represent approximately 45 % (by vol.) of entire blood. 2. The blood plasma or liquid portion of the blood represents approximately 55 % of the entire blood. Blood cells In a process termed haematopoiesis the adult blood cells are slowly differentiated under the inuence of growth factors such as the colony-stimulating factor (CSF) and erythropoietin (see Chapter 14) from a homogeneous progenitor cell population, the pluripotent stem cells, into the various adult blood cells. In the fetal stage of development this process takes place primarily in the placenta, the fetal liver and in the bone marrow; in the adult stage this process is limited to the bone marrow.In the rst stage of differentiation two types of precursor cells are developed, which are the progenitor cells of all subsequent cell types: 1. Lymphoid precursor cells, which are differentiated into the various types of lymphocytes such as B lymphocytes and T lymphocytes. 2. Myeloid precursor cells, which are further differentiated into erythrocytes, leukocytes and thrombocytes.

Fig: Differentiation of the various types of blood cells

The various types of blood cells are slowly differentiated from homogeneous pluripotent stem cells into lymphoid and myeloid precursor cells and .nally into adult blood cells. Blood contains three main types of cells: 1. Erythrocytes or red blood cells. The term is derived from two Greek words: erythros (red) and kytos (hollow). Erythrocytes are biconcave, .attened cells with a discoid shape containing no nucleus and have a diameter of approximately 7.5_10_3 mm, a thickness of approximately 2_10_3mm and an expected lifetime of 100120 days. Blood contains approximately 4 5_109 erythrocytes/ml of blood, representing approximately 96 % of all blood cells. In adults erythrocytes are produced in the bone marrow and are disposed in the spleen. Erythrocytes contain the protein hemoglobin in vast amounts responsible for the red colour of blood. Each erythrocyte carries approximately 3_108 hemoglobin molecules. Erythrocytes are the main carrier of oxygen from the lung to the peripheral tissues such as muscles, liver and intestines. Erythrocytes are quite easily deformed, thus enabling a safe passage through the narrow blood capillary system.

Fig: Electron micrograph of erythrocytes

2. Leukocytes or white blood cells. The term is derived from two Greek words: leukos (white) and kytos (hollow). Blood contains approximately 48_106 leukocytes/ml of blood with an approximate size of 715_10_3 mm, representing only approximately 3%of all blood cells. Leukocytes are involved in the immune defence and produce antibodies on one side and are differentiated into memory cells on the other side. Three main subtypes exist: (a) Granulocytes.

The expression is derived from the Latin word granula (granule). Granulocytes represent approximately 70%of leukocytes and contain a nucleolus and their lifetime is only a few hours. Three types of granulocytes exist, termed according to their staining properties. (i) Neutrophils represent approximately 65 % of leukocytes and are usually the .rst to respond to bacterial infection and are involved in smaller in.ammatory processes. (ii) Eosinophils represent approximately 4 % of leukocytes and primarily react against infections by parasites. (iii) Basophils represent <1 % of leukocytes and are mainly responsible for antigenic and allergic response by histamine release, thus causing in.ammation. They are all polymorphic nuclear cells. (b) Monocytes or macrophages (once they have entered tissue). Monocytes are the largest leukocytes with a lifetime of one to two days and represent approximately 6 % of leukocytes. The term macrophage is derived from two Greek words: macros (large) and phagein (eat). They are large devouring cells, which ingest foreign cells, dead cells and cell debris by endocytosis. (c) Lymphocytes. Lymphocytes represent approximately 25%of leukocytes and produce the antibodies, approximately 2000 molecules/second, and lymphocyte. There are three types of lymphocytes in blood: (i) Bcells (B stands for the origin from the bone marrow) produce the antibodies and have a memory for previously ingested pathogens in the form of memory Bcells and therefore their lifetime might reach several tenths of years. (ii) T cells (T stands for the origin from the thymus gland) play a central role in cell-mediated immunity. Several subtypes of T cells exist with distinct functions: Monocytes and lymphocytes are so-called agranulocytes, characterized by the absence of granules in the cytoplasm. The various types of leukocytes are shown in Figure 2.3. Neutrophils represent approximately 65%of all leukocytes and exhibit a rather spherical shape (Figure(a)), with a diameter of 1215_10_3 mm. Macrophages are the largest leukocytes and represent approximately 6%of all leukocytes (Figure (b)). Lymphocytes represent approximately 25 % of all leukocytes. B lymphocytes are shown as an example in Figure (c).

(b)

(c)
Fig: Electron micrographs of various types of leukocytes

Fig: Electron micrographs of platelets

3. Thrombocytes or platelets. Platelets contain no nucleus and exhibit a discoid shape with a diameter of approximately 13_10_3mm and their life time is 810

days. Blood contains approximately 23_108 platelets/ml of blood. Blood platelets are essential in the healing process of vascular injuries by closing the site of injury via intercalation with the fibrin network during the coagulation cascade (see Chapter 7). During this process activated platelets undergo a dramatic shape change from discoid to spherical, exposing spines termed pseudopodia (shown in Figure 2.4(a)), which become sticky, thus annealing the injured blood vessel. Figure 2.4(b) shows spherical platelets embedded in the .brin network at the beginning of clot formation. Blood plasma The liquid part of blood, the blood plasma, represents approximately 55%(by volume) of entire blood. There are many types of components dissolved in blood plasma, which exhibit very different functions. The components of blood plasma can be divided into several groups: 1. Water. Water is by far the main component of blood plasma, approximately 90 %. 2. Mineral salts and ions. There are many salts and ions dissolved in blood plasma, e.g. sodium chloride (at physiological concentration), buffer salts such as bicarbonate to guarantee a constant pH or metal ions such as calcium, copper or iron, which are essential in many biological processes and are contained in many blood plasma proteins, as will be seen later. 3. Low molecular weight components. Blood plasma contains many types of low molecular weight compounds: carbohydrates such as glucose and fructose, the whole set of amino acids, nucleotides such as ATP and cAMP, many vitamins, hormones, fatty acids, lipids and triglycerides, bile acids, urea and ammonia and many more components. 4. High molecular weight components. Peptides and (glyco)-proteins, oligosaccharides and polysaccharides, oligonucleotides and polynucleotides, e.g. DNA and RNA. 5. Gases in soluble form. Many gases such as oxygen, carbon dioxide and nitric oxide are dissolved in blood. 6. Metabolites. Blood plasma serves not only as the medium to transport the abovementioned components but also the products of the metabolism. The blood group system At the beginning of the twentieth century Karl Landsteiner described blood group substances that evolved into the ABO blood group system.

The cell surface of cells such as erythrocytes or endothelial cells of the blood vessels are composed of a glycocalyx containing glycolipids and glycoproteins with complex carbohydrate structures. The glycocalyx exhibits many functions such as protection from physical and chemical damage, reducing friction in blood .ow and preventing loss of .uid through the blood vessel wall. The membrane of erythrocytes contains more than 100 blood group eterminants, of which at least 15 are genetically different. However, there are mainly three systems in clinical use: 1. TheABOblood group system. TheABOblood group system contains three antigens: A, B and O (H). The blood group genes code for glycosyltransferases (EC 2.4): (a) A: N-acetylgalactoseamine transferase. (b) B: galactosyltransferase (this sequence differs from A at only four positions). (c) O (H): neither enzyme A or B, fucose is the terminal sugar moiety and is not antigenic. The O phenotype results from a single base deletion in the N-terminal region of the gene, leading to a frame shift.

Blood type

Blood type (or blood group) is determined, in part, by the ABO blood group antigens present on red blood cells. A blood type (also called a blood group) is a classification of blood based on the presence or absence of inherited antigenic substances on the surface of red blood cells (RBCs). These antigens may be proteins, carbohydrates, glycoproteins, or glycolipids, depending on the blood group system. Some of these antigens are also present on the surface of other types of cells of various tissues. Several of these red blood cell surface antigens that stem from one allele (or very closely linked genes), collectively form a blood group system.[1] Blood types are inherited and represent contributions from both parents. A total of 30 human blood group systems are now recognized by the International Society of Blood Transfusion (ISBT).[2] Many pregnant women carry a fetus with a different blood type from their own, and the mother can form antibodies against fetal RBCs. Sometimes these maternal antibodies are IgG, a small immunoglobulin, which can cross the placenta and cause hemolysis of fetal RBCs, which in turn can lead to hemolytic disease of the newborn, an illness of low fetal blood counts which ranges from mild to severe.[3]

Serology
If an individual is exposed to a blood group antigen that is not recognized as self, the immune system may produce antibodies that can specifically bind to that particular blood group antigen, and an immunological memory against that antigen is formed. The individual will have become sensitized to that blood group antigen. These antibodies can bind to antigens on the surface of transfused red blood cells (or other tissue cells), often leading to destruction of the cells by recruitment of other components of the immune

system. When IgM antibodies bind to the transfused cells, the transfused cells can clump. It is vital that compatible blood is selected for transfusions and that compatible tissue is selected for organ transplantation. Transfusion reactions involving minor antigens or weak antibodies may lead to minor problems. However, more serious incompatibilities can lead to a more vigorous immune response with massive RBC destruction, low blood pressure, and even death.

ABO and Rh blood grouping

Agglutination of blood cells tested with antibodies for determination of blood type in the laboratory. The discovery of this type of agglutination was an important medical breakthrough.[4] Anti-A and Anti-B, the common IgM antibodies to the RBC surface antigens of the ABO blood group system, are sometimes described as being "naturally occurring"; however, this is a misnomer, because these antibodies are formed in infancy by sensitization in the same way as other antibodies. The theory that explains how these antibodies are developed states that antigens similar to the A and B antigens occur in nature, including in food, plants, and bacteria. After birth an infant's gut becomes colonized with normal flora that express these A-like and B-like antigens, causing the immune system to make antibodies to those antigens that the red blood cells do not possess. People who are blood type A will have Anti-B antibodies, blood type B will have Anti-A antibodies, blood type O will have both Anti-A and Anti-B antibodies, and blood type AB will have neither. Because of these so called "naturally occurring" and expected antibodies, it is important to correctly determine a patient's blood type prior to transfusion of any blood component. These "naturally occurring" antibodies are of the IgM class, which have the capability of agglutinating (clumping) and damaging red blood cells within the blood vessels, possibly leading to death. It is not necessary to determine any other blood groups because almost all other red blood cell antibodies can develop only through active immunization, which can occur only through either previous blood transfusion or pregnancy. A test called the Antibody Screen is always performed on patients who may require red blood cell transfusion, and this test will detect most clinically significant red blood cell antibodies. The D antigen of the Rh blood group system is also important in determining a person's blood type. The terms "positive" or "negative" refer to either the presence or absence of the D antigen irrespective of the presence or absence of the other antigens of the Rh system. Anti-D is not a naturally occurring antibody as the Anti-A and Anti-B antibodies

are. Cross-matching for the D antigen is extremely important, because the D antigen is immunogenic, meaning that a person who is D negative is very likely to make Anti-D when exposed to the D antigen (perhaps through either transfusion or pregnancy). Once an individual is sensitized to D antigens, his or her blood will contain D IgG antibodies, which can bind to D positive RBCs and may cross the placenta.[5]

Blood group systems

A total of 30 human blood group systems are now recognized by the International Society of Blood Transfusion (ISBT).[2] A complete blood type would describe a full set of 30 substances on the surface of RBCs, and an individual's blood type is one of the many possible combinations of blood-group antigens. Across the 30 blood groups, over 600 different blood-group antigens have been found,[6] but many of these are very rare or are mainly found in certain ethnic groups. Almost always, an individual has the same blood group for life, but very rarely an individual's blood type changes through addition or suppression of an antigen in infection, malignancy, or autoimmune disease.[7][8][9][10] An example of this rare phenomenon is the case of Demi-Lee Brennan, an Australian citizen, whose blood group changed after a liver transplant.[11][12] Another more common cause in blood-type change is a bone marrow transplant. Bone-marrow transplants are performed for many leukemias and lymphomas, among other diseases. If a person receives bone marrow from someone who is a different ABO type (eg, a type A patient receives a type O bone marrow), the patient's blood type will eventually convert to the donor's type. Some blood types are associated with inheritance of other diseases; for example, the Kell antigen is sometimes associated with McLeod syndrome.[13] Certain blood types may affect susceptibility to infections, an example being the resistance to specific malaria species seen in individuals lacking the Duffy antigen.[14] The Duffy antigen, presumably as a result of natural selection, is less common in ethnic groups from areas with a high incidence of malaria.[15]

ABO blood group system

ABO blood group system - diagram showing the carbohydrate chains that determine the ABO blood group Main article: ABO blood group system The ABO system is the most important blood-group system in human-blood transfusion. The associated anti-A antibodies and anti-B antibodies are usually "Immunoglobulin M", abbreviated IgM, antibodies. ABO IgM antibodies are produced in the first years of life by sensitization to environmental substances such as food, bacteria, and viruses. The "O" in ABO is often called "0" (zero/null) in other languages.[16] Phenotype A B AB O Genotype AA or AO BB or BO AB OO

Rh blood group system

The Rh system is the second most significant blood-group system in human-blood transfusion with currently 50 antigens. The most significant Rh antigen is the D antigen because it is the most immunogenic of the five main rhesus antigens. It is common for Dnegative individuals not to have any anti-D IgG or IgM antibodies, because anti-D antibodies are not usually produced by sensitization against environmental substances. However, D-negative individuals can produce IgG anti-D antibodies following a sensitizing event: possibly a fetomaternal transfusion of blood from a fetus in pregnancy or occasionally a blood transfusion with D positive RBCs.[5] Rh disease can develop in these cases.[17]

ABO and Rh distribution by country

[show]Racial & Ethnic Distribution of ABO (without Rh) Blood Types[46] ABO and Rh blood type distribution by nation (population averages) (This table has more entries than the table above but does not distinguish between Rh types.) Country Population[18] A+ B+ AB+ OAPEOPLE GROUP OO+ A B AB [19] Australia Aborigines 21,262,641 40% 31% 8% 2% 9% 7% 61 39 0 0 Austria[20] Abyssinians 8,210,281 30% 33% 12% 6% 7% 8% 43 27 25 5 [21] Belgium Ainu (Japan) 10,414,336 38% 34% 8.5% 4.1% 7% 6% 17 32 32 18 Brazil[22] Albanians 198,739,269 36% 34% 8% 2.5% 9% 8% 38 43 13 6 [23] Canada Grand Andamanese33,487,208 39% 36% 7.6% 2.5% 7% 6% 9 60 23 9 Denmark[24] 5,500,510 35% 37% 8% 4% 6% 7% Arabs 34 31 29 6 [25] Estonia Armenians 1,299,371 30% 31% 20% 6% 4.5% 4.5% 31 50 13 6 Finland[26] Asian (in USA - General) 5,250,275 27% 38% 15% 7% 4% 6% 40 28 27 5 [27] France Austrians 62,150,775 36% 37% 9% 3% 6% 7% 36 44 13 6 Germany[28] 82,329,758 35% 37% 9% 4% 6% 6% Bantus 46 30 19 5 [29] Hong Kong SAR 7,055,071 40% 26% 27% 7% 0.31% 0.19% Basques 51 44 4 1 Iceland[30] Belgians 306,694 47.6% 26.4% 9.3% 1.6% 8.4% 4.6% 47 42 8 3 India[31] Blackfoot (N. Am. Indian) 1,166,079,217 17 36.5% 22.1% 30.9% 6.4% 2.0% 0.8% 82 0 1 Ireland[32] Bororo (Brazil) 4,203,200 47% 26% 9% 2% 8% 5% 100 0 0 0 [33] Israel 7,233,701 32% 34% 17% 7% 3% 4% Brazilians 47 41 9 3 [34] Netherlands 16,715,999 39.5% 44 35% 6.7% 2.5% 7.5% 7% Bulgarians 32 15 8 [35] New Zealand 4,213,418 38% 32% 9% 3% 9% 6% Burmese 36 24 33 7 [36] Norway Buryats (Siberia) 4,660,539 34% 42.5% 6.8% 3.4% 6% 7.5% 33 21 38 8 [37] Poland Bushmen 38,482,919 31% 32% 15% 7% 6% 6% 56 34 9 2 [38] Portugal Chinese-Canton 10,707,924 36.2% 39.8% 6.6% 2.9% 6.0% 6.6% 46 23 25 6 Saudi Arabia[39] 28,686,633 48% 24% 17% 4% 4% 2% Chinese-Peking 29 27 32 13 [40] South Africa 49,320,000 39% 32% 12% 3% 7% 5% Chuvash 30 29 33 7 Spain[41] Czechs 40,525,002 36% 34% 8% 2.5% 9% 8% 30 44 18 9 [42] Sweden Danes 9,059,651 32% 37% 10% 5% 6% 7% 41 44 11 4 Turkey[43] Dutch 76,805,524 29.8% 37.8% 14.2% 7.2% 3.9% 4.7% 45 43 9 3 [44] United Kingdom 61,113,205 37% 35% 8% 3% 7% 7% Egyptians 33 36 24 8 United States[45] 307,212,123 37.4% 35.7% 8.5% 3.4% 6.6% 6.3% English 47 42 9 3 . Eskimos (Alaska) 38 44 13 5 Population-weighted (total population 54 Eskimos (Greenland) 36 23 8 36.44% 28.27% 20.59% 5.06% 4.33% 3.52% mean = 2,261,025,244) Estonians 34 36 23 8 Fijians 44 34 17 6

BAB2% 1% 3% 1% 1.5% 0.8% 2% 0.5% 1.4% 0.5% 2% 1% 3% 1% 2% 1% 1% 1% 2% 1% 0.14% 0.05% 1.7% 0.4% 1.1% 0.2% 2% 1% 2% 1% 1.3% 0.5% 2% 1% 1.2% 0.6% 2% 1% 1.1% 0.5% 1% 0.23% 2% 1% 2% 0.5% 2% 1% 1.6% 0.8% 2% 1% 1.5% 0.6% 1.39% 0.45%

Finns French Georgians Germans Greeks Gypsies (Hungary) Hawaiians Hindus (Bombay) Hungarians Icelanders Indians (India - General) Indians (USA - General) Irish Italians (Milan) Japanese Jews (Germany) Jews (Poland) Kalmuks Kikuyu (Kenya) Koreans Lapps Latvians Lithuanians Malaysians Maoris Mayas Moros Navajo (N. Am. Indian) Nicobarese (Nicobars) Norwegians Papuas (New Guinea) Persians Peru (Indians) Filipinos Poles

34 43 46 41 40 29 37 32 36 56 37 79 52 46 30 42 33 26 60 28 29 32 40 62 46 98 64 73 74 39 41 38 100 45 33

41 47 37 43 42 27 61 29 43 32 22 16 35 41 38 41 41 23 19 32 63 37 34 18 54 1 16 27 9 50 27 33 0 22 39

18 7 12 11 14 35 2 28 16 10 33 4 10 11 22 12 18 41 20 31 4 24 20 20 1 1 20 0 15 8 23 22 0 27 20

7 3 4 5 5 10 1 11 5 3 7 1 3 3 10 5 8 11 1 10 4 7 6 0 0 1 0 0 1 4 9 7 0 6 9

Portuguese Romanians Russians Sardinians Scots Serbians Shompen (Nicobars) Slovaks South Africans Spanish Sudanese Swedes Swiss Tartars Thais Turks Ukrainians USA (US blacks) USA (US whites) Vietnamese Mean Standard deviation

35 34 33 50 51 38 100 42 45 38 62 38 40 28 37 43 37 49 45 42 43.91 16.87

53 41 36 26 34 42 0 37 40 47 16 47 50 30 22 34 40 27 40 22 34.80 13.80

8 19 23 19 12 16 0 16 11 10 21 10 7 29 33 18 18 20 11 30 16.55 9.97

4 6 8 5 3 5 0 5 4 5 0 5 3 13 8 6 6 4 4 5 5.14 3.41

Blood group B has its highest frequency in Northern India and neighboring Central Asia, and its incidence diminishes both towards the west and the east, falling to single digit percentages in Spain.[47][48] It is believed to have been entirely absent from Native American and Australian Aboriginal populations prior to the arrival of Europeans in those areas.[48][49] Blood group A is associated with high frequencies in Europe, especially in Scandinavia and Central Europe, although its highest frequencies occur in some Australian Aborigine populations and the Blackfoot Indians of Montana.[50][51]

Other blood group systems

Main article: Human blood group systems

The International Society of Blood Transfusion currently recognizes 30 blood-group systems (including the ABO and Rh systems).[2] Thus, in addition to the ABO antigens and Rh antigens, many other antigens are expressed on the RBC surface membrane. For example, an individual can be AB, D positive, and at the same time M and N positive (MNS system), K positive (Kell system), Lea or Leb negative (Lewis system), and so on, being positive or negative for each blood group system antigen. Many of the blood group systems were named after the patients in whom the corresponding antibodies were initially encountered.

Clinical significance
Blood transfusion
Transfusion medicine is a specialized branch of hematology that is concerned with the study of blood groups, along with the work of a blood bank to provide a transfusion service for blood and other blood products. Across the world, blood products must be prescribed by a medical doctor (licensed physician or surgeon) in a similar way as medicines. In the USA, blood products are tightly regulated by the U.S. Food and Drug Administration.

Main symptoms of acute hemolytic reaction due to blood type mismatch.[52][53] Much of the routine work of a blood bank involves testing blood from both donors and recipients to ensure that every individual recipient is given blood that is compatible and is as safe as possible. If a unit of incompatible blood is transfused between a donor and recipient, a severe acute hemolytic reaction with hemolysis (RBC destruction), renal failure and shock is likely to occur, and death is a possibility. Antibodies can be highly active and can attack RBCs and bind components of the complement system to cause massive hemolysis of the transfused blood. Patients should ideally receive their own blood or type-specific blood products to minimize the chance of a transfusion reaction. Risks can be further reduced by crossmatching blood, but this may be skipped when blood is required for an emergency.

Cross-matching involves mixing a sample of the recipient's serum with a sample of the donor's red blood cells and checking if the mixture agglutinates, or forms clumps. If agglutination is not obvious by direct vision, blood bank technicians usually check for agglutination with a microscope. If agglutination occurs, that particular donor's blood cannot be transfused to that particular recipient. In a blood bank it is vital that all blood specimens are correctly identified, so labeling has been standardized using a barcode system known as ISBT 128. The blood group may be included on identification tags or on tattoos worn by military personnel, in case they should need an emergency blood transfusion. Frontline German Waffen-SS had blood group tattoos during World War II. Rare blood types can cause supply problems for blood banks and hospitals. For example Duffy-negative blood occurs much more frequently in people of African origin,[54] and the rarity of this blood type in the rest of the population can result in a shortage of Duffynegative blood for patients of African ethnicity. Similarly for RhD negative people, there is a risk associated with travelling to parts of the world where supplies of RhD negative blood are rare, particularly East Asia, where blood services may endeavor to encourage Westerners to donate blood.[55]

Hemolytic disease of the newborn (HDN)

A pregnant woman can make IgG blood group antibodies if her fetus has a blood group antigen that she does not have. This can happen if some of the fetus' blood cells pass into the mother's blood circulation (e.g. a small fetomaternal hemorrhage at the time of childbirth or obstetric intervention), or sometimes after a therapeutic blood transfusion. This can cause Rh disease or other forms of hemolytic disease of the newborn (HDN) in the current pregnancy and/or subsequent pregnancies. If a pregnant woman is known to have anti-D antibodies, the Rh blood type of a fetus can be tested by analysis of fetal DNA in maternal plasma to assess the risk to the fetus of Rh disease.[56] One of the major advances of twentieth century medicine was to prevent this disease by stopping the formation of Anti-D antibodies by D negative mothers with an injectable medication called Rho(D) immune globulin.[57][58] Antibodies associated with some blood groups can cause severe HDN, others can only cause mild HDN and others are not known to cause HDN.[3]

Compatibility
Blood products
In order to provide maximum benefit from each blood donation and to extend shelf-life, blood banks fractionate some whole blood into several products. The most common of these products are packed RBCs, plasma, platelets, cryoprecipitate, and fresh frozen plasma (FFP). FFP is quick-frozen to retain the labile clotting factors V and VIII, which are usually administered to patients who have a potentially fatal clotting problem caused

by a condition such as advanced liver disease, overdose of anticoagulant, or disseminated intravascular coagulation (DIC). Units of packed red cells are made by removing as much of the plasma as possible from whole blood units. Clotting factors synthesized by modern recombinant methods are now in routine clinical use for hemophilia, as the risks of infection transmission that occur with pooled blood products are avoided.

Red blood cell compatibility

Blood group AB individuals have both A and B antigens on the surface of their RBCs, and their blood serum does not contain any antibodies against either A or B antigen. Therefore, an individual with type AB blood can receive blood from any group (with AB being preferable), but can donate blood only to another type AB individual. Blood group A individuals have the A antigen on the surface of their RBCs, and blood serum containing IgM antibodies against the B antigen. Therefore, a group A individual can receive blood only from individuals of groups A or O (with A being preferable), and can donate blood to individuals with type A or AB. Blood group B individuals have the B antigen on the surface of their RBCs, and blood serum containing IgM antibodies against the A antigen. Therefore, a group B individual can receive blood only from individuals of groups B or O (with B being preferable), and can donate blood to individuals with type B or AB. Blood group O (or blood group zero in some countries) individuals do not have either A or B antigens on the surface of their RBCs, but their blood serum contains IgM anti-A antibodies and anti-B antibodies against the A and B blood group antigens. Therefore, a group O individual can receive blood only from a group O individual, but can donate blood to individuals of any ABO blood group (ie A, B, O or AB). If anyone needs a blood transfusion in a dire emergency, and if the time taken to process the recipient's blood would cause a detrimental delay, O Negative blood can be issued.

RBC Compatibility chart In addition to donating to the same blood group; type O blood donors can give to A, B and AB; blood donors of types A and B can give to AB. Red blood cell compatibility table[59][60] Donor[1] O O+ A A+ B B+

Recipient[1] O O+ A A+ B B+ AB AB+

AB

AB+

Table note 1. Assumes absence of atypical antibodies that would cause an incompatibility between donor and recipient blood, as is usual for blood selected by cross matching.

A Rh D-negative patient who does not have any anti-D antibodies (never being previously sensitized to D-positive RBCs) can receive a transfusion of D-positive blood once, but this would cause sensitization to the D antigen, and a female patient would become at risk for hemolytic disease of the newborn. If a D-negative patient has developed anti-D antibodies, a subsequent exposure to D-positive blood would lead to a potentially dangerous transfusion reaction. Rh D-positive blood should never be given to D-negative women of child bearing age or to patients with D antibodies, so blood banks must conserve Rh-negative blood for these patients. In extreme circumstances, such as for a major bleed when stocks of D-negative blood units are very low at the blood bank, D-positive blood might be given to D-negative females above child-bearing age or to Rhnegative males, providing that they did not have anti-D antibodies, to conserve Dnegative blood stock in the blood bank. The converse is not true; Rh D-positive patients do not react to D negative blood. This same matching is done for other antigens of the Rh system as C, c, E and e and for other blood group systems with a known risk for

immunization such as the Kell system in particular for females of child-bearing age or patients with known need for many transfusions.

Plasma compatibility

Plasma compatibility chart In addition to donating to the same blood group; plasma from type AB can be given to A, B and O; plasma from types A and B can be given to O. Recipients can receive plasma of the same blood group, but otherwise the donor-recipient compatibility for blood plasma is the converse of that of RBCs: plasma extracted from type AB blood can be transfused to individuals of any blood group; individuals of blood group O can receive plasma from any blood group; and type O plasma can be used only by type O recipients. Plasma compatibility table[60] Recipient Donor[1] O A B AB O A B AB
Table note 1. Assumes absence of strong atypical antibodies in donor plasma

Rh D antibodies are uncommon, so generally neither D negative nor D positive blood contain anti-D antibodies. If a potential donor is found to have anti-D antibodies or any strong atypical blood group antibody by antibody screening in the blood bank, they would not be accepted as a donor (or in some blood banks the blood would be drawn but the product would need to be appropriately labeled); therefore, donor blood plasma issued by a blood bank can be selected to be free of D antibodies and free of other atypical antibodies, and such donor plasma issued from a blood bank would be suitable for a recipient who may be D positive or D negative, as long as blood plasma and the recipient are ABO compatible.

Universal donors and universal recipients

With regard to transfusions of whole blood or packed red blood cells, individuals with type O Rh D negative blood are often called universal donors, and those with type AB Rh D positive blood are called universal recipients; however, these terms are only generally true with respect to possible reactions of the recipient's anti-A and anti-B antibodies to transfused red blood cells, and also possible sensitization to Rh D antigens. Exceptions include individuals with hh antigen system (also known as the Bombay blood group) who can only receive blood safely from other hh donors, because they form antibodies against the H substance.[61][62] Blood donors with particularly strong anti-A, anti-B or any atypical blood group antibody are excluded from blood donation. The possible reactions of anti-A and anti-B antibodies present in the transfused blood to the recipients RBCs need not be considered, because a relatively small volume of plasma containing antibodies is transfused. By way of example: considering the transfusion of O Rh D negative blood (universal donor blood) into a recipient of blood group A Rh D positive, an immune reaction between the recipient's anti-B antibodies and the transfused RBCs is not anticipated. However, the relatively small amount of plasma in the transfused blood contains anti-A antibodies, which could react with the A antigens on the surface of the recipients RBCs, but a significant reaction is unlikely because of the dilution factors. Rh D sensitization is not anticipated. Additionally, red blood cell surface antigens other than A, B and Rh D, might cause adverse reactions and sensitization, if they can bind to the corresponding antibodies to generate an immune response. Transfusions are further complicated because platelets and white blood cells (WBCs) have their own systems of surface antigens, and sensitization to platelet or WBC antigens can occur as a result of transfusion. With regard to transfusions of plasma, this situation is reversed. Type O plasma, containing both anti-A and anti-B antibodies, can only be given to O recipients. The antibodies will attack the antigens on any other blood type. Conversely, AB plasma can be given to patients of any ABO blood group due to not containing any anti-A or anti-B antibodies.

Blood group genotyping

In addition to the current practice of serologic testing of blood types, the progress in molecular diagnostics allows the increasing use of blood group genotyping. In contrast to serologic tests reporting a direct blood type phenotype, genotyping allows the prediction of a phenotype based on the knowledge of the molecular basis of the currently known antigens. This allows a more detailed determination of the blood type and therefore a better match for transfusion, which can be crucial in particular for patients with needs for many transfusions to prevent allo-immunization.[63][64]

Conversion
In April 2007 a method was discovered to convert blood types A, B, and AB to O, using enzymes. This method is still experimental and the resulting blood has yet to undergo human trials.[65][66] The method specifically removes or converts antigens on the red blood cells, so other antigens and antibodies would remain. This does not help plasma compatibility, but that is a lesser concern since plasma has much more limited clinical utility in transfusion and is much easier to preserve.

History
The two most significant blood group systems were discovered by Karl Landsteiner during early experiments with blood transfusion: the ABO group in 1901[67] and in cooperation with Alexander S. Wiener the Rhesus group in 1937.[68] Development of the Coombs test in 1945,[69] the advent of transfusion medicine, and the understanding of hemolytic disease of the newborn led to discovery of more blood groups, and now 30 human blood group systems are recognized by the International Society of Blood Transfusion (ISBT),[2] and across the 30 blood groups, over 600 different blood group antigens have been found,[6] many of these are very rare or are mainly found in certain ethnic groups. Blood types have been used in forensic science and in paternity testing, but both of these uses are being replaced by genetic fingerprinting, which provides greater certainty [70].

Cultural beliefs and other claims

The Japanese blood type theory of personality is a popular belief that a person's ABO blood type is predictive of their personality, character, and compatibility with others. This belief is also widespread in South Korea.[71] Deriving from ideas of historical scientific racism, the theory reached Japan in a 1927 psychologist's report, and the militarist government of the time commissioned a study aimed at breeding better soldiers.[71] The fad faded in the 1930s due to its unscientific basis. The theory has long since been rejected by the scientists, but it was revived in the 1970s by Masahiko Nomi, a broadcaster who had no medical background.[71]

The blood type diet is a diet advocated by Peter D'Adamo, a naturopathic physician, and outlined in his book Eat Right 4 Your Type. D'Adamo's claim is that ABO blood type is an important factor in determining a healthy diet, and he promotes distinct diets for people with O, A, B, and AB blood types. This is viewed skeptically by many scientists and physicians (e.g.,http://www.earthsave.org/health/bloodtyp.htm).

References
1. ^ Maton, Anthea; Jean Hopkins, Charles William McLaughlin, Susan Johnson, Maryanna Quon Warner, David LaHart, Jill D. Wright (1993). Human Biology and Health. Englewood Cliffs, New Jersey, USA: Prentice Hall. ISBN 0-13981176-1. 2. ^ a b c d "Table of blood group systems". International Society of Blood Transfusion. October 2008. http://ibgrl.blood.co.uk/isbt%20pages/isbt %20terminology%20pages/table%20of%20blood%20group%20systems.htm. Retrieved 2008-09-12. 3. ^ a b E.A. Letsky; I. Leck, J.M. Bowman (2000). "Chapter 12: Rhesus and other haemolytic diseases". Antenatal & neonatal screening (Second ed.). Oxford University Press. ISBN 0-19-262827-7. 4. ^ D'Adamo, Peter J; Catherine Whitney (2002). Complete blood type encyclopedia: the A-Z reference guide for the blood type. Riverhead Books. ISBN 1573229202. http://books.google.es/books?id=TgPtBGDaAzwC. Retrieved 200909-10. 5. ^ a b Talaro, Kathleen P. (2005). Foundations in microbiology (5th ed.). New York: McGraw-Hill. pp. 5101. ISBN 0-07-111203-0. 6. ^ a b "American Red Cross Blood Services, New England Region, Maine, Massachusetts, New Hampshire, Vermont". American Red Cross Blood Services - New England Region. 2001. http://www.newenglandblood.org/medical/rare.htm. Retrieved 2008-07-15. "there are more than 600 known antigens besides A and B that characterize the proteins found on a person's red cells" 7. ^ Dean, Laura. "The ABO blood group". Blood Groups and Red Cell Antigens. online: NCBI. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi? book=rbcantigen&part=ch05ABO. "A number of illnesses may alter a person's ABO phenotype" 8. ^ Stayboldt C, Rearden A, Lane T (1987). "B antigen acquired by normal A1 red cells exposed to a patient's serum". Transfusion 27 (1): 414. doi:10.1046/j.15372995.1987.27187121471.x. PMID 3810822. 9. ^ Matsushita S, Imamura T, Mizuta T, Hanada M (1983). "Acquired B antigen and polyagglutination in a patient with gastric cancer". Jpn J Surg 13 (6): 5402. doi:10.1007/BF02469500. PMID 6672386. 10. ^ Kremer Hovinga I, Koopmans M, de Heer E, Bruijn J, Bajema I (2007). "Change in blood group in systemic lupus erythematosus". Lancet 369 (9557): 1867; author reply 187. doi:10.1016/S0140-6736(07)60099-3. PMID 17240276. 11. ^ Demi-Lee Brennan has changed blood types and immune system Kate Sikora, The Daily Telegraph, January 25, 2008

12. ^ Aust doctors hail teen's transplant 'miracle' Sean Rubinsztein-Dunlop, ABC News (Australia), January 24, 2008 13. ^ Allen FH Jr, Krabbe SM, Corcoran PA. A new phenotype (McLeod) in the Kell blood-group system. Vox Sang. 1961 Sep;6:555-60. PMID 13477267 14. ^ Miller LH, Mason SJ, Clyde DF, McGinniss MH. "The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy." N Engl J Med. 1976 Aug 5;295(6):302-4 PMID 778616 15. ^ Kwiatkowski, DP (August 2005). "How Malaria Has Affected the Human Genome and What Human Genetics Can Teach Us about Malaria". Am J Hum Genet. 77 (2): 171192. doi:10.1086/432519. Full text at PMC: 1224522. PMID 16001361. PMC 1224522. http://www.pubmedcentral.nih.gov/articlerender.fcgi? artid=1224522#N0x904fbd0.0x92f5ba8. Retrieved 2006-11-16."The different geographic distributions of thalassemia, G6PD deficiency, ovalocytosis, and the Duffy-negative blood group are further examples of the general principle that different populations have evolved different genetic variants to protect against malaria". 16. ^ "Your blood a textbook about blood and blood donation" (PDF). pp. 63. http://www.bloddonor.dk/fileadmin/Fil_Arkiv/PDF_filer/Andre/Your_Blood__Ju ne_2006.pdf. Retrieved 2008-07-15. 17. ^ http://www.ncbi.nlm.nih.gov/pubmed/18591322? ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pub med_DefaultReportPanel.Pubmed_RVDocSum 18. ^ CIA World Factbook 19. ^ Blood Types - What Are They?, Australian Red Cross 20. ^ Austrian Red Cross - Blood Donor Information 21. ^ Rode Kruis Wielsbeke - Blood Donor information material 22. ^ Tipos Sanguneos 23. ^ Types & Rh System, Canadian Blood Services 24. ^ Frequency of major blood groups in the Danish population. 25. ^ Veregruppide esinemissagedus Eestis 26. ^ Suomalaisten veriryhmjakauma 27. ^ "Les groupes sanguins (systme ABO)" (in French). Centre Hospitalier Princesse GRACE - Monaco. C.H.P.G. MONACO. 2005. http://www.chpg.mc/go/article.php3?id_article=111. Retrieved 2008-07-15. 28. ^ de:Blutgruppe#Hufigkeit der Blutgruppen 29. ^ Blood Donation, Hong Kong Red Cross 30. ^ Blflokkar 31. ^ Indian Journal for the Practising Doctor 32. ^ "Irish Blood Transfusion Service - Irish Blood Group Type Frequency Distribution". Irish Blood Transfusion Service. http://www.ibts.ie/All_About_Blood/Blood_Group_Basics/. Retrieved 2009-1107. 33. ^ The national rescue service in Israel 34. ^ "Voorraad Erytrocytenconcentraten Bij Sanquin" (in Dutch). http://www.sanquin.nl/Sanquin-nl/erygrafiek.nsf/All/VoorraadErytrocytenconcentraten-Bij-Sanquin.html. Retrieved 2009-03-27.

35. ^ What are Blood Groups? - NZ Blood 36. ^ Norwegian Blood Donor Organization 37. ^ Regionalne Centrum Krwiodawstwa i Krwiolecznictwa we Wroclawiu 38. ^ Portuguese Blood Institute (assuming Rh and AB antigens are independent) 39. ^ Fequency of ABO blood groups in the eastern region of Saudi Arabia 40. ^ South African National Blood Service - What's Your Type? 41. ^ Federacin Nacional de Donantes de Sangre/La sangre/Grupos 42. ^ Frequency of major blood groups in the Swedish population. 43. ^ Turkey Blood Group Site. 44. ^ Frequency of major blood groups in the UK. 45. ^ Blood Types in the U.S. 46. ^ RACIAL & ETHNIC DISTRIBUTION of ABO BLOOD TYPES, BLOODBOOK.COM 47. ^ Blood Transfusion Division, United States Army Medical Research Laboratory (1971). Selected contributions to the literature of blood groups and immunology. 1971 v. 4. United States Army Medical Research Laboratory, Fort Knox, Kentucky. http://books.google.com/books?id=ALilcA7Acd0C. "... In northern India, in Southern and Central China and in the neighboring Central Asiatic areas, we find the highest known frequencies of B. If we leave this center, the frequency of the B gene decreases almost everywhere ..." 48. ^ a b Encyclopaedia Britannica (2002). The New Encyclopaedia Britannica. Encyclopaedia Britannica, Inc.. ISBN 0852297874. http://books.google.com/books?id=fpdUAAAAMAAJ. "... The maximum frequency of the B gene occurs in Central Asia and northern India. The B gene was probably absent from American Indians and Australian Aborigines before racial admixture occurred with the coming of the white man ..." 49. ^ Carol R. Ember, Melvin Ember (1973). Anthropology. Appleton-CenturyCrofts. http://books.google.com/books?id=fvpFAAAAMAAJ. "... Blood type B is completely absent in most North and South American Indians ..." 50. ^ Laura Dean, MD (2005). Blood Groups an Red Cell Antigens. National Center for Biotechnology Information, United States Government. ISBN 1932811052. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=rbcantigen. "... Type A is common in Central and Eastern Europe. In countries such as Austria, Denmark, Norway, and Switzerland, about 45-50% of the population have this blood type, whereas about 40% of Poles and Ukrainians do so. The highest frequencies are found in small, unrelated populations. For example, about 80% of the Blackfoot Indians of Montana have blood type A ..." 51. ^ (PDF) Technical Monograph No. 2: The ABO Blood Group System and ABO Subgroups. Biotec. March 2005. http://www.biotec.com/pdf/Technical %20Monograph%20No.%202%20-%20ABO%20system%20and %20subgroups.pdf. "... The frequency of blood group A is quite high (25-55%) in Europe, especially in Scandinavia and parts of central Europe. High group A frequency is also found in the Aborigines of South Australia (up to 45%) and in certain American Indian tribes where the frequency reaches 35% ..." 52. ^ Possible Risks of Blood Product Transfusions from American Cancer Society. Last Medical Review: 03/08/2008. Last Revised: 01/13/2009

53. ^ 7 ADVERSE REACTIONS TO TRANSFUSION Pathology Department at University of Michigan. Version July 2004, Revised 11/5/08 54. ^ Nickel, RG; Willadsen SA, Freidhoff LR, et al. (August 1999). "Determination of Duffy genotypes in three populations of African descent using PCR and sequence-specific oligonucleotides". Hum Immunol. 60 (8): 73842. doi:10.1016/S0198-8859(99)00039-7. PMID 10439320. 55. ^ Bruce, MG (May 2002). "BCF - Members - Chairman's Annual Report". The Blood Care Foundation. http://www.bloodcare.org.uk/html/resources_chairman_2001.htm. Retrieved 2008-07-15. "As Rhesus Negative blood is rare amongst local nationals, this Agreement will be of particular value to Rhesus Negative expatriates and travellers" 56. ^ Daniels G, Finning K, Martin P, Summers J (2006). "Fetal blood group genotyping: present and future.". Ann N Y Acad Sci 1075: 8895. doi:10.1196/annals.1368.011. PMID 17108196. 57. ^ "Use of Anti-D Immunoglobulin for Rh Prophylaxis". Royal College of Obstetricians and Gynaecologists. May 2002. http://www.rcog.org.uk/index.asp? PageID=1972. 58. ^ "Pregnancy - routine anti-D prophylaxis for D-negative women". NICE. May 2002. http://www.nice.org.uk/guidance/TA41/?c=91520. 59. ^ "RBC compatibility table". American National Red Cross. December 2006. http://chapters.redcross.org/br/northernohio/INFO/bloodtype.html. Retrieved 2008-07-15. 60. ^ a b Blood types and compatibility bloodbook.com 61. ^ Fauci, Anthony S.; Eugene Braunwald, Kurt J. Isselbacher, Jean D. Wilson, Joseph B. Martin, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo (1998). Harrison's Principals of Internal Medicine. New York: McGraw-Hill. pp. 719.. ISBN 0-07-020291-5.) 62. ^ Universal acceptor and donor groups 63. ^ Anstee DJ (2009). "Red cell genotyping and the future of pretransfusion testing". Blood 114 (2): 24856. doi:10.1182/blood-2008-11-146860. PMID 19411635. 64. ^ Avent ND (2009). "Large-scale blood group genotyping: clinical implications". Br J Haemat 144 (1): 313. doi:10.1111/j.1365-2141.2008.07285.x. PMID 19016734. 65. ^ "Blood groups 'can be converted'". BBC News. 2007-04-02. http://news.bbc.co.uk/1/hi/health/6517137.stm. Retrieved 2008-07-15. 66. ^ Liu Q, Sulzenbacher G, Yuan H, Bennett E, Pietz G, Saunders K, Spence J, Nudelman E, Levery S, White T, Neveu J, Lane W, Bourne Y, Olsson M, Henrissat B, Clausen H (2007). "Bacterial glycosidases for the production of universal red blood cells". Nat Biotechnol 25 (4): 454. doi:10.1038/nbt1298. PMID 17401360. 67. ^ Landsteiner K. Zur Kenntnis der antifermentativen, lytischen und agglutinierenden Wirkungen des Blutserums und der Lymphe. Zentralblatt Bakteriologie 1900;27:357-62.

68. ^ Landsteiner K, Wiener AS. An agglutinable factor in human blood recognized by immune sera for rhesus blood. Proc Soc Exp Biol Med 1940;43:223-224. 69. ^ Coombs RRA, Mourant AE, Race RR. A new test for the detection of weak and "incomplete" Rh agglutinins. Brit J Exp Path 1945;26:255-66. 70. ^ http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1351151 71. ^ a b c Associated Press (2005-05-06). "Myth about Japan blood types under attack". AOL Health. http://aol.mediresource.com/channel_health_news_details.asp? news_id=6661&news_channel_id=11&channel_id=11. Retrieved 2007-12-29.

ABO blood group system

.

ABO blood group antigens present on red blood cells and IgM antibodies present in the serum The ABO blood group system is the most important blood type system (or blood group system) in human blood transfusion. The associated anti-A antibodies and anti-B antibodies are usually IgM antibodies, which are usually produced in the first years of life by sensitization to environmental substances such as food, bacteria and viruses. ABO blood types are also present in some animals, for example apes such as chimpanzees, bonobos, and gorillas.[1]

History of discoveries
The ABO blood group system is widely credited to have been discovered by the Austrian scientist Karl Landsteiner, who found three different blood types in 1900;[2] he was awarded the Nobel Prize in Physiology or Medicine in 1930 for his work. Due to inadequate communication at the time it was subsequently found that Czech serologist Jan Jansk had independently pioneered the classification of human blood into four groups,[3] but Landsteiner's independent discovery had been accepted by the scientific world while Jansk remained in relative obscurity. Jansk's classification is however still used in Russia and states of former USSR (see below). In America, Moss published his own (very similar) work in 1910.[4] Landsteiner described A, B, and O; Decastrello and Sturli discovered the fourth type, AB, in 1902.[5] Ludwik Hirszfeld and E. von Dungern discovered the heritability of ABO blood groups in 191011, with Felix Bernstein demonstrating the correct blood group inheritance pattern of multiple alleles at one locus in 1924.[6] Watkins and Morgan, in England, discovered that the ABO epitopes were conferred by sugars, specifically Nacetylgalactosamine for the A-type and galactose for the B-type.[7][8][9] After much published literature claiming that the ABH substances were all attached to glycosphingolipids, Laine's group (1988) found that the band 3 protein expressed a long polylactosamine chain[10] which contained the major portion of the ABH substances attached.[11] Later, Yamamoto's group showed the precise glycosyl transferase set that confers the A, B and O epitopes.[12]

ABO antigens

Diagram showing the carbohydrate chains which determine the ABO blood group The H antigen is an essential precursor to the ABO blood group antigens. The H locus is located on chromosome 19. It contains 3 exons that span more than 5 kb of genomic DNA, and it encodes a fucosyltransferase that produces the H antigen on RBCs. The H antigen is a carbohydrate sequence with carbohydrates linked mainly to protein (with a

minor fraction attached to ceramide moiety). It consists of a chain of -D-galactose, -DN-Acetylglucosamine, -D-galactose, and 2-linked, -L-fucose, the chain being attached to the protein or ceramide. The ABO locus is located on chromosome 9. It contains 7 exons that span more than 18 kb of genomic DNA. Exon 7 is the largest and contains most of the coding sequence. The ABO locus has three main alleleic forms: A, B, and O. The A allele encodes a glycosyltransferase that bonds -N-Acetylgalactosamine to D-galactose end of H antigen, producing the A antigen. The B allele encodes a glycosyltransferase that joins -Dgalactose bonded to D-galactose end of H antigen, creating the B antigen. In case of O allele the exon 6 contains a deletion that results in a loss of enzymatic activity. The O allele differs slightly from the A allele by deletion of a single nucleotide Guanine at position 261. The deletion causes a frameshift and results in translation of an almost entirely different protein that lacks enzymatic activity. This results in H antigen remaining unchanged in case of O groups. The majority of the ABO antigens are expressed on the ends of long polylactosamine chains attached mainly to Band 3 protein, the anion exchange protein of the RBC membrane, and a minority of the epitopes are expressed on neutral glycosphingolipids.

Serology
Anti-A and anti-B antibodies (called isohaemagglutinins), which are not present in the newborn, appear in the first years of life. They are isoantibodies, that is, they are produced by an individual against antigens produced by members of the same species (isoantigens). Anti-A and anti-B antibodies are usually IgM type, which are not able to pass through the placenta to the fetal blood circulation. O-type individuals can produce IgG-type ABO antibodies.

Origin theories
It is possible that food and environmental antigens (bacterial, viral or plant antigens) have epitopes similar enough to A and B glycoprotein antigens. The antibodies created against these environmental antigens in the first years of life can cross react with ABOincompatible red blood cells when it comes in contact with during blood transfusion later in life. Anti-A antibodies are hypothesized to originate from immune response towards influenza virus, whose epitopes are similar enough to the -D galactose on the B glycoprotein antigens to be able to elicit a cross-reaction. Anti-B antibodies are hypothesized to originate from antibodies produced against Gram-negative bacteria, such as E. coli, cross-reacting with the -N galactosamine on the A glycoprotein.[13] The "Light in the Dark theory" (DelNagro, 1998) suggests that when budding viruses acquire host cell membranes from one human patient (in particular from the lung and mucosal epithelium where they are highly expressed) they also take along ABO blood antigens from those membranes, and may carry them into secondary recipients where

these antigens can elicit a host immune response against these non-self foreign blood antigens. These viral-carried human blood antigens may be responsible for priming newborns into producing neutralizing antibodies against foreign blood antigens. Support for this theory has come to light in recent experiments with HIV. HIV can be neutralized in "in-vitro" experiments using antibodies against blood group antigens specifically expressed on the HIV producing cell lines.[14][15] The "Light in the Dark theory" suggests a new novel evolutionary hypothesis: that there is true communal immunity, which has developed to reduce the inter-transmissibility of viruses within a population. It suggests that individuals in a population supply and make a diversity of unique antigenic moieties so as to keep the population as a whole more resistant to infection. A system set up ideally to work with variable recessive alleles.[citation
needed]

Transfusion reactions
Due to the presence of isoantibodies against non self blood group antigens, individuals of type A blood group immediately raises anti-B antibodies against B-blood group RBCs if transfused with blood from B group. The anti-B antibodies bind to B antigens on RBC and causes complement-mediated lysis of the RBCs. The same happens for B and O groups (which raises both anti-A and anti-B antibodies). However only blood group AB does not have anti-A and anti-B isoantibodies. This is because both A and B-antigens are present on the RBCs and are both self antigens, hence they can receive blood from all groups and are universal recipient.

Individuals with type A blood can receive blood from donors of type A and type O blood. Individuals with type B blood can receive blood from donors of type B and type O blood. Individuals with type AB blood can receive blood from donors of type A, type B, type AB, or type O blood. Individuals with type O blood can receive blood from donors of only type O. Individuals of type A, B, AB and O blood can receive blood from donors of type O blood. Type O- blood is called the universal donor.

One caveat to this axiom of 'universal donor' is that this applies to packed RBC's and not to whole blood products. Using the first table, type O carries anti-A and anti-B antibodies in the serum. To transfuse a type A, B, or AB recipient with type O whole blood would produce a hemolytic transfusion reaction due to the antibodies found in the serum of whole blood.

recipient donor A A or O B B or O AB A, B, AB, or O O O No antibodies are formed against the H antigen, except in those individuals with the Bombay phenotype. In ABH secretors, ABH antigens are secreted by most mucus-producing cells of the body interfacing with the environment, including lung, skin, liver, pancreas, stomach, intestines, ovaries and prostate.[16]

ABO hemolytic disease of the newborn

ABO blood group incompatibilities between the mother and child does not usually cause hemolytic disease of the newborn (HDN) because antibodies to the ABO blood groups are usually of the IgM type, which do not cross the placenta; however, in an O-type mother, IgG ABO antibodies are produced and the baby can develop ABO hemolytic disease of the newborn.

Inheritance

A and B are codominant, giving the AB phenotype.

Blood group inheritance

Mother/Father O A O O O, A A O, A O, A B O, B O, A, B, AB AB A, B A, B, AB

B O, B O, A, B, AB O, B A, B, AB

AB A, B A, B, AB A, B, AB A, B, AB

Blood groups are inherited from both parents. The ABO blood type is controlled by a single gene (the ABO gene) with three alleles: i, IA, and IB. The gene encodes a glycosyltransferasethat is, an enzyme that modifies the carbohydrate content of the red blood cell antigens. The gene is located on the long arm of the ninth chromosome (9q34). The IA allele gives type A, IB gives type B, and i gives type O. As both IA and IB are dominant over i, only ii people have type O blood. Individuals with IAIA or IAi have type A blood, and individuals with IBIB or IBi have type B. IAIB people have both phenotypes, because A and B express a special dominance relationship: codominance, which means that type A and B parents can have an AB child. A type A and a type B couple can also have a type O child if they are both heterozygous (IBi,IAi) The cis-AB phenotype has a single enzyme that creates both A and B antigens. The resulting red blood cells do not usually express A or B antigen at the same level that would be expected on common group A1 or B red blood cells, which can help solve the problem of an apparently genetically impossible blood group.[17]

Distribution and evolutionary history

The distribution of the blood groups A, B, O and AB varies across the world according to the population. There are also variations in blood type distribution within human subpopulations. In the UK, the distribution of blood type frequencies through the population still shows some correlation to the distribution of placenames and to the successive invasions and migrations including Vikings, Danes, Saxons, Celts, and Normans who contributed the morphemes to the placenames and the genes to the population.[18] There are six common alleles in white individuals of the ABO gene that produce one's blood type:[19][20] A

B A101 (A1) A201 (A2)

O B101 (B1)

O01 (O1) O02 (O1v) O03 (O2)

Many rare variants of these alleles have been found in human populations around the world.

Some evolutionary biologists theorize that the IA allele evolved earliest, followed by O (by the deletion of a single nucleotide, shifting the reading frame) and then IB.[citation needed] This chronology accounts for the percentage of people worldwide with each blood type. It is consistent with the accepted patterns of early population movements and varying prevalent blood types in different parts of the world: for instance, B is very common in populations of Asian descent, but rare in ones of Western European descent.) Another theory states that there are four main lineages of the ABO gene and that mutations creating type O have occurred at least three times in humans.[21] From oldest to youngest, these lineages comprise the following alleles: A101/A201/O09, B101, O02 and O01. The continued presence of the O alleles is hypothesized to be the result of balancing selection. [21] Both theories contradict the previously-held theory that type O blood evolved earliest, supported by the fact that all human beings (except Type hh) can receive it.The British National Blood Transfusion Service states this to be the case (see the web-link under External Links below) and says that originally all human beings were type O.

Association with von Willebrand factor

The ABO antigen is also expressed on the von Willebrand factor (vWF) glycoprotein,[22] which participates in hemostasis (control of bleeding). In fact, having type O blood predisposes to bleeding,[23] as 30% of the total genetic variation observed in plasma vWF is explained by the effect of the ABO blood group,[24] and individuals with group O blood normally have significantly lower plasma levels of vWF (and Factor VIII) than do non-O individuals.[25][26] In addition, vWF is degraded more rapidly due to the higher prevalence of blood group O with the Cys1584 variant of vWF (an amino acid polymorphism in VWF):[27] the gene for ADAMTS13 (vWF-cleaving protease) maps to the ninth chromosome (9q34), the same locus as ABO blood type. Higher levels of vWF are more common amongst people who have had ischaemic stroke (from blood clotting) for the first time.[28] The results of this study found that the occurrence was not affected by ADAMTS13 polymorphism, and the only significant genetic factor was the person's blood group.

Subgroups
A1 and A2
The A blood type contains about twenty subgroups, of which A1 and A2 are the most common (over 99%). A1 makes up about 80% of all A-type blood, with A2 making up the rest.[29] These two subgroups are interchangeable as far as transfusion is concerned, however complications can sometimes arise in rare cases when typing the blood.[29]

Bombay phenotype

Individuals with the rare Bombay phenotype (hh) do not express antigen H on their red blood cells. As H antigen serves as precursor for producing A and B antigens, the absence of H antigen means the individuals do not have A or B antigens as well (similar to O blood group). However, unlike O group H antigen is absent, hence the individuals produce isoantibodies to antigen H as well as to both A and B antigens. In case they receive blood from O blood group, the anti-H antibodies will bind to H antigen on RBC of donor blood and destroy the RBCs by complement-mediated lysis. Therefore Bombay phenotype can receive blood only from other hh donors (although they can donate as though they were type O).

Nomenclature in Europe and former USSR

In parts of Europe the "O" in ABO blood type is substituted with "0" (zero), signifying the lack of A or B antigen. In the former USSR blood types are referenced using numbers and Roman numerals instead of letters. This is Jansk's original classification of blood types. It designates the blood types of humans as I, II, III, and IV, which are elsewhere designated, respectively, as O, A, B, and AB.[30] The designation A and B with reference to blood groups was proposed by Ludwik Hirszfeld.

Examples of ABO and Rhesus D slide testing method

Blood group O positive: neither anti-A nor Result: Blood group B negative: anti-A and anti-B have agglutinated, but anti-Rh has anti-Rh have not agglutinated but anti-B has In the slide testing method shown above, three drops of blood are placed on a glass slide with liquid reagents. Agglutination indicates the presence of blood group antigens in the blood.

Universal blood created from other types, and artificial blood

In April 2007 an international team of researchers announced in the journal Nature Biotechnology an inexpensive and efficient way to convert types A, B and AB blood into type O.[31] This is done by using glycosidase enzymes from specific bacteria to strip the blood group antigens from red blood cells. The removal of A and B antigens still does not address the problem of the Rhesus blood group antigen on the blood cells of Rhesus positive individuals, and so blood from Rhesus negative donors must be used. Patient trials will be conducted before the method can be relied on in live situations.

Another approach to the blood antigen problem is the creation of artificial blood which could act as a substitute in emergencies. BBC.

Conjectures
There are numerous popular conjectures surrounding ABO blood groups. These beliefs have existed since the ABO blood groups were identified and can be found in different cultures throughout the world. For example, during the 1930s, connecting blood groups to personality types became popular in Japan and other areas of the world.[32] The popularity of Peter J. D'Adamo's book, Eat Right For Your Blood Type suggests that these conjectures persist. This book claims that ABO blood type determines optimal diet.
[33]

Additional myths include the idea that Group A causes severe hangovers, group O is associated with perfect teeth, and those with blood group A2 have the highest IQs. Scientific evidence in support of these concepts is scant or nonexistent.[34]

References
1. ^ Maton, Anthea; Jean Hopkins, Charles William McLaughlin, Susan Johnson, Maryanna Quon Warner, David LaHart, Jill D. Wright (1993). Human Biology and Health. Englewood Cliffs, New Jersey, USA: Prentice Hall. ISBN 0-13981176-1. 2. ^ Landsteiner K (1900). "Zur Kenntnis der antifermentativen, lytischen und agglutinierenden Wirkungen des Blutserums und der Lymphe". Zentralblatt Bakteriologie 27: 35762. 3. ^ Jansk J (1907). "(Haematologick studie u. psychotiku" (in Czech). Sborn. Klinick 8: 85139. 4. ^ Moss WL (1910). "Studies on isoagglutinins and isohemolysins". Bulletin Johns Hopkins Hospital 21: 6370. 5. ^ von Decastello A, Sturli A (1902). "Ueber die Isoagglutinine im Serum gesunder und kranker Menschen". Mfinch med Wschr 49: 10905. 6. ^ Crow J (1993). "Felix Bernstein and the first human marker locus". Genetics 133 (1): 47. PMID 8417988. Full text at PMC: 1205297 7. ^ Morgan, W. T. J. & Watkins, W. M. Br. Med. Bull. 25, 3034 (1969) 8. ^ Watkins, W. M. Advances in Human Genetics Vol. 10 (eds Harris, H. & Hirschhorn, K.) 1136 (Plenum, New York, 1980) 9. ^ Watkins, W. M. & Morgan, W. T. J. Vox Sang. 4, 97119 (1959). 10. ^ Jarnefelt, Rush, Li, Laine, J. Biol. Chem. 253: 80068009(1978) 11. ^ Laine and Rush in Molecular Immunology of Complex Carbohydrates (A. Wu, E. Kabat, Eds.) Plenum Publishing Corporation, N.Y. NY (1988) 12. ^ Yamamoto, et al., Molecular genetic basis of the histo-blood group ABO system, Nature 345: 229233 (1990)

13. ^ Letter to the Editor: Natural Versus Regular Antibodies Journal The Protein Journal Publisher Springer Netherlands ISSN 1572-3887 (Print) 1573-4943 (Online) Issue Volume 23, Number 6 / August, 2004 Category Letter to the Editor DOI 10.1023/B:JOPC.0000039625.56296.6e Page 357 Subject Group Chemistry and Materials Science Online Date Friday, January 07, 2005 14. ^ Arendrup, M; Hansen JE, Clausen H, Nielsen C, Mathiesen LR, Nielsen JO (April 1991). "Antibody to histo-blood group A antigen neutralizes HIV produced by lymphocytes from blood group A donors but not from blood group B or O donors". AIDS 5 (4): 4414. doi:10.1097/00002030-199104000-00014. PMID 1711864. 15. ^ Neil, SJ; McKnight A, Gustafsson K, Weiss RA (2005-06-15). "HIV-1 incorporates ABO histo-blood group antigens that sensitize virions to complement-mediated inactivation". Blood 105 (12): 46939. doi:10.1182/blood2004-11-4267. PMID 15728127. http://bloodjournal.hematologylibrary.org/cgi/content/full/105/12/4693. 16. ^ Laine, R.A. and Rush, J.S. (1988) "Chemistry of Human Erythrocyte Polylactosamine Glycopeptides (Erythroglycans) as Related to ABH Blood Group antigenic Determinants: Evidence that Band 3 Carbohydrate on Human Erythrocytes Carries the Majority of ABH Blood Group Substance" in Molecular Immunology of Complex Carbohydrates (A. Wu, E. Kabat, Eds.) Plenum Publishing Corporation, N.Y. NY. 17. ^ Yazer M, Olsson M, Palcic M (2006). "The cis-AB blood group phenotype: fundamental lessons in glycobiology". Transfus Med Rev 20 (3): 20717. doi:10.1016/j.tmrv.2006.03.002. PMID 16787828. 18. ^ Potts, WTW (1979). "History and Blood Groups in the British Isles". in Sawyer PH. English Medieval Settlement. St. Martin's Press. ISBN 0-7131-6257-0. 19. ^ Seltsam A, Hallensleben M, Kollmann A, Blasczyk R (2003). "The nature of diversity and diversification at the ABO locus". Blood 102 (8): 303542. doi:10.1182/blood-2003-03-0955. PMID 12829588. 20. ^ Ogasawara K, Bannai M, Saitou N, et al. (1996). "Extensive polymorphism of ABO blood group gene: three major lineages of the alleles for the common ABO phenotypes". Human Genetics 97 (6): 77783. doi:10.1007/BF02346189. PMID 8641696. 21. ^ a b Calafell, Francesc; et al. (September 2008). "Evolutionary dynamics of the human ABO gene". Human Genetics 124 (2): 123135. doi:10.1007/s00439-0080530-8. PMID 18629539. http://www.springerlink.com/content/yv4072vu67mv1166/fulltext.html. Retrieved 2008-09-24. 22. ^ Sarode, R; Goldstein J, Sussman II, Nagel RL, Tsai HM (June 2000). "Role of A and B blood group antigens in the expression of adhesive activity of von Willebrand factor". Br J Haematol. 109 (4): 85764. doi:10.1046/j.13652141.2000.02113.x. PMID 10929042. 23. ^ O'Donnell, J; Laffan MA (August 2001). "The relationship between ABO histoblood group, factor VIII and von Willebrand factor". Transfus Med. 11 (4): 343 51. doi:10.1046/j.1365-3148.2001.00315.x. PMID 11532189.

24. ^ O'Donnell, J; Boulton FE, Manning RA, Laffan MA (2002-02-01). "Amount of H antigen expressed on circulating von Willebrand factor is modifiedby ABO blood group genotype and is a major determinant of plasma von Willebrand factor antigen levels". Arterioscler Thromb Vasc Biol. (American Heart Association, Inc.) 22 (2): 33541. doi:10.1161/hq0202.103997. PMID 11834538. http://atvb.ahajournals.org/cgi/content/full/22/2/335. 25. ^ Gill, JC; Endres-Brooks J, Bauer PJ, Marks WJ, Montgomery RR (June 1987). "The effect of ABO blood group on the diagnosis of von Willebrand disease" (abstract). Blood 69 (6): 16915. PMID 3495304. http://www.bloodjournal.org/cgi/content/abstract/69/6/1691. 26. ^ Shima, M; Fujimura Y, Nishiyama T et al. (1995). "ABO blood group genotype and plasma von Willebrand factor in normal individuals". Vox Sang 68 (4): 236 40. doi:10.1111/j.1423-0410.1995.tb02579.x. PMID 7660643. 27. ^ Bowen, DJ; Collins PW, Lester W, et al. (March 2005). "The prevalence of the cysteine1584 variant of von Willebrand factor is increased in type 1 von Willebrand disease: co-segregation with increased susceptibility to ADAMTS13 proteolysis but not clinical phenotype". Br J Haematol (Blackwell Synergy) 128 (6): 8306. doi:10.1111/j.1365-2141.2005.05375.x. PMID 15755288. 28. ^ Bongers T, de Maat M, van Goor M, et al. (2006). "High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability". Stroke 37 (11): 26727. doi:10.1161/01.STR.0000244767.39962.f7. PMID 16990571. 29. ^ a b Blood Group A Suptypes, The Owen Foundation, retrieved 2008-07-01. 30. ^ Erb IH (1 May 1940). "Blood Group Classifications, a Plea for Uniformity". Canadian Medical Association Journal 42 (5): 41821. http://www.pubmedcentral.nih.gov/articlerender.fcgi? tool=pmcentrez&artid=537907. 31. ^ Liu, QP; Sulzenbacher G, Yuan H, Bennett EP, Pietz G, Saunders K, Spence J, Nudelman E, Levery SB, White T, Neveu JM, Lane WS, Bourne Y, Olsson ML, Henrissat B, Clausen H (April 2007). "Bacterial glycosidases for the production of universal red blood cells". Nat Biotechnol 25 (4): 45464. doi:10.1038/nbt1298. PMID 17401360. http://www.nature.com/nbt/journal/v25/n4/abs/nbt1298.html. 32. ^ American Red Cross, Southern California Blood Services Region (n.d.). "Answers to Commonly Asked Questions About Blood and Blood Banking" (PDF). Blood: the Basics: 4. http://www.socalredcross.org/pdf/BloodThe.pdf. Retrieved 2007-11-16. 33. ^ http://www.dadamo.com/ 34. ^ Klein, Harvey G (March 7, 2005). "Why Do People Have Different Blood Types?". Scientific American. http://www.sciam.com/article.cfm?id=why-dopeople-have-differ. Retrieved 2007-11-16.

Chemistry of the blood group substances :

The exact chemical structure of some blood groups has been identified, as have the gene products (i.e., those molecules synthesized as a result of an inherited genetic code on a gene of a chromosome) that assist in synthesizing the antigens on the red cell surface that determine the blood type. Blood group antigens are present on glycolipid and glycoprotein molecules of the red cell membrane. The carbohydrate chains of the membrane glycolipids are oriented toward the external surface of the red cell membrane and carry antigens of the ABO, Hh, Ii, and P systems. Glycoproteins, which traverse the red cell membrane, have a polypeptide backbone to which carbohydrates are attached. An abundant glycoprotein, band 3, contains ABO, Hh, and Ii antigens. Another integral membrane glycoprotein, glycophorin A, contains large numbers of sialic acid molecules and MN blood group structures; another, glycophorin B, contains Ss and U antigens. The genes responsible for inheritance of ABH and Lewis antigens are glycosyltransferases (a group of enzymes that catalyze the addition of specific sugar residues to the core precursor substance). For example, the H gene codes for the production of a specific glycosyltransferase that adds l-fucose to a core precursor substance, resulting in the H antigen; the Le gene codes for the production of a specific glycosyltransferase that adds l-fucose to the same core precursor substance, but in a different place, forming the Lewis antigen; the A gene adds N-acetyl-d-galactosamine (H must be present), forming the A antigen; and the B gene adds d-galactose (H must be present), forming the B antigen. The P system is analogous to the ABH and Lewis blood groups in the sense that the P antigens are built by the addition of sugars to precursor globoside and paragloboside glycolipids, and the genes responsible born June 14, 1868, Vienna, Austrian Empire [Austria] died June 26, 1943, New York, N.Y., U.S.

Austrian American immunologist and pathologist who received the 1930 Nobel Prize for Physiology or Medicine for his discovery of the major blood groups and the development of the ABO system of blood typing that has made blood transfusion a routine medical practice. After receiving his M.D. in 1891 from the University of Vienna, Landsteiner studied organic chemistry with many notable scientists in Europe, including the German chemist Emil Fischer. In 1897 he returned to the University of Vienna, where he pursued his

interest in the emerging field of immunology and in 1901 published his discovery of the human ABO blood group system. At that time, although it was known that the mixing of blood from two individuals could result in clumping, or agglutination, of red blood cells, the underlying mechanism of this phenomenon was not understood. Landsteiner discovered the cause of agglutination to be an immunological reaction that occurs when antibodies are produced by the host against donated blood cells. This immune response is elicited because blood from different individuals may vary with respect to certain antigens located on the surface of red blood cells. Landsteiner identified three such antigens, which he labeled A, B, and C (later changed to O). A fourth blood type, later named AB, was identified the following year. He found that if a person with one blood typeA, for examplereceives blood from an individual of a different blood type, such as B, the hosts immune system will not recognize the B antigens on the donor blood cells and thus will consider them to be foreign and dangerous, as it would regard an infectious microorganism. To defend the body from this perceived threat, the hosts immune system will produce antibodies Blood Chemistry Definitions : Hematology HEMATOCRIT (HCT) The word hematocrit means "to separate blood", a procedure which is done following the blood draw through the proper use of a centrifuge. Hematocrit is the measurement of the percentage of red blood cells in whole blood. It is an important determinant of anemia (decreased), polycythemia (increased), dehydration (elevated), increased R.B.C. breakdown in the spleen (decreased), or possible overhydration (decreased). Normal Adult Female Range: 37 - 47 % Optimal Adult Female Value: 42 % Normal Adult Male Range: 40 - 54 % Optimal Adult Male Value: 47 % Normal Newborn Range: 50 - 62 % Optimal Newborn Value: 56 % Panels: Hematology HEMOGLOBIN (HGB) Hemoglobin is the main transport of oxygen and carbon dioxide in the blood. It is composed of globin a group of amino acids that form a protein and heme which contains iron atoms and imparts the red color to hemoglobin. As with Hematocrit, it is an important determinant of anemia (decreased), dehydration (increased), polycythemia (increased), poor diet/nutrition, or possibly a malabsorption problem.

Normal Adult Female Range: 12 - 16 % Optimal Adult Female Value: 14 % Normal Adult Male Range: 14 - 18 % Optimal Adult Male Value: 16 % Normal Newborn Range: 14 - 20 % Optimal Newborn Value: 17 % Panels: Hematology MCH (Mean Corpuscular Hemoglobin) Hemoglobin x 10 R.B.C. Mean Corpuscular Hemoglobin (MCH) gives the average weight of hemoglobin in the red blood cell. Due to its use of red blood cells in its calculation, MCH is not as accurate as MCHC in its diagnosis of severe anemias. Decreased MCH is associated with microcytic anemia and increased MCH is associated with macrocytic anemia. Normal Adult Range: 27 - 33 pg Optimal Adult Value: 30 pg Panels: Hematology MCV (Mean Corpuscular Volume) Hematocrit x 10 R.B.C. The Mean Corpuscular Volume reflects the size of red blood cells by expressing the volume occupied by a single red blood cell. Increased values may indicate macrocytic anemia or B6 or Folic Acid deficiency and decreased values may indicate microcytic anemia, possibly caused by iron deficiency. Normal Adult Range: 80 - 100 fL Optimal Adult Value: 90 fL Higher ranges are found in newborns and infants Panels: Hematology MCHC (Mean Corpuscular Hemoglobin Concentration) Hemoglobin x 100 Hematocrit

This test measures the average concentration of hemoglobin in red blood cells. It is most valuable in evaluating therapy for anemia because Hemoglobin and Hematocrit are used, not R.B.C. in the calculation. Low MCHC means that a unit of packed R.B.C.s contain less hemoglobin than normal and a high MCHC means that there is more hemoglobin in a unit of R.B.C.s. Increased MCHC is seen in spherocytosis, and not seen in pernicious anemia whereas decreased levels may indicate iron deficiency, blood loss, B6 deficiency, or thalassemia. Normal Adult Range: 32 - 36 % Optimal Adult Value: 34 % Higher ranges are found in newborns and infants Panel: Hematology R.B.C. (Red Blood Cell Count) Red blood cells main function is to carry oxygen to the tissues and to transfer carbon dioxide to the lungs. This process is possible through the R.B.C. containing hemoglobin which combines easily with oxygen and carbon dioxide. Normal Adult Female Range: 3.9 - 5.2 mill/uL Optimal Adult Female Value: 4.55 mill/uL Normal Adult Male Range: 4.2 - 5.6 mill/uL Optimal Adult Male Value: 4.9 mill/uL Lower ranges are found in children, newborns, and infants Panel: Hematology W.B.C. (White Blood Cell Count) White blood cells main function is to fight infection, defend the body by phagocytosis against invasion by foreign organisms, and to produce, or at least transport and distribute, antibodies in the immune response. There are a number of types of leukocytes (see differential) that are classified as follows: Granulocytes Banded Neutrophils Neutrophils Eosinophils Basophils Nongranulocytes Lymphocytes Monocytes

Each cell, or leukocyte, has a different job in the body which is explained in the Differential section.

Normal Adult Range: 3.8 - 10.8 thous/uL Optimal Adult Value: 7.3 thous/uL Higher ranges are found in children, newborns, and infants. Panels: Allergy, Hematology PLATELET COUNT Platelets (also known as thrombocytes) are the smallest formed elements of the blood. They are vital to coagulation of the blood to prevent excessive bleeding. Elevated levels suggest dehydration or stimulation of the bone marrow where the cells are produced and decreased levels may indicate an immune system failure, drug reactions, B12, or folic acid deficiency. Normal Adult Range: 130 - 400 thous/uL Optimal Adult Value: 265 thous/uL Higher ranges are found in children, newborns and infants. Panel: Hematology Electrolytes SODIUM Sodium is the most abundant cation in the blood and its chief base. It functions in the body to maintain osmotic pressure, acid-base balance, and to transmit nerve impulses. Normal Adult Range: 135 - 146 mmol/L Optimal Adult Value: 140.5 mmol/L Panels: Electrolyte POTASSIUM Potassium is the major intracellular cation in the blood. It, along with sodium, helps to maintain osmotic balance and is also involved in acid-base balance. It is needed for proper nerve and muscle action. Normal Range: 3.5 - 5.5 mmol/L Optimal Adult Value: 4.5 mmol/L Panels: Electrolyte

CHLORIDE Chloride's significance relates to its maintenance of cellular integrity through its influence on osmotic pressure, it also helps monitor acid-base balance and water balance. Elevated levels are related to acidosis as well as too much water crossing the cell membrane. Decreased levels with decreased serum albumin may indicate water deficiency crossing the cell membrane (edema). Panels: Electrolyte Normal Adult Range: 95 - 109 mmol/L Optimal Adult Value: 103 mmol/L CO2 (Carbon Dioxide) The CO2 level is related to the respiratory exchange of carbon dioxide in the lungs and is part of the body's buffering system. Generally when used with the other electrolytes, it is a good indicator of acidity and alkalinity. Normal Adult Range: 22 - 32 mmol/L Optimal Adult Value: 27 mmol/L Normal Child Range: 20 - 28 mmol/L Optimal Child Value: 24 mmol/L Panels: Electrolyte CALCIUM The most abundant mineral in the body, it is involved in bone metabolism, protein absorption, fat transfer muscular contraction, transmission of nerve impulses, blood clotting, and cardiac function. It is highly sensitive to elements such as magnesium, iron, and phosphorus as well as hormonal activity, vitamin D levels, alkalinity and acidity, and many drugs. Normal Adult Range: 8.5 - 10.3 mg/dL Optimal Adult Value: 9.4 mg/dL Panels: Electrolyte, Kidney Function PHOSPHORUS Phosphorus is an abundant element found in most tissues and cells. It is closely related to the calcium level with an inverse relationship. When calcium is increased, phosphorus tends to decrease and vice versa. Careful following of blood draw procedures are necessary because improper handling may cause falsely elevated values. Phosphorus is needed for its buffering action, calcium transport, and osmotic pressure.

Normal Adult Range: 2.5 - 4.5 mg/dL Optimal Adult Value: 3.5 mg/dL Normal Child Range: 3 - 6 mg/dL Optimal Child Range: 4.5 mg/dL Panels: Electrolyte, Kidney Function Liver Enzymes sGOT (serum Glutamic-Oxaloacetic Transaminase - AST) Serum Glutamic Oxaloacetic Transaminase or AST (Aspartate Aminotransferase) is an enzyme found primarily in the liver, heart, kidney, pancreas, and muscles. Seen in tissue damage, especially heart and liver, this enzyme is normally elevated. Vitamin B deficiency and pregnancy are two instances where the enzyme may be decreased. Normal Adult Range: 0 - 42 IU/L Optimal Adult Value: 21 IU/L Panels: Cardiac Marker, Liver Function sGPT (serum Glutamic-Pyruvic Transaminase - ALT) Serum Glutamic Pyruvic Transaminase or ALT (Alanine Aminotransferase) is an enzyme found primarily in the liver but also to a lesser degree, in the heart and other tissues. It is useful in diagnosing liver function more so than sGOT levels. Decreased sGPT in combination with increased cholesterol levels is seen in cases of a congested liver. Increased levels are also seen in mononucleosis, alcoholism, liver damage, kidney infection, chemical pollutants, or myocardial infarction. Normal Adult Range: 0 - 48 IU/L Optimal Adult Value: 24 IU/L Panels: Liver Function ALKALINE PHOSPHATASE Produced in the cells of the bone and liver with some activity in the kidney, intestine, and placenta. Used extensively as a tumor marker it is also present in bone injury, pregnancy, or skeletal growth (elevated values). Growing children have normally higher levels of this enzyme also. Low levels are sometimes found in hypoadrenia, protein deficiency, malnutrition, and a number of vitamin deficiencies. Normal Adult Range: 20 - 125 IU/L Optimal Adult Value: 72.5 IU/L

Normal Child Range: 40 - 400 IU/L Optimal Child Value: 220 IU/L Panels: Liver Function GGT (Gamma-Glutamyltransferase or Gamma-Glutamyl Transpeptidase) Believed to be involved in the transport of amino acids and peptides into cells as well as glutathione metabolism, Gamma-Glutamyl Transferase is mainly found in liver cells and as such is extremely sensitive to alcohol use. Elevated levels may be found in liver disease, alcoholism, bile-duct obstruction, cholangitis, drug abuse, and in some cases excessive magnesium ingestion. Decreased levels can be found in hypothyroidism, hypothalamic malfunction, and low levels of magnesium. Normal Adult Female Range: 0 - 45 IU/L Optimal Female Value: 22.5 IU/L Normal Adult Male Range: 0 - 65 IU/L Optimal Male Value: 32.5 IU/L Panels: Liver Function LD (Lactic Dehydrogenase - LDH) Lactic dehydrogenase is an intracellular enzyme from particularly in the kidney, heart, skeletal muscle, brain, liver, and lungs. Increases are usually found in cellular death and/or leakage from the cell or, in some cases, it can be useful in confirming myocardial or pulmonary infarction (only in relation to other tests). Decreased levels of the enzyme may be seen in cases of malnutrition, hypoglycemia, adrenal exhaustion, or low tissue or organ activity. Normal Adult Range: 0 - 250 IU/L Optimal Adult Value: 125 IU/L Panels: Cardiac Marker, Kidney Function, Liver Function BILIRUBIN, TOTAL A byproduct of the breakdown of hemoglobin from red blood cells in the liver, bilirubin is a good indication of the liver's function. Excreted into the bile, bilirubin gives the bile its pigmentation. Elevated in liver disease, mononucleosis, hemolytic anemia, low levels of exposure to the sun, and toxic effects to some drugs, decreased levels are seen in people with an inefficient liver, excessive fat digestion, and possibly a diet low in nitrogen bearing foods.

Normal Adult Range: 0 - 1.3 mg/dL Optimal Adult Value: 0.65 mg/dL Panels: Liver Function Nitrogen Elements B.U.N. (Blood Urea Nitrogen) The nitrogen component of urea, B.U.N. is the end product of protein metabolism and its concentration is influenced by the rate of excretion. Increases can be caused by excessive protein intake, kidney damage, certain drugs, low fluid intake, intestinal bleeding, exercise, or heart failure. Decreased levels may be due to a poor diet, malabsorption, liver damage, or low nitrogen intake. Normal Adult Range: 7 - 25 mg/dL Optimal Adult Value: 16 mg/dL Panels: Kidney Function, Nitrogen CREATININE Creatinine is the waste product of muscle metabolism. Its level is a reflection of the body's muscle mass. Low levels are sometimes seen in kidney damage, protein starvation, liver disease, or pregnancy. Elevated levels are sometimes seen in kidney disease due to the kidneys job of excreting creatinine, muscle degeneration, and some drugs involved in impairment of kidney function. Normal Adult Range: 0.7 - 1.4 mg/dL Optimal Adult Value: 1.05 mg/dL Panels: Kidney Function, Nitrogen URIC ACID Uric acid is the end product of purine metabolism and is normally excreted through the urine. High levels are noted in gout, infections, kidney disease, alcoholism, high protein diets, and with toxemia in pregnancy. Low levels may be indicative of malabsorption, a diet low in purines, liver damage, or an overly acid kidney. Normal Adult Female Range: 2.5 - 7.5 mg/dL Optimal Adult Female Value: 5.0 mg/dL Normal Adult Male Range: 3.5 - 7.5 mg/dL Optimal Adult Male Value: 5.5 mg/dL

Panels: Kidney Function, Nitrogen

Protein PROTEIN, TOTAL Proteins are the most abundant compound in serum. The protein makeup of the individual is of important diagnostic significance because of protein's involvement in enzymes, hormones, and antibodies as well as osmotic pressure balance, maintaining acid-base balance, and as a reserve source of nutrition for the body's tissues and muscles. The major serum proteins measured are Albumin and Globulin (alpha1, alpha2, beta, and gamma). Decreased levels may be due to poor nutrition, liver disease, malabsorption, diarrhea, or severe burns. Increased levels are seen in lupus, liver disease, chronic infections, alcoholism, leukemia, tuberculosis amongst many others. Careful review of the individuals albumin, globulin, and A/G ratio are recommended. Normal Adult Range: 6.0 - 8.5 g/dL Optimal Adult Value: 7.25 g/dL Panels: Kidney Function, Liver Function, Protein ALBUMIN Albumin is the major constituent of serum protein (usually over 50%). It is manufactured by the liver from the amino acids taken from the diet. It helps in osmotic pressure regulation, nutrient transport, and waste removal. High levels are rarely seen and are primarily due to dehydration. Low levels are seen in poor diets, diarrhea, fever, infection, liver disease, inadequate iron intake, third-degree burns and edemas, and hypocalcemia. Panels: Kidney Function, Liver Function, Protein Normal Adult Range: 3.2 - 5.0 g/dL Optimal Adult Value: 4.1 g/dL GLOBULIN Globulin, a larger protein than albumin, is important for its immunologic responses, especially its gamma component (IgA, IgG, IgM, and IgE). Globulins have many diverse functions such as, the carrier of some hormones, lipids, metals, and antibodies. When

chronic infections, liver disease, rheumatoid arthritis, myelomas, and lupus are present, elevated levels are seen. Lower levels may be found in immune compromised patients, poor dietary habits, malabsorption, and liver or kidney disease. Normal Adult Range: 2.2 - 4.2 g/dL (calculated) Optimal Adult Value: 3.2 g/dL Panels: Allergy, Kidney Function, Liver Function, Protein A/G RATIO (Albumin/Globulin Ratio) A/G ratio is an important indicator of disease states although a high level is not considered clinically significant. Normal Adult Range: 1.1 - 2.4 (calculated) Optimal Adult Value: 1.9 Panels: Protein, Kidney Function, Liver Function, Ratios Lipids CHOLESTEROL Cholesterol is a critical fat that is a structural component of cell membrane and plasma lipoproteins, and is important in the synthesis of steroid hormones, glucocorticoids, and bile acids. Mostly synthesized in the liver, some is absorbed through the diet, especially one high in saturated fats. High density lipoproteins (HDL) is desired as opposed to the low density lipoproteins (LDL), two types of cholesterol. Elevated cholesterol has been seen in artherosclerosis, diabetes, hypothyroidism, and pregnancy. Low levels are seen in depression, malnutrition, liver insufficiency, malignancies, anemia, and infection. Normal Adult Range: 120 - 240 mg/dL Optimal Adult Value: 180 mg/dL Panels: Cardiac Marker, Kidney Function, Lipids, Liver Function TRIGLYCERIDES Triglycerides, stored in adipose tissues as glycerol, fatty acids and monoglycerides, are reconverted as triglycerides by the liver. Ninety percent of the dietary intake and 95% of the fat stored in tissues are triglycerides. Increased levels may be present in artherosclerosis, hypothyroidism, liver disease, pancreatitis, myocardial infarction, metabolic disorders, toxemia, and nephrotic syndrome. Decreased levels may be present in chronic obstructive pulmonary disease, brain infarction, hyperthyroidism, malnutrition, and malabsorption.

Normal Adult Range: 0 - 200 mg/dL Optimal Adult Value: 100 mg/dL Panels: Cardiac Marker, Lipids LDL (Low Density Lipoprotein) LDL is the cholesterol rich remnants of the lipid transport vehicle VLDL (very-low density lipoproteins) there have been many studies to correlate the association between high levels of LDL and arterial artherosclerosis. Due to the expense of direct measurement of LDL a calculation, known as the Friedewald formula is used. It is Total Cholesterol - HDL Cholesterol - (Triglycerides/5). When triglyceride levels are greater than 400 mg/dL, this calculation is not accurate. Normal Adult Range: 62 - 130 mg/dL Optimal Adult Value: 81 mg/dL Panels: Cardiac Marker, Lipids HDL (High Density Lipoprotein) HDL or High-density lipoprotein is the cholesterol carried by the alpha lipoproteins. A high level of HDL is an indication of a healthy metabolic system if there is no sign of liver disease or intoxication. The two mechanisms that explain how HDL offers protection against chronic heart disease are that 1. HDL inhibits cellular uptake of LDL and 2. serves as a carrier that removes cholesterol from the peripheral tissues and transports it back to the liver for catabolism and excretion. Normal Adult Range: 35 - 135 mg/dL Optimal Adult Value: >85 mg/dL Panels: Cardiac Marker, Lipids CHOLESTEROL/LDL RATIO The ratio of total cholesterol and LDL (low density lipoprotein). Normal Adult Range: 1 - 6 Optimal Adult Value: 3.0 Panels: Cardiac Marker, Ratios Ratios

ANION GAP (Sodium + Potassium - CO2 - Chloride) The anion gap is used to measure the concentration of cations (sodium and potassium) and the anions (chloride and CO2) in the extracellular fluid of the blood. There are numerous clinical implications that can be gathered from the Anion Gap. An increased measurement is associated with metabolic acidosis due to the overproduction of acids (a state of alkalinity is in effect). Decreased levels may indicate metabolic alkalosis due to the overproduction of alkaloids (a state of acidosis is in effect). Normal Adult Range: 4 - 14 (calculated) Optimal Adult Value: 9 Panels: Ratios B.U.N./CREATININE A high value in this calculation is normally indicative of too much B.U.N. being formed and a low value may show that the B.U.N. is low or that the creatinine is not being cleared effectively by the kidney. This calculation is a good measurement of kidney and liver function. Normal Adult Range: 6 - 25 (calculated) Optimal Adult Value: 15.5 Panels: Nitrogen, Ratios CALCIUM/PHOSPHORUS Due to the delicate balance between calcium and phosphorus in the system, this calculation is helpful in noting subtle and acute imbalances in the relationship between the two elements. Normal Adult Range: 2.3 - 3.3 (calculated) Optimal Adult Value: 2.8 Normal Child Range: 1.3 - 3.3 (calculated) Optimal Child Value: 2.3 Panels: Ratios SODIUM/POTASSIUM As the two major blood electrolytes, sodium as the extracellular cation and potassium as the intracellular cation, this is an important ratio to review and act upon when subtle or acute imbalances are noted.

Normal Adult Range: 26 - 38 (calculated) Optimal Adult Value: 32 Panels: Ratios Differential NEUTROPHILS and NEUTROPHIL COUNT Also known as Granulocytes or poly-segmented neutrophils, this is the main defender of the body against infection and antigens. High levels may indicate an active infection, a low count may indicate a compromised immune system or depressed bone marrow (low neutrophil production. Normal Adult Range: 48 - 73 % Optimal Adult Value: 60.5 % Normal Child Range: 30 - 60 % Optimal Child Value: 45 % Panels: Differential, Differential Count LYMPHOCYTES and LYMPHOCYTE COUNT Lymphocytes are involved in protection of the body from viral infections such as measles, rubella, chickenpox, or infectious mononucleosis. Elevated levels may indicate an active viral infection and a depressed level may indicate an exhausted immune system or, if the neutrophils are elevated, an active infection. Normal Adult Range: 18 - 48 % Optimal Adult Value: 33 % Normal Child Range: 25 - 50 % Optimal Child Value: 37.5 % Panels: Allergy, Differential, Differential Count MONOCYTES and MONOCYTE COUNT These cells are helpful in fighting severe infections and are considered the body's second line of defense against infection and are the largest cells in the blood stream. Elevated levels are seen in tissue breakdown, chronic infections, carcinomas, leukemia (monocytic), or lymphomas. Low levels are indicative of a good state of health. Normal Adult Range: 0 - 9 % Optimal Adult Value: 4.5 %

Panels: Differential, Differential Count, Allergy EOSINOPHILS and EOSINOPHIL COUNT Eosinophils are used by the body to protect against allergic reactions and parasites. Therefore, elevated levels may indicate an allergic response. A low count is normal. Normal Adult Range: 0 - 5 % Optimal Adult Value: 2.5 % Panels: Allergy, Differential, Differential Count BASOPHILS and BASOPHIL COUNT Basophilic activity is not fully understood but it is known to carry histamine, heparin, and serotonin. High levels are found in allergic reactions, low levels are normal. Normal Adult Range: 0 - 2 % Optimal Adult Value: 1 % Panels: Differential, Differential Count Thyroid THYROXINE (T4) Thyroxine is the thyroid hormone that contains four atoms of iodine. It is used to evaluate thyroid function. It is the direct measurement of total T4 concentration in the blood serum. Increased levels are found in hyperthyroidism, acute thyroiditis, and hepatitis. Low levels can be found in Cretinism, hypothyroidism, cirrhosis, malnutrition, and chronic thyroiditis. Normal Adult Range: 4 - 12 ug/dL Optimal Adult Value: 8 ug/dL Panels: Thyroid T-UPTAKE (T3-Uptake) This test is an indirect measurement of unsaturated thyroxine binding globulin in the blood. Increased levels are found in hyperthyroidism, severe liver disease, metastatic malignancy, and pulmonary insufficiency. Decreased levels are found in hypothyroidism, normal pregnancy, and hyperestrogenis status.

Normal Adult Range: 27 - 47% Optimal Adult Value: 37 % Panels: Thyroid FREE T4 INDEX (T7) This index is a calculation used to correct the estimated total thyroxine for the amount of thyroxine binding globulin present. It uses the T4 value and the T-uptake ratio. Normal Adult Range: 4 - 12 Optimal Adult Value: 8 Panels: Thyroid THYROID-STIMULATING HORMONE (TSH) TSH, produced by the anterior pituitary gland, causes the release and distribution of stored thyroid hormones. When T4 and T3 are too high, TSH secretion decreases, when T4 and T3 are low, TSH secretion increases. Normal Adult Range: 0.5 - 6 mIU/L Optimal Adult Value: 1.75 mIU/L Panels: Thyroid Other GLUCOSE (Fasting) Glucose, formed by the digestion of carbohydrates and the conversion of glycogen by the liver, is the primary source of energy for most cells. It is regulated by insulin, glucagon, thyroid hormone, liver enzymes, and adrenal hormones. It is elevated in diabetes, liver disease, obesity, pancreatitis, due to steroid medications, or during stress. Low levels may be indicative of liver disease, overproduction of insulin, hypothyroidism, or alcoholism. Normal Adult Range: 60 - 109 mg/dL Optimal Adult Value: 87.5 mg/dL IRON, TOTAL Iron is necessary for the formation of some proteins, hemoglobin, myoglobin, and cytochrome. Also, it is necessary for oxygen transport, cellular respiration, and peroxide deactivation. Low levels are seen in many anemias, copper deficiencies, low vitamin C intake, liver disease, chronic infections, high calcium intake, and women with heavy

menstrual flows. High levels are seen in hemochromatosis, liver damage, pernicious anemia, and hemolytic anemia. Normal Adult Range: 30 - 170 ug/dL Optimal Adult Value: 100 ug/dL Blood type A blood type is a description an individual's characteristics of red blood cells due to substances (carbohydrates and proteins) on the cell membrane. The two most important classifications to describe blood types in humans are ABO and Rh factor. There are 46 other known antigens, most of which are much rarer than ABO and Rh. Blood transfusions from incompatible groups can cause an immunological transfusion reaction , resulting in hemolytic anemia, renal failure, shock, and death. ABO Humans have the following blood types along with their respective antigens and antibodies:

Individuals with type A blood have red blood cells with antigen A on their surface and produce antibodies against antigen B in their blood serum. Using the blood compatibility chart below, for example, an A-negative person cannot receive blood except from another A-negative person or from an O-negative person. Individuals with type B blood have the opposite arrangement, antigen B on the cell and produce antibodies to substance A in their serum. Type AB people have red blood cells with both antigens A and B, and do not produce antibodies against either substance in their serum. Therefore, a person with type AB blood can safely receive any ABO type blood and is called a "universal receiver", but cannot donate blood except to the corresponding AB type people shown in the blood compatibility table below. Type O people have red blood cells with neither antigen, but produce antibodies against both types of antigens. Because of this arrangement, type O can be safely given to any person with any ABO blood type. Hence, a person with type O blood is said to be a "universal donor" but cannot receive blood except from the corresponding O type people shown in the blood compatibility table below. Thus, for example, an O-negative person cannot receive blood except from another Onegative person.

Overall, the O blood type is the most common blood type in the world, although in some areas, such as Norway, the A group dominates. The A antigen is overall more common than the B antigen. Since the AB blood type requires the presence of both A and B antigens, the AB blood type is the rarest of the ABO blood types. There are known racial and geographic distributions of the ABO blood types [1].

The precise reason why people are born with antibodies against an antigen they have never been exposed to is unknown. It is believed that some bacterial antigens are similar enough to the A and B glycoproteins, and that antibodies created against the bacteria will react to ABO-incompatible blood cells. Apart from on red blood cells, the ABO antigen is also expressed on the glycoprotein von Willebrand factor (vWF), which participates in hemostasis (control of bleeding). In fact, blood type O predisposes very slightly to bleeding, as vWF is degraded more rapidly. Austrian scientist Karl Landsteiner was awarded the Nobel Prize in Physiology or Medicine in 1930 for his work in discovering ABO blood types. Rhesus Another characteristic of blood is Rhesus factor or Rh factor. It is named after the Rhesus Monkey, where the factor was first identified in 1940. Someone either has or does not have the Rh factor on the surface of their red blood cells. This is indicated as + or -. This is often combined with the ABO type. Type O+ blood is most common, though in some areas type A prevails, and there are other areas in which as many as 80 percent of the people are type B. Matching the Rhesus factor in the ABO system is very important, as mismatching (an Rh positive donor to an Rh negative recipient) will cause hemolysis. The converse is not true: Rh+ patients do not react to Rh- blood. Rh disease occurs when an Rh negative mother who has already had an Rh positive child (or an accidental Rh+ blood transfusion) carries another Rh positive child. After the first pregnancy, the mother develops antibodies against Rh+ red blood cells, which cross the placenta and hemolyses the blood of the second child. This reaction doesn't always occur and is less likely to occur if the child carries either the A or B antigen and the mother does not. In the past, Rh incompatibility could result in stillbirth or death of the mother. Rh incompatibility was until recently the most common cause of long term disability in the United States. At first, this was treated by transfusing the blood of infants who survived. At present, it can be treated with certain anti-Rh(+) antisera, the most common of which is Rhogam (anti-D). It can be anticipated by determining the blood type of every child of a RhD- mother; if it is Rh+, the mother is treated with anti-D to prevent development of antibodies against Rh+ red blood cells. Inheritance ABO Blood groups are inherited from both parents. The ABO blood type is controlled by a single gene with three alleles: i, A, and B. The gene encodes a glycosyltransferase , an enzyme that modifies the carbohydrate content of the red blood cell antigens. The gene is located on the long arm of the ninth chromosome (9q34).

A allele gives type A, B gives type B, and i gives type O. A and B are dominant over i, so ii people have type O, AA or Ai have A, BB or Bi have type B. AB people have both phenotypes because A and B express a special dominance relationship: codominance. Thus, it is usually impossible for a type AB parent to have a type O child (it is, however, no direct proof of illegitimacy). Evolutionary biologists theorize that the A allele evolved earliest, followed by O and then B. This chronology accounts for the percentage of people worldwide with each blood type. It is consistent with the accepted patterns of early population movements and varying prevalent blood types in different parts of the world. (For instance, B is very common in populations of Asian descent, but rare in ones of European descent.) Rhesus Rh (or the D antigen) is inherited on one locus (on the short arm of the first chromosome, 1p36.2-p34) 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. Two very similar epitopes, Cc and Ee, appear to be closely related to Rh. Rare phenotypes Bombay phenotype The rare individuals with Bombay phenotype do not express substance H on their red blood cells and therefore do not bind A or B antigens. Instead, they produce antibodies to H substance (which is present on all red cells except those of hh phenotype) as well as to both A and B antigens and are therefore compatible only with other hh donors. Individuals with Bombay phenotype blood groups can only be transfused with blood from other Bombay phenotype individuals. Given that this condition is very rare to begin with, any person with this blood group, who needs an urgent blood transfusion, may be simply out of luck, as it would be quite unlikely that any blood bank would have any in stock. Patients who test as type O may have the Bombay phenotype: they have inherited two recessive alleles of the H gene, (their blood group is Oh and their genotype is "hh"), and so do not produce the "H" protein that is the precursor to the "A" and "B" antigens. It then no longer matters whether the A or B enzymes are present or not, as no A or B antigen can be produced since the precursor antigen is not present. Despite the designation O, Oh -ve is not a sub-group of any other group, not even O -ve or O +ve. When this Blood group was first encountered, it was found not to be of either group A or B and so was thought to be of Group O. But on further test, it did not match even for O-ve or O+ve because of the absence of Antigen 'h'. The H antigen is a

precursor to the A and B antigens. For instance, the B allele must be present to produce the B enzyme that modifies the H antigen to become the B antigen. It is the same for the A allele. However, if only recessive alleles for the H antigen are inherited (hh), as in the case above, the H antigen will not be produced. Subsequently, the A and B antigens also will not be produced. The result is an O phenotype by default since a lack of A and B antigens is the O type. The name "Bombay group" originates from the city of Bombay, now known as Mumbai, in India. The blood phenotype was first discovered in Bombay. Compatibility Blood donors and blood recipients must have compatible blood types. O- is the universally compatible blood type. The chart below illustrates how people with different blood types can receive or donate other blood (X means compatible). An A- person, for example, can receive either O- or A-, and can donate to people with AB+, AB-, A+ or Ablood. In general, people with type O Rh- are referred to as universal donors, as their blood can be transfused to anyone in need. It is thus the most highly sought after blood type in blood banks and hospitals. A type AB Rh+ is referred to as a universal receiver because he or she can receive blood of any type.

Frequency Blood types are not evenly distributed throughout the human population. O+ is the most common, AB- is the rarest. There are also variations in blood-type distribution within human subpopulations. Blood compatibility chart Type Frequency O+ A+ B+ OAAB+ BAB38% 34% 9% 7% 6% 3% 2% 1% Other blood types Other blood type systems exist to describe the presence or absence of Recipient AB+ ABA+ AB+ BO+ ODonor O- O+ B- B+ A- A+ AB- AB+ X X X X X X X X X X X X X X X X X X X X X X X X X X X

other antigens. Many are named after the patients in whom they were initially encountered.

Diego positive blood is found only among East Asians and Native Americans. MNS systems gives blood types of M, N, and MN. It has use in tests of maternity or paternity. Duffy negative blood gives partial immunity to malaria. The Lutheran system describes a set of 21 antigens. Other systems include Colton, Kell, Kidd, Lewis, Landsteiner-Wiener, P, Yt or Cartwright, XG, Scianna, Dombrock, Chido/Rodgers, Kx, Gerbich, Cromer, Knops, Indian, Ok, Raph, and JMH.

Social significance In Japan (and to a certain extent in Taiwan) a popular belief is that personality is related to blood type. Visitors to the country are often surprised to be asked their blood type by people they encounter. Japanese people are also often surprised when foreigners say that they do not know their own blood type. Whilst many Japanese people understand that blood typing doesn't hold any social significance in Western societies, others may conclude that the visitor is too "ashamed" of their blood type to reveal it to others. Furthermore, from the preponderance of some blood types in a population, Japanese "experts" claim to be able to deduce the character of that population. The experts also believe that they can calculate how well the blood types of different people match, a Japanese employer could therefore aim to get a proper mix of blood types among their personnel. Some nationalisms such as the Basque one have used the different proportion of blood types in different regions or populations as a mark of different race. In the United States, few African Americans donate blood, resulting in a shortage of Unegative and Duffy-negative blood for African American patients. References

Landsteiner K. Zur Kenntnis der antifermentativen, lytischen und agglutinierenden Wirkungen des Blutserums und der Lymphe. Zentralblatt Bakteriologie 1900;27:357-62.

Metal Complexes in the Blood for Oxygen Transport : Introduction to the Chemistry and Physiology of Blood Our bodies consist of cells that are organized into many specialized organs and tissues to perform a variety of functions. Our stomachs digest food so that the nutrients contained in the food can be distributed to the rest of the body. Our lungs take in the oxygen needed by the body from the air and release carbon dioxide as a waste product. Our muscles

allow the body to move. Our brains coordinate all of these (and many other) activities of the body. These processes are based upon many different chemical reactions, and the sum total of the chemical reactions in the body is known as the body's metabolism. The metabolism includes the reactions needed for normal everyday activities such as eating, sleeping, and studying. When we exercise, the metabolism increases to allow our body to cope with the increased demands and stress of exercising. All of our specialized body parts are united by their fundamental need for a particular chemical environment that will enable the body's metabolic reactions. This environment must include a supply of nutrients (e.g., sugars and vitamins, to supply the building blocks for cells and enable biochemical reactions) and oxygen (to provide energy for the body; the process of using oxygen to make the body's energy supply is described in the Chem 152 tutorial, "Energy for the Body: Oxidative Phosphorylation"), and the ability to eliminate the waste products of the body's metabolic activities. This environment is provided by bathing our body's cells in blood. Blood is part of the body's circulatory system, and thus is continually being pumped through our bodies as long as we are alive. The blood distributes oxygen and nutrients to the many different cells in the body, carries CO2 generated by the cells to the lungs for exhalation, and carries other waste products to the kidneys and liver for processing and elimination. Many finely tuned chemical processes occur in the blood to allow the blood to carry out all of these functions and provide for the needs of the body. The tutorials in Chem 151 and 152 will describe several of these vital chemical processes, such as the release of iron in controlled amounts to the blood ("Iron Use and Storage in the Body: Ferritin and Molecular Representations" tutorial), removal of waste products from the blood ("Maintaining the Body's Chemistry: Dialysis in the Kidneys" tutorial), and the regulation of the levels of CO2 and H+ to control the pH of the blood ("Blood, Sweat, and Buffers: pH Regulation During Exercise" tutorial). In this tutorial, we will study one of the most important functions of blood, the transport of oxygen from the lungs to the other cells of the body (e.g., muscle cells) that perform metabolic functions. Oxygen Transport via Metal Complexes An adult at rest consumes the equivalent of 250 ml of pure oxygen per minute. This oxygen is used to provide energy for all the tissues and organs of the body, even when the body is at rest. The body's oxygen needs increase dramatically during exercise or other strenuous activities. The oxygen is carried in the blood from the lungs to the tissues where it is consumed. However, only about 1.5% of the oxygen transported in the blood is dissolved directly in the blood plasma. Transporting the large amount of oxygen required by the body, and allowing it to leave the blood when it reaches the tissues that demand the most oxygen, require a more sophisticated mechanism than simply dissolving the gas in the blood. To meet this challenge, the body is equipped with a finely-tuned transport system that centers on the metal complex heme. Metal Complexes in the Body

The ability of metal ions to coordinate with (bind) and then release ligands in some processes, and to oxidize and reduce in other processes makes them ideal for use in biological systems. The most common metal used in the body is iron, and it plays a central role in almost all living cells. For example, iron complexes are used in the transport of oxygen in the blood and tissues. Metal-ion complexes consist of a metal ion that is bonded via "coordinate-covalent bonds" (Figure 1) to a small number of anions or neutral molecules called ligands. For example the ammonia (NH3) ligand used in this experiment is a monodentate ligand; i.e., each monodentate ligand in a metal-ion complex possesses a single electron-pair-donor atom and occupies only one site in the coordination sphere of a metal ion. Some ligands have two or more electron-pair-donor atoms that can simultaneously coordinate to a metal ion and occupy two or more coordination sites; these ligands are called polydentate ligands. They are also known as chelating agents (from the Greek word meaning "claw"), because they appear to grasp the metal ion between two or more electron-pair-donor atoms. The coordination number for a metal refers to the total number of occupied coordination sites around the central metal ion (i.e., the total number of metal-ligand bonds in the complex).

Figure 1 You have already learned that a covalent bond forms when electrons are

shared between atoms. A coordinatecovalent bond (represented by a green arrow in this diagram) forms when both of the shared electrons come from the same atom, called the donor atom (blue). An anion or molecule containing the donor atom is known as a ligand. The top illustration shows a coordinatecovalent bond between a metal ion (e.g., Fe, shown in red) and a monodentate ligand (a ligand that contains only one electron-pair-donor atom, shown in light blue). The bottom illustration shows a metal ion with coordinate-covalent bonds to a bidentate ligand (a ligand that contains two donor atoms simultaneously coordinated to the metal ion, shown in yellow). Oxygen-Carrying Protein in the Blood: Hemoglobin Hemoglobin is the protein that transports oxygen (O2) in human blood from the lungs to the tissues of the body. Proteins are formed by the linking of amino acids into polypeptide chains. An individual amino acid in a protein is known as a "residue." The arrangement and interactions of the amino-acid residues within the protein determine the protein's shape and contribute substantially to its function. Hemoglobin is a globular protein (i.e., folded into a compact, nearly spherical shape) and consists of four subunits, as shown in Figure 2. Each protein subunit is an individual molecule that joins to its neighboring subunits through intermolecular interactions. (These subunits are also known as peptide chains. You will learn more about the nature of amino acids and peptide subunits in the tutorial entitled, "Iron Use and Storage in the Body: Ferritin and Molecular Representations".)

Figure 2 This is a molecular model of hemoglobin with the subunits displayed in the ribbon representation. A ribbon representation traces the backbone atoms of a protein and is often used to represent its three-dimensional structure. The four heme groups are displayed in the ball-and-stick representation. Note: The coordinates for the hemoglobin protein (in this and subsequent molecular representations of all or part of the protein) were determined using x-ray crystallography, and the image was rendered using SwissPDB Viewer and POV-Ray (see References). Note: To view the molecule interactively, please use Chime, and click on the button to the left. Chime currently works in IE 6.0, Netscape 4.75 or Netscape 4.79. It does not work any other version of Netscape. You will need to check the MDL Website periodically for any updates. To understand the oxygen-binding properties of hemoglobin, we will focus briefly on the structure of the protein and the metal complexes embedded in it. The Protein Subunit

Each subunit in Figure 2 contains regions with a coiled shape; many of the amino acids that make up the polypeptide chain interact to form this particular structure, called an alpha helix. In an alpha helix (Figure 3), each amino acid is "hydrogen-bonded" to the amino acid that is four residues ahead of it in the chain. In hemoglobin, the hydrogenbonding interaction occurs between the H of an -NH group and the O of a -CO group of the polypeptide backbone chain; the amino-acid side chains extend outward from the backbone of the helix. Approximately 75% of the amino-acid composition of hemoglobin adopts an alpha-helical structure. Another common structural motif is the beta-pleated sheet, in which amino acids line up in straight parallel rows.

Figure 3 This is a molecular model of the alpha-helix structure in a subunit of hemoglobin. The blue strands are a ribbon representation to emphasize the helical structure. The green dotted lines show the hydrogen bonding between the -NH and -CO functional groups.

Note: To view the molecule Please click on the pink button interactively, please use above to view a QuickTime Chime, and click on the movie showing a rotation of button above. Chime currently the alpha-helix structure works in IE 6.0, Netscape shown in Figure 3. 4.75 or Netscape 4.79. It does not work any other version of Click the blue button below to Netscape. You will need to download QuickTime 4.0 to

check the MDL Website periodically for any updates.

view the movie.

The Heme Group In hemoglobin, each subunit contains a heme group, which is displayed using the balland-stick representation in Figure 2. Each heme group contains an iron atom that is able to bind to one oxygen (O2) molecule. Therefore, each hemoglobin protein can bind four oxygen molecules. One of the most important classes of chelating agents in nature are the porphyrins. A porphyrin molecule can coordinate to a metal using the four nitrogen atoms as electronpair donors, and hence is a polydentate ligand (see Figure 1). Heme is a porphyrin that is coordinated with Fe(II) and is shown in Figure 4.

Figure 4 On the left is a three-dimensional molecular model of heme coordinated to the histidine residue (a monodentate ligand, see Figure 1) of the hemoglobin protein. On the right is a two-dimensional drawing of heme coordinated to the histidine residue, which is part of the hemoglobin protein. In this figure, the protein is deoxygenated; i.e., there is no oxygen molecule bound to the heme group. Note: The coordinate-covalent bonds between the central iron atom and the

nitrogens from the porphyrin are gold; the coordinate-covalent bond between the central iron atom and the histidine residue is green. In the threedimensional model, the carbon atoms are are gray, the iron atom is dark red, the nitrogen atoms are dark blue, and the oxygen atoms are light red. The rest of the hemoglobin protein is purple. Note: To view the molecule interactively, please use Chime, and click on the button to the left. Chime currently works in IE 6.0, Netscape 4.75 or Netscape 4.79. It does not work any other version of Netscape. You will need to check the MDL Website periodically for any updates. In the body, the iron in the heme is coordinated to the four nitrogen atoms of the porphyrin and also to a nitrogen atom from a histidine residue (one of the amino-acid residues in hemoglobin) of the hemoglobin protein (see Figure 4). The sixth position (coordination site) around the iron of the heme is occupied by O2 when the hemoglobin protein is oxygenated.

Questions on the Oxygen-Carrying Protein in the Blood: Hemoglobin

One peptide subunit in hemoglobin contains 141 amino-acid residues. If the subunit were stretched out, it would measure approximately 49 nm in length. However, the longest dimension of the subunit in hemoglobin is only about 5 nm. Briefly, explain how alpha helices may help account for this difference in length. What is the coordination number of Fe in the oxygenated heme group? Briefly, justify your answer by describing the ligands to which Fe is coordinated.

Conformational Changes Upon Binding of Oxygen Careful examination of Figure 4 shows that the heme group is nonplanar when it is not bound to oxygen; the iron atom is pulled out of the plane of the porphyrin, toward the histidine residue to which it is attached. This nonplanar configuration is characteristic of the deoxygenated heme group, and is commonly referred to as a "domed" shape. The valence electrons in the atoms surrounding iron in the heme group and the valence electrons in the histidine residue form "clouds" of electron density. (Electron density refers to the probability of finding an electron in a region of space.) Because electrons repel one another, the regions occupied by the valence electrons in the heme group and the histidine residue are pushed apart. Hence, the porphyrin adopts the domed (nonplanar) configuration and the Fe is out of the plane of the porphyrin ring (Figure 5,

left). However, when the Fe in the heme group binds to an oxygen molecule, the porphyrin ring adopts a planar configuration and hence the Fe lies in the plane of the porphyrin ring (Figure 5, right).

Figure 5 On the left is a schematic diagram showing representations of electrondensity clouds of the deoxygenated heme group (pink) and the attached histidine residue (light blue). These regions of electron density push one another apart, and the iron atom in the center is drawn out of the plane. (The nonplanar shape of the heme group is represented by the bent line.) On the right is a schematic diagram showing representations of electrondensity clouds of the oxygenated heme group (pink), the attached histidine residue (light blue), and the attached oxygen molecule (gray). The oxygenated heme assumes a planar configuration, and the central iron atom occupies a space in the plane of the heme group (depicted by a straight red line). The shape change in the heme group has important implications for the rest of the hemoglobin protein, as well. When the iron atom moves into the porphyrin plane upon oxygenation, the histidine residue to which the iron atom is attached is drawn closer to the heme group. This movement of the histidine residue then shifts the position of other amino acids that are near the histidine (Figure 6). When the amino acids in a protein are shifted in this manner (by the oxygenation of one of the heme groups in the protein), the structure of the interfaces between the four subunits is altered. Hence, when a single heme group in the hemoglobin protein becomes oxygenated, the whole protein changes its shape. In the new shape, it is easier for the other three heme groups to become oxygenated. Thus, the binding of one molecule of O2 to hemoglobin enhances the ability of hemoglobin to bind more O2 molecules. This property of hemoglobin is known as "cooperative binding."

Figure 6 This figure shows the heme group and a portion of the hemoglobin protein that is directly attached to the heme. When hemoglobin is deoxygenated (left), the heme group adopts a domed configuration. When hemoglobin is oxygenated (right), the heme group adopts a planar configuration. As shown in the figure, the conformational change in the heme group causes the protein to change its conformation, as well. Please click on the pink button below to view a QuickTime movie showing how the amino acid residues near the heme group in hemoglobin shift as the heme group converts between the nonplanar (domed) and the planar conformation by binding and releasing a molecule of O2. Click the blue button below to download QuickTime 4.0 to view the movie.

Questions on Conformational Changes Upon Binding of Oxygen:

Explain, in terms of electron repulsion, why the heme group adopts a nonplanar (domed) configuration upon deoxygenation. Explain how a change in the heme group configuration causes the entire hemoglobin subunit to change shape.

Spectroscopy and the Color of Blood The changes that occur in blood upon oxygenation and deoxygenation are visible not only at the microscopic level, as detailed above, but also at the macroscopic level. Clinicians have long noted that blood in the systemic arteries (traveling from the heart to the oxygen-using cells of the body) is red-colored, while blood in the systemic veins

(traveling from the oxygen-using cells back to the heart) is blue-colored (see Figure 7). The blood in the systemic arteries is oxygen-rich; this blood has just traveled from the lungs (where it picked up oxygen inhaled from the air) to the heart, and then is pumped throughout the body to deliver its oxygen to the body's cells. The blood in the systemic veins, on the other hand, is oxygen-poor; it has unloaded its oxygen to the body's cells (exchanging the O2 for CO2, as described below), and must now return to the lungs to replenish the supply of oxygen. Hence, a simple macroscopic observation, i.e., noting the color of the blood, can tell us whether the blood is oxygenated or deoxygenated. What causes this color change in the blood? We know that the shape of the heme group and the hemoglobin protein change, depending on whether hemoglobin is oxygenated or deoxygenated. The two conformations must have different light-absorbing properties. The oxygenated conformation of hemoglobin must absorb light in the blue-green range, and reflect red light, to account for the red appearance of oxygenated blood. The deoxygenated conformation of hemoglobin must absorb light in the orange range, and reflect blue light, to account for the bluish appearance of deoxygenated blood. We could use a spectrophotometer to examine a dilute solution of blood and determine the wavelength of light absorbed by each conformation. For an approximate prediction of the wavelength of light absorbed and for the colors of light absorbed for a given complementary color, a table such as Table 1 in the introduction to the Experiment ("Relations Between Electronic Transition Energy and Color") could be used.

Questions on Spectroscopy and the Color of Blood

Propose an explanation for why the change in heme group conformation results in a color change. A researcher prepares two solutions of deoxygenated hemoglobin. One solution is ten times as concentrated as the other solution. The researcher then obtains absorption spectra for the two solutions.

a. Do you expect the wavelength of maximum absorption ( max) to be the same or different for the two solutions? If max is different for the two solutions, indicate which solution will have a higher max. Briefly, explain your reasoning. b. Do you expect the absorbance (A) at max to be the same or different for the two solutions? If the absorbance is different for the two solutions, indicate which solution will have a higher absorbance. Briefly, explain your reasoning. The Effect of CO2 and H+ on O2 Binding In 1904, Christian Bohr discovered that increased concentrations of CO2 and H+ promote the release of O2 from hemoglobin in the blood. This phenomenon, known as the Bohr effect, is a highly adaptive feature of the body's blood-gas exchange mechanism. The blood that is pumped from the heart to the body tissues and organs (other than the lungs)

is rich in oxygen (Figure 7). These tissues require oxygen for their metabolic activities (e.g., muscle contraction). Hence, it is necessary for oxygen to remain bound to hemoglobin as the blood travels through the arteries (so that it can be carried to the tissues), but be easily removable when the blood passes through the capillaries feeding the body tissues. CO2 and H+ are produced from metabolic activities of the body, and so the concentration of these species is high in the metabolically active tissues of the body. Thus, the tissues that perform the most metabolic activity (and therefore require the largest amount of O2) produce large quantities of CO2 and H+, facilitating the release of O2 from the blood where the O2 is most needed. In the lungs, the reverse effect occurs: high concentrations of O2 cause the release of CO2 from hemoglobin. 1. Blood rich in carbon dioxide is pumped from the heart into the lungs through the pulmonary arteries. (Arteries are blood vessels carrying blood away from the heart; veins are blood vessels carrying blood to the heart.) 2. In the lungs, CO2 in the blood is exchanged for O2. 3. The oxygen-rich blood is carried back to the heart through the pulmonary veins. 4. This oxygen-rich blood is then pumped from the heart to the many tissues and organs of the body, through the systemic arteries. 5. In the tissues, the arteries narrow to tiny capillaries. Here, O2 in the blood is exchanged for CO2. 6. The capillaries widen into the systemic veins, which carry the carbon-dioxiderich blood back to the heart. Figure 7

This is a schematic diagram of the flow of blood through the circulatory system, showing the sites of O2/CO2 exchange in the body. Note: The components of this diagram are not drawn to scale. How do CO2 and H+ promote the release of O2 from hemoglobin? These species help form interactions between amino-acid residues at the interfaces of the four subunits in hemoglobin. These interactions are called "salt bridges," because they are between positively-charged and negatively-charged amino-acid residues on different subunits of the same protein (Figure 8). When "salt bridges" form, the subunits are held in a position that "tugs on" the histidine that is attached to the heme iron. (See Figure 5.) This favors the domed configuration, which is the deoxygenated form of hemoglobin.

Figure 8 On the left is a schematic diagram of the interface of two subunits of the deoxygenated hemoglobin protein. In the presence of CO2 and H+ (e.g., in the muscles), charged groups are formed on the amino acid residues lining the subunit interface. These charged groups are held together by ionic interactions, forming "salt bridges" between the two subunits, and stabilizing the deoxygenated form of hemoglobin. When blood passes through the alveolar capillaries of the lungs, CO2 and H+ are removed from the hemoglobin, and the oxygenated configuration is favored (right). Note: The components of this diagram are not drawn to scale. When the concentration of protons (H+) is low (pH 9), positive charges do not form on the residues at the subunit interfaces, so the salt bridges cannot form (right image in Figure 8). However, at pH 7, histidine residues at the subunit interfaces (not the histidine residues that bind the heme groups) can accept an additional proton (H+), and hence

become positively charged (Equation 1). When salt bridges form by the interaction of these interfacial histidine residues and nearby negatively-charged amino-acid residues, the deoxygenated hemoglobin structure is favored, and oxygen is released (left image in Figure 8).

(1

The number of negatively-charged residues in the salt bridges is increased in the presence of carbon dioxide. CO2 binds to the amino (-NH2) group of certain amino acid residues at the subunit interfaces to produce a negatively-charged group (-NHCOO-) on the residue (Equation 2). This negatively-charged group can form salt bridges with the positive charges on the protonated histidines described above. The H+ produced by Equation 2 can also be accepted by histidine residues at the subunit interfaces (via Equation 1).

Thus, hemoglobin's biological function is regulated by the changing of the overall protein structure. This structure is altered by the binding or releasing of CO2 and H+ to the interfaces of the subunits in hemoglobin (Figure 8).

Questions on the Bohr Effect:

Does CO2 bind at the same site on the hemoglobin molecule as O2? If not, where does CO2 bind? In muscles, the oxygen released by hemoglobin is taken up by myoglobin. Myoglobin is a muscular protein that stores oxygen and allows it to diffuse throughout the muscle fibers so that it can be used by the muscle. Myoglobin contains only one subunit (and thus only one heme group), which is very similar to one of the subunits of hemoglobin. Would you expect myoglobin to exhibit the Bohr effect (i.e., would myoglobin release O2 in the presence of CO2 and H+)? Briefly, explain your reasoning.

Summary

Blood is an amazing and vitally important part of the body, because it contains many finely-tuned chemical systems that allow it to maintain the chemical environment needed for the body's metabolism. One of the most important functions of blood is delivering O2 to all parts of the body by the hemoglobin protein. O2 is carried in the hemoglobin protein by the heme group. The heme group (a component of the hemoglobin protein) is a metal complex, with iron as the central metal atom, that can bind or release molecular oxygen. Both the hemoglobin protein and the heme group undergo conformational changes upon oxygenation and deoxygenation. When one heme group becomes oxygenated, the shape of hemoglobin changes in such a way as to make it easier for the other three heme groups in the protein to become oxygenated, as well. This feature helps the protein to pick up oxygen more efficiently as the blood travels through the lungs. Hemoglobin also enables the body to eliminate CO2, which is generated as a waste product, via gas exchange in the blood (CO2 exchanged for O2 in the lungs, and O2 exchanged for CO2 in the muscles). The species generated as waste by the oxygen-consuming cells actually help to promote the release of O2 from hemoglobin when it is most needed by the cells. Hence, hemoglobin is a beautiful example of the finely tuned chemical systems that enable the blood to distribute necessary molecules to cells throughout the body, and remove waste products from those cells.

CHIME Files To view the molecules interactively, please use Chime. To download the pdb files for viewing and rotating the molecules shown above, please click on the appropriate name below or on the "interactive" button below each molecular-model figure in the text.

Alpha-helix structure (alphahelix.pdb) One subunit from Hemoglobin (subunit.pdb) Hemoglobin (hemoglobin.pdb) Heme group bound to histidine residue (heme.pdb)

Additional Links:

Naming Coordination Compounds summarizes the steps and provides examples of naming compounds containing coordination complexes. For additional information on hemoglobin, see the hemoglobin tutorial by Eric Martz of the University of Massachusetts.

Note: You need CHIME to view this tutorial. You can download Chemscape Chime here.

To learn about porphyrin and other chelating agents, see this "Chemical of the Week" site from the University of Wisconsin.

Another porphyrin molecule, similar to heme but containing Mg rather than Fe as the central atom, is chlorophyll. You can learn about the structure , function, and spectroscopy of chlorophyll from this site. (Note: You will be studying chlorophyll in lab at the beginning of Chemistry 152.)

References: Guex, N. and Peitsch, M.C. Electrophoresis, 1997, 18, 2714-2723. (SwissPDB Viewer) URL: http://www.expasy.ch/spdbv/mainpage.htm. Ji, X. et al. "Positive and negative cooperativities at subsequent steps of oxygenation regulate the allosteric behavior of multistate sebacylhemoglobin," (1996) Biochemistry, 35, 3418. Hemoglobin PDB coordinates, Brookhaven Protein Data Bank. Kavanaugh, J.S. et al. "High-resolution x-ray study of deoxyhemoglobin Rothschild 37beta trp->arg: a mutation that creates an intersubunit chloride-binding site," (1992) Biochemistry, 31, 4111. Deoxyhemoglobin PDB coordinates, Brookhaven Protein Data Bank. Kilmartin, J.V. "Interaction of haemoglobin with protons, CO2, and 2,3diphosphoglycerate," (1976) Br. Med. Bull., 32, 209. Persistence of Vision Ray Tracer (POV-Ray). URL: http://www.povray.org. Royer Jr., W.E. "High-resolution crystallographic analysis of co-operative dimeric hemoglobin," J. Mol. Biol., 235, 657. Oxyhemoglobin PDB coordinates, Brookhaven Protein Data Bank. Stryer, L. Biochemistry, 4th ed. W.H. Freeman and Co., New York, 1995, p. 154-168.

Blood Groups, Blood Typing and Blood Transfusions The discovery of blood groups

Experiments with blood transfusions, the transfer of blood or blood components into a person's blood stream, have been carried out for hundreds of years. Many patients have died and it was not until 1901, when the Austrian Karl Landsteiner discovered human blood groups, that blood transfusions became safer. Mixing blood from two individuals can lead to blood clumping or agglutination. The clumped red cells can crack and cause toxic reactions. This can have fatal consequences. Karl Landsteiner discovered that blood clumping was an immunological reaction which occurs when the receiver of a blood transfusion has antibodies against the donor blood cells. Karl Landsteiner's work made it possible to determine blood groups and thus paved the way for blood transfusions to be carried out safely. For this discovery he was awarded the Nobel Prize in Physiology or Medicine in 1930.

What is blood made up of? An adult human has about 46 liters of blood circulating in the body. Among other things, blood transports oxygen to various parts of the body. Blood consists of several types of cells floating around in a fluid called plasma. The red blood cells contain hemoglobin, a protein that binds oxygen. Red blood cells transport oxygen to, and remove carbon dioxide from, the body tissues. The white blood cells fight infection. The platelets help the blood to clot, if you get a wound for example. The plasma contains salts and various kinds of proteins.

What are the different blood groups? The differences in human blood are due to the presence or absence of certain protein molecules called antigens and antibodies. The antigens are located on the surface of the red blood cells and the antibodies are in the blood plasma. Individuals have different types and combinations of these molecules. The blood group you belong to depends on what you have inherited from your parents. There are more than 20 genetically determined blood group systems known today, but the AB0 and Rh systems are the most important ones used for blood transfusions. Not all blood groups are compatible with each other. Mixing incompatible blood groups leads to blood clumping or agglutination, which is dangerous for individuals. Nobel Laureate Karl Landsteiner was involved in the discovery of both the AB0 and Rh blood groups.

AB0 blood grouping system According to the AB0 blood group system there are four different kinds of blood groups: A, B, AB or 0 (null). Blood group A If you belong to the blood group A, you have A antigens on the surface of your red blood cells and B antibodies in your blood plasma.

Blood group B If you belong to the blood group B, you have B antigens on the surface of your red blood cells and A antibodies in your blood plasma.

Blood group AB If you belong to the blood group AB, you have both A and B antigens on the surface of your red blood cells and no A or B antibodies at all in your blood plasma.

Blood group 0 If you belong to the blood group 0 (null), you have neither A or B antigens on the surface of your red blood cells but you have both A and B antibodies in your blood plasma.

Rh factor blood grouping system Many people also have a so called Rh factor on the red blood cell's surface. This is also an antigen and those who have it are called Rh+. Those who haven't are called Rh-. A person with Rh- blood does not have Rh antibodies naturally in the blood plasma (as one can have A or B antibodies, for instance). But a person with Rh- blood can develop Rh antibodies in the blood plasma if he or she receives blood from a person with Rh+ blood, whose Rh antigens can trigger the production of Rh antibodies. A person with Rh+ blood can receive blood from a person with Rh- blood without any problems.

Blood group notation According to above blood grouping systems, you can belong to either of following 8 blood groups: A Rh+ A RhB Rh+ B RhAB Rh+ AB Rh0 Rh+ 0 Rh-

Do you know which blood group you belong to?

Blood typing how do you find out to which blood group someone belongs? 1. You mix the blood with three different reagents including either of the three different antibodies, A, B or Rh antibodies. 2. Then you take a look at what has happened. In which mixtures has agglutination occurred? The agglutination indicates that the blood has reacted with a certain antibody and therefore is not compatible with blood containing that kind of antibody. If the blood does not agglutinate, it indicates that the blood does not have the antigens binding the special antibody in the reagent. 3. If you know which antigens are in the person's blood, it's easy to figure out which blood group he or she belongs to!

A person with A+ blood receives B+ blood. The B antibodies (yellow) in the A+ blood attack the foreign red blood cells by binding to them. The B antibodies in the A+ blood bind the antigens in the B+ blood and agglutination occurs. This is dangerous because the agglutinated red blood cells break after a while and their contents leak out and become toxic.

What happens when blood clumps or agglutinates? For a blood transfusion to be successful, AB0 and Rh blood groups must be compatible between the donor blood and the patient blood. If they are not, the red blood cells from the donated blood will clump or agglutinate. The agglutinated red cells can clog blood vessels and stop the circulation of the blood to various parts of the body. The agglutinated red blood cells also crack and its contents leak out in the body. The red blood cells contain hemoglobin which becomes toxic when outside the cell. This can have fatal consequences for the patient. The A antigen and the A antibodies can bind to each other in the same way that the B antigens can bind to the B antibodies. This is what would happen if, for instance, a B

blood person receives blood from an A blood person. The red blood cells will be linked together, like bunches of grapes, by the antibodies. As mentioned earlier, this clumping could lead to death. Blood transfusions who can receive blood from whom? Of course you can always give A blood to persons with blood group A, B blood to a person with blood group B and so on. But in some cases you can receive blood with another type of blood group, or donate blood to a person with another kind of blood group. People with blood group 0 Rh - are called "universal donors" and people with blood group AB Rh+ are called "universal receivers." Rh blood can never be given to someone with Rh - blood, but the other way around works. For example, 0 Rh+ blood can not be given to someone with the blood type AB Rh -.
+

The transfusion will work if a person who is going to receive blood has a blood group that doesn't have any antibodies against the donor blood's antigens. But if a person who is going to receive blood has antibodies matching the donor blood's antigens, the red blood cells in the donated blood will clump. Can Can give receive Antibodies blood to blood from AB Rh+ AB Rh+ AB Rh A Rh+ A Rh B Rh+ B Rh 0 Rh+ 0 Rh -

Blood Group AB Rh+

Antigens

A, B and Rh None

AB Rh - A and B

None AB Rh - AB Rh (Can AB Rh+ develop Rh antibodies) B A Rh+ A Rh+ AB Rh+ A Rh 0 Rh+ 0 Rh -

A Rh+

A and Rh

A Rh -

B A Rh - A Rh (Can A Rh+ 0 Rh develop Rh AB Rh

antibodies) AB Rh+ B Rh+ B and Rh A B Rh+ B Rh+ AB Rh+ B Rh 0 Rh+ 0 RhB RhB Rh B Rh+ 0 Rh AB Rh AB Rh+ 0 Rh+ 0 Rh+ + A Rh 0 Rh + B Rh AB Rh+

B Rh -

A (Can develop Rh antibodies) A and B

0 Rh+

Rh

0 Rh -

None

A and B (Can develop Rh antibodies)

AB Rh+ 0 Rh AB Rh A Rh+ A Rh B Rh+ B Rh 0 Rh+ 0 Rh -