N 14. Blood. Blood groups. Leukemia

Blood is a highly specialized circulating tissue consisting of several types of cells suspended in a fluid medium known as plasma. The cellular constituents are: red blood cells, which carry respiratory gases and give it its red color because they contain haemoglobin (an iron-containing protein that binds oxygen in the lungs and transports it to tissues in the body), white blood cells (leukocytes), which fight disease, and platelets, cell fragments which play an important part in the clotting of the blood.

Medical terms related to blood often begin with hemo- or hemato- (BE: haemo- and haemato-) from the Greek word "haima" for "blood." Anatomically, blood is considered a connective tissue from both its origin in the bones and its function.

Human blood smear: a - erythrocytes; b - neutrophil; c - eosinophil; d - lymphocyte.

Human blood smear: a - erythrocytes; b - neutrophil; c - eosinophil; d - lymphocyte.

 

Blood is a constantly circulating fluid providing the body with nutrition, oxygen, and waste removal. Blood is mostly liquid, with numerous cells and proteins suspended in it, making blood "thicker" than pure water. The average person has about 5 liters (more than a gallon) of blood.

 

A liquid called plasma makes up about half of the content of blood. Plasma contains proteins that help blood to clot, transport substances through the blood, and perform other functions. Blood plasma also contains glucose and other dissolved nutrients.

 

About half of blood volume is composed of blood cells:

 

 • Red blood cells, which carry oxygen to the tissues

 • White blood cells, which fight infections

 • Platelets, smaller cells that help blood to clot

 

Blood is conducted through blood vessels (arteries and veins). Blood is prevented from clotting in the blood vessels by their smoothness, and the finely tuned balance of clotting factors.

Blood Conditions

Hemorrhage (bleeding): Blood leaking out of blood vessels may be obvious, as from a wound penetrating the skin. Internal bleeding (such as into the intestines, or after a car accident) may not be immediately apparent.

 Hematoma: A collection of blood inside the body tissues. Internal bleeding often causes a hematoma.

Leukemia: A form of blood cancer, in which white blood cells multiply abnormally and circulate through the blood. The excessive large numbers of white cells deposit in the body's tissues, causing damage.

 Multiple myeloma: A form of blood cancer of plasma cells similar to leukemia. Anemia, kidney failure and high blood calcium levels are common in multiple myeloma.

 Lymphoma: A form of blood cancer, in which white blood cells multiply abnormally inside lymph nodes and other tissues. The enlarging tissues, and disruption of blood's functions, can eventually cause organ failure.

Anemia: An abnormally low number of red blood cells in the blood. Fatigue and breathlessness can result, although anemia often causes no noticeable symptoms.

Hemolytic anemia: Anemia caused by rapid bursting of large numbers of red blood cells (hemolysis). An immune system malfunction is one cause.

Hemochromatosis: A disorder causing excessive levels of iron in the blood. The iron deposits in the liver, pancreas and other organs, causing liver problems and diabetes.

 Sickle cell disease: A genetic condition in which red blood cells periodically lose their proper shape (appearing like sickles, rather than discs). The deformed blood cells deposit in tissues, causing pain and organ damage.

Bacteremia: Bacterial infection of the blood. Blood infections are serious, and often require hospitalization and continuous antibiotic infusion into the veins.

Malaria: Infection of red blood cells by Plasmodium, a parasite transmitted by mosquitos. Malaria causes episodic fevers, chills, and potentially organ damage.

Thrombocytopenia: Abnormally low numbers of platelets in the blood. Severe thrombocytopenia may lead to bleeding.

Leukopenia: Abnormally low numbers of white blood cells in the blood. Leukopenia can result in difficulty fighting infections.

 Disseminated intravascular coagulation (DIC): An uncontrolled process of simultaneous bleeding and clotting in very small blood vessels. DIC usually results from severe infections or cancer.

Hemophilia: An inherited (genetic) deficiency of certain blood clotting proteins. Frequent or uncontrolled bleeding can result from hemophilia.

Hypercoaguable state: Numerous conditions can result in the blood being prone to clotting. A heart attack, stroke, or blood clots in the legs or lungs can result.

Polycythemia: Abnormally high numbers of red blood cells in the blood. Polycythemia can result from low blood oxygen levels, or may occur as a cancer-like condition.

Deep venous thrombosis (DVT): A blood clot in a deep vein, usually in the leg. DVTs are dangerous because they may become dislodged and travel to the lungs, causing a pulmonary embolism (PE).

Myocardial infarction (MI): Commonly called a heart attack, a myocardial infarction occurs when a sudden blood clot develops in one of the coronary arteries, which supply blood to the heart.

Blood Tests

Complete blood count: An analysis of the concentration of red blood cells, white blood cells, and platelets in the blood. Automated cell counters perform this test.

http://www.webmd.com/a-to-z-guides/complete-blood-count-cbc

Blood smear: Drops of blood are smeared across a microscope slide, to be examined by an expert in a lab. Leukemia, anemia, malaria, and numerous other blood conditions can be identified with a blood smear.

Blood type: A test for compatibility before receiving a blood transfusion. The major blood types (A, B, AB, and O) are determined by the protein markers (antigens) present on the surface of red blood cells.

Coombs test: A blood test looking for antibodies that could bind to and destroy red blood cells. Pregnant women and people with anemia may undergo Coombs testing.

Blood culture: A blood test looking for infection present in the bloodstream. If bacteria or other organisms are present, they may multiply in the tested blood, allowing their identification.

Mixing study: A blood test to identify the reason for blood being "too thin" (abnormally resistant to clotting). The patient's blood is mixed in a tube with normal blood, and the mixed blood's properties may provide a diagnosis.

Bone marrow biopsy: A thick needle is inserted into a large bone (usually in the hip), and bone marrow is drawn out for tests. Bone marrow biopsy can identify blood conditions that simple blood tests cannot.

Blood Treatments

Chemotherapy: Medicines that kill cancer cells. Leukemias and lymphomas are usually treated with chemotherapy.

Blood transfusion: A blood donor's red blood cells are separated from their plasma and packed into a small bag. Transfusing the concentrated red blood cells into a recipient replaces blood loss.

Platelet transfusion: A blood donor's platelets are separated from the rest of blood and concentrated into a plastic bag. Platelet transfusion is generally only performed when platelet counts fall to very low levels.

Fresh frozen plasma: A blood donor's plasma (liquid blood) is separated from the blood cells, and frozen for storage. Plasma transfusion can improve blood clotting and prevent or stop bleeding that's due to clotting problems.

 Cryoprecipitate: Specific proteins are separated from blood and frozen in a small volume of liquid. Cryoprecipitate transfusion can replace specific blood clotting proteins when their levels are low, such as in people with hemophilia.

Anticoagulation: Medicines to "thin" the blood and prevent clotting in people at high risk from blood clots. Heparin, enoxaparin (Lovenox) and warfarin (Coumadin) are the medicines most often used.

Antiplatelet drugs: Aspirin and clopidogrel (Plavix) interfere with platelet function and help prevent blood clots, including those that cause heart attacks and strokes.

 Antibiotics: Medicines to kill bacteria and parasites can treat blood infections caused by these organisms.

Erythropoietin: A hormone produced by the kidney that stimulates red blood cell production. A manufactured form of erythropoietin can be given to improve the symptoms of anemia.

Bloodletting: In people with problems caused by too much blood (such as from hemochromatosis or polycythemia), occasional controlled removal of blood may be necessary.

 

Functions

Problems with blood composition or circulation can lead to downstream tissue dysfunction. The term ischaemia refers to tissue which is inadequately perfused with blood.

The blood is circulated around the lungs and body by the pumping action of the heart. Additional return pressure may be generated by gravity and the actions of skeletal muscles. In mammals, blood is in equilibrium with lymph, which is continuously formed from blood (by capillary ultrafiltration) and returned to the blood (via the thoracic duct). The lymphatic circulation may be thought of as the "second circulation".

Anatomy of mammalian blood

Blood is composed of several kinds of cells (occasionally called corpuscles); these formed elements of the blood constitute about 45% of whole blood by volume, mostly red blood cells. The other 55% is blood plasma, a fluid that is the blood's liquid medium, appearing yellow in color. The proportion of blood occupied by red blood cells is referred to as the hematocrit.

A scanning electron microscope (SEM) image of normal circulating human blood. One can see red blood cells, several white blood cells including knobby lymphocytes, a monocyte, a neutrophil, and many small disc-shaped platelets.

http://en.wikipedia.org/skins-1.5/common/images/magnify-clip.png

A scanning electron microscope (SEM) image of normal circulating human blood. One can see red blood cells, several white blood cells including knobby lymphocytes, a monocyte, a neutrophil, and many small disc-shaped platelets.

The normal pH of human arterial blood is approximately 7.40 (normal range is 7.35-7.45), a weak alkaline solution. Blood that has a pH below 7.35 is acidic, while blood pH above 7.45 is alkaline. Blood pH along with arterial carbon dioxide tension (PaCO2) and HCO3 readings are helpful in determining the acid-base balance of the body. The respiratory system and urinary system normally control the acid-base balance of blood as part of homeostasis. Blood is about 7% of the human body weight,[1] so the average adult has a blood volume of about 5 litres, of which 2.7-3 litres is plasma. Human blood density is around 1060 kg/m³.[2] The combined surface area of all the red cells in the human body would be roughly 2,000 times as great as the body's exterior surface.[citation needed]

The cells are:

Red blood cells or erythrocytes (96%) 

In mammals, mature red blood cells lack a nucleus and organelles. They contain the blood's haemoglobin and distribute oxygen. The red blood cells (together with endothelial vessel cells and some other cells) are also marked by glycoproteins that define the different blood types.

White blood cells or leukocytes (3.0%) 

White blood cells are part of the immune system; they destroy infectious agents, pathogens.

Platelets or thrombocytes (1.0%) 

Platelets are responsible for blood clotting (coagulation). They change fibrinogen into fibrin. This fibrin creates a mesh onto which red blood cells collect and clot. This clot stops more blood from leaving the body and also helps to prevent bacteria from entering the body.

Blood plasma is essentially an aqueous solution containing 92% water, 8% blood plasma proteins, and trace amounts of other materials. Some components are:

Together, plasma and cells form a non-Newtonian fluid whose flow properties are uniquely adapted to the architecture of the blood vessels.

The term serum refers to plasma from which the clotting proteins have been removed. Most of the protein remaining is albumin and immunoglobulins.

Physiology of blood

Production and degradation

Blood cells are produced in the bone marrow, this process is termed hematopoiesis. The proteinaceous component (including clotting proteins) is produced overwhelmingly in the liver, while hormones are produced by the endocrine glands and the watery fraction is regulated by the hypothalamus and maintained by the kidney and indirectly by the gut.

Blood cells are degraded by the spleen and the Kupffer cells in the liver. The liver also clears some proteins, lipids and amino acids. The kidney actively secretes waste products into the urine. Erythrocytes usually live up to 120 days before they are systematically replaced by new erythrocytes created by the process of hematopoiesis.

Transport of oxygen

Blood oxygenation is measured in several ways, but the most important measure is the hemoglobin (Hb) saturation percentage. This is a non-linear (sigmoidal) function of the partial pressure of oxygen. About 98.5% of the oxygen in a sample of arterial blood in a healthy human breathing air at normal pressure is chemically combined with the Hb. Only 1.5% is physically dissolved in the other blood liquids and not connected to Hb. The hemoglobin molecule is the primary transporter of oxygen in mammals and many other species (for exceptions, see below).

With the exception of pulmonary and umbilical arteries and their corresponding veins, arteries carry oxygenated blood away from the heart and deliver it to the body via arterioles and capillaries, where the oxygen is consumed; afterwards, venules and veins carry deoxygenated blood back to the heart.

Differences in infrared absorption between oxygenated and deoxygenated blood form the basis for realtime oxygen saturation measurement in hospitals and ambulances.

Under normal conditions in humans at rest, haemoglobin in blood leaving the lungs is about 98-99% saturated with oxygen. In a healthy adult at rest, deoxygenated blood returning to the lungs is still approximately 75% saturated.[3][4] Increased oxygen consumption during sustained exercise reduces the oxygen saturation of venous blood, which can reach less than 15% in a trained athlete; although breathing rate and blood flow increase to compensate, oxygen saturation in arterial blood can drop to 95% or less under these conditions.[5] Oxygen saturation this low is considered dangerous in an individual at rest (for instance, during surgery under anesthesia): "As a general rule, any condition which leads to a sustained mixed venous saturation of less than 50% will be poorly tolerated and a mixed venous saturation of less than 30% should be viewed as a medical emergency."[6]

A fetus, receiving oxygen via the placenta, is exposed to much lower oxygen pressures (about 20% of the level found in an adult's lungs) and so fetuses produce another form of hemoglobin with a much higher affinity for oxygen (hemoglobin F) in order to extract as much oxygen as possible from this sparse supply.[7]

Substances other than oxygen can bind to the hemoglobin; in some cases this can cause irreversible damage to the body. Carbon monoxide for example is extremely dangerous when absorbed into the blood. When combined with the hemoglobin, it irreversibly makes carboxyhemoglobin which reduces the volume of oxygen that can be carried in the blood. This can very quickly cause suffocation, as oxygen is vital to many organisms (including humans). This damage can occur when smoking a cigarette (or similar item) or in event of a fire. Thus carbon monoxide is considered far more dangerous than the actual fire itself because it reduces the oxygen carrying content of the blood.

Insects

In insects, the blood (more properly called hemolymph) is not involved in the transport of oxygen. (Openings called tracheae allow oxygen from the air to diffuse directly to the tissues). Insect blood moves nutrients to the tissues and removes waste products in an open system.

Small invertebrates

In some small invertebrates like insects, oxygen is simply dissolved in the plasma. Larger animals use respiratory proteins to increase the oxygen carrying capacity. Hemoglobin is the most common respiratory protein found in nature. Hemocyanin (blue) contains copper and is found in crustaceans and mollusks. It is thought that tunicates (sea squirts) might use vanabins (proteins containing vanadium) for respiratory pigment (bright green, blue, or orange).

In many invertebrates, these oxygen-carrying proteins are freely soluble in the blood; in vertebrates they are contained in specialized red blood cells, allowing for a higher concentration of respiratory pigments without increasing viscosity or damaging blood filtering organs like the kidneys.

Deep sea invertebrates

Giant tube worms have extraordinary hemoglobins that allow them to live in extraordinary environments. These hemoglobins also carry sulfides normally fatal in other animals.

Transport of carbon dioxide

When systemic arterial blood flows through capillaries, carbon dioxide diffuses from the tissues into the blood. Some carbon dioxide is dissolved in the blood. Some carbon dioxide reacts with hemoglobin and other proteins to form carbamino compounds. The remaining carbon dioxide is converted to bicarbonate and hydrogen ions through the action of RBC carbonic anhydrase. Most carbon dioxide is transported through the blood in the form of bicarbonate ions.

Transport of hydrogen ions

Some oxyhemoglobin loses oxygen and becomes deoxyhemoglobin. Deoxyhemoglobin has a much greater affinity for H+ than does oxyhemoglobin so it binds most of the hydrogen ions.

Color

In humans and other hemoglobin-using creatures, oxygenated blood is bright red. This is due to oxygenated iron in the red blood cells. Deoxygenated blood is a darker shade of red, which can be seen during blood donation and when venous blood samples are taken. However, due to an optical effect caused by the way in which light penetrates through the skin, veins typically appear blue in colour. This has led to a common misconception that venous blood is blue before it is exposed to air. Another reason for this misconception is that medical charts always show venous blood as blue in order to distinguish it from arterial blood which is depicted as red on the same chart.

The blood of horseshoe crabs is blue, which is a result of its high content in copper-based hemocyanin instead of the iron-based hemoglobin found, for example, in humans.

Provision of force

In mammals the restriction of blood flow is commonly used as a temporary provision of force, as in an erection.

Health and disease

Ancient Medicine

Hippocratic medicine considered blood one of the four humors (together with phlegm, yellow bile and black bile). As many diseases were thought to be due to an excess of blood, bloodletting and leeching were a common intervention until the 19th century (it is still used for some rare blood disorders).

In classical Greek medicine, blood was associated with air, springtime, and with a merry and gluttonous (sanguine) personality. It was also believed to be produced exclusively by the liver.

Diagnosis

Blood pressure and blood tests are amongst the most commonly performed diagnostic investigations that directly concern the blood.

Pathology

Problems with blood circulation and composition play a role in many diseases.

  • Wounds can cause major blood loss (see bleeding). The thrombocytes cause the blood to coagulate, blocking relatively minor wounds, but larger ones must be repaired at speed to prevent exsanguination. Damage to the internal organs can cause severe internal bleeding, or hemorrhage.
  • Circulation blockage can also create many medical conditions from ischemia in the short term to tissue necrosis and gangrene in the long term.
  • Hemophilia is a genetic illness that causes dysfunction in one of the blood's clotting mechanisms. This can allow otherwise inconsequential wounds to be life-threatening, but more commonly results in hemarthrosis, or bleeding into joint spaces, which can be crippling.
  • Leukemia is a group of cancers of the blood-forming tissues.
  • Major blood loss, whether traumatic or not (e.g. during surgery), as well as certain blood diseases like anemia and thalassemia, can require blood transfusion. Several countries have blood banks to fill the demand for transfusable blood. A person receiving a blood transfusion must have a blood type compatible with that of the donor.
  • Blood is an important vector of infection. HIV, the virus which causes AIDS, is transmitted through contact between blood, semen, or the bodily secretions of an infected person. Hepatitis B and C are transmitted primarily through blood contact. Owing to blood-borne infections, bloodstained objects are treated as a biohazard.
  • Bacterial infection of the blood is bacteremia or sepsis. Viral Infection is viremia. Malaria and trypanosomiasis are blood-borne parasitic infections.

Treatment

Blood transfusion is the most direct therapeutic use of blood. It is obtained from human donors by blood donation. As there are different blood types, and transfusion of the incorrect blood may cause severe complications, crossmatching is done to ascertain the correct type is transfused.

Other blood products administered intravenously are platelets, blood plasma, cryoprecipitate and specific coagulation factor concentrates.

Many forms of medication (from antibiotics to chemotherapy) are administered intravenously, as they are not readily or adequately absorbed by the digestive tract.

As stated above, some diseases are still treated by removing blood from the circulation.

It is the fluid part of the blood that saves lives where severe blood loss occurs, other preparations can be given such as ringers atopical plasma volume expander as a non-blood alternative, and these alternatives where used are rivalling blood use when used.

Blood type

Blood type (or blood group) is determined, in part, by the ABO blood group antigens present on red blood cells.

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, and 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.

The ABO blood group system and the Rhesus blood group system are more likely to cause harmful immunological reactions than the other blood group systems. In the routine blood transfusion work of a blood bank, the presence or absence of the three most significant blood group antigens, the A antigen, the B antigen and the RhD antigen (also known as the Rhesus factor or Rhesus D antigen), is determined. This gives the ABO blood group and the RhD antigen status, which are reflected in the common terminology A positive, O negative, etc. with the capital letters (A, B or O) referring to the ABO blood group, and positive or negative referring to the presence or absence of the RhD antigen of the Rhesus blood group system. In the routine preparation and selection of donor blood for blood transfusion, it is not necessary to determine the status of any more blood groups (or antigens), because antibody screening and cross-matching prior to transfusion, detects if there are any other blood group incompatibilities between potential donor blood and intended recipients.

If an individual is exposed to a blood group antigen that is not recognised as self, the immune system will 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. It is vital that compatible blood is selected for transfusion 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.

Blood types are inherited and represent contributions from both parents. Often, pregnant women carry a fetus with a different blood type from their own, and sometimes the mother forms antibodies against the red blood cells of the fetus, which causes hemolysis of fetal RBCs, and which in turn can lead to low fetal blood counts, a condition known as hemolytic disease of the newborn. Some blood types are associated with inheritance of other diseases; for example, the Kell antigen is associated with McLeod syndrome.[1] Certain blood types may affect susceptibility to infections, an example being the resistance to specific malaria species seen in individuals lacking the Duffy antigen.[2]The Duffy antigen, as a result of natural selection, is more common in ethnic groups from areas with a high incidence of malaria.[3]

The two most significant blood group systems were discovered during early experiments with blood transfusion: the ABO group in 1901[4] and the Rhesus group in 1937.[5] Development of the Coombs test in 1945,[6] the advent of transfusion medicine, and the understanding of hemolytic disease of the newborn led to discovery of more blood groups. Today, a total of 29 human blood group systems are recognized by the International Society of Blood Transfusion (ISBT).[7] A complete blood type would describe a full set of 29 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 29 blood groups, over 600 different blood group antigens have been found,[8] 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.[9] Blood types have been used in forensic science and in paternity testing, but this use is being replaced by DNA analysis, which provides greater certitude.

Blood group systems

ABO blood group system - diagram showing the carbohydrate chains which determine the ABO blood group

 

ABO blood group system - diagram showing the carbohydrate chains which determine the ABO blood group

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 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.[10]

Rhesus blood group system

The Rhesus system is the second most significant blood group system in human blood transfusion. The most significant Rhesus antigen is the RhD antigen because it is the most immunogenic of the five main rhesus antigens. It is common for RhD negative individuals not to have any anti-RhD IgG or IgM antibodies, because anti-RhD antibodies are not usually produced by sensitization against environmental substances. However, RhD negative individuals can produce IgG anti-RhD antibodies following a sensitizing event: possibly a fetomaternal transfusion of blood from a fetus in pregnany or occasionally a blood transfusion with RhD positive RBCs.

Table of ABO and Rh distribution by nation

Overall, type O blood is the most common blood type in the world.[21] Type A blood is more prevalent in Central and Eastern Europe countries.[21] Type B blood is most prevalent in Chinese/Asian communities when compared to other races.[21] Type AB blood is easier to find in Japan, China and Pakistan[21].

The associated anti-A 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 other animals, for example apes such as chimpanzees, bonobos, and gorillas.

 

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; 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 Janský had independently pioneered the classification of human blood into four groups, but Landsteiner's independent discovery had been accepted by the scientific world while Janský remained in relative obscurity. Janský's classification is however still used in Russia and states of former USSR (see below). In America, Moss[who?] published his own (very similar) work in 1910.

 

Landsteiner described A, B, and O; Alfred von Decastello and Adriano Sturli discovered the fourth type, AB, in 1902. Ludwik Hirszfeld and E. von Dungern discovered the heritability of ABO blood groups in 1910–11, with Felix Bernstein demonstrating the correct blood group inheritance pattern of multiple alleles at one locus in 1924. Watkins and Morgan, in England, discovered that the ABO epitopes were conferred by sugars, to be specific, N-acetylgalactosamine for the A-type and galactose for the B-type. 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 that contains the major portion of the ABH substances attached. Later, Yamamoto's group showed the precise glycosyl transferase set that confers the A, B and O epitopes.

 

ABO antigens

Diagram showing the carbohydrate chains that determine the ABO blood group

 

The H antigen is an essential precursor to the ABO blood group antigens. The H locus, which is located on chromosome 19, contains 3 exons that span more than 5 kb of genomic DNA; 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 β-D-galactose, β-D-N-acetylglucosamine, β-D-galactose, and 2-linked, α-L-fucose, the chain being attached to the protein or ceramide.

 

The ABO locus, which is located on chromosome 9, 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 α-N-acetylgalactosamine to the D-galactose end of the H antigen, producing the A antigen. The B allele encodes a glycosyltransferase that bonds α-D-galactose to the D-galactose end of the H antigen, creating the B antigen.

 

In the case of the O allele, when compared to the A allele, exon 6 lacks one nucleotide (guanine), which results in a loss of enzymatic activity. This difference, which occurs at position 261, causes a frameshift that results in the premature termination of the translation and, thus, degradation of the mRNA. This results in the 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 glycosphingolipid.

 

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 ABO-incompatible red blood cells (RBCs) that 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 α-D-N-galactosamine on the A glycoprotein 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 α-D-galactose on the B glycoprotein.

 

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.

 

The "Light in the Dark theory" suggests a novel evolutionary hypothesis: 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.

 

However, it is more likely that the force driving evolution of allele diversity is simply negative frequency-dependent selection; cells with rare variants of membrane antigens are more easily distinguished by the immune system from pathogens carrying antigens from other hosts. Thus, individuals possessing rare types are better equipped to detect pathogens. The high within-population diversity observed in human populations would, then, be a consequence of natural selection on individuals.

 

Nonantigen biology

 

The carbohydrate molecules on the surfaces of red blood cells have roles in cell membrane integrity, cell adhesion, membrane transportation of molecules, and acting as receptors for extracellular ligands, and enzymes. ABO antigens are found having similar roles on epithelial cells as well as red blood cells.

 

Transfusion reactions

 

Due to the presence of isoantibodies against non-self blood group antigens, individuals of type A blood group immediately raise anti-B antibodies against B-blood group RBCs if transfused with blood from B group. The anti-B antibodies bind to B antigens on RBCs and cause 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 recipients.

 

As far as transfusion compatibility is concerned, it is not strictly as simple as matching A, B, and O groups. In other words, no individual will ever receive a blood transfusion based on the ABO system alone. The rhesus factor must also be considered. Together, the rhesus factor and ABO grouping are the two most important compatibility factors to consider. An individual may be Rh+ or Rh-. In simpler terms, if an individual is blood type A and positive for the rhesus factor, then he or she is deemed "A+".

ABO and Rh blood type donation showing matches between donor and recipient types       Donors

O+     A+     B+     AB+   O- ** A-      B-      AB-

Recipients    O+                                                                    

A+                                                              

B+                                                              

AB+ *                                                          

O-                                                                       

A-                                                                    

B-                                                                     

AB-                                                                       

 

* Type AB+ is the universal recipient: Although those with AB blood type may be referred to as universal recipients, in actuality, type AB+ blood is that of the universal recipient, whereas type AB- is not. This is an important distinction to make.

** Because A-, A+, B-, B+, AB-, AB+, O- and O+ individuals can all receive blood from donors of type O- blood, an individual with type O- blood is deemed a universal donor. In a similar manner, O+ is not the universal donor blood type.

 

One caveat to this axiom of 'universal donor' is that this applies to packed RBCs, 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.

 

No antibodies are formed against the H antigen, except in those individuals with the Bombay phenotype.

 

In ABH secretors, roughly 80% of the human population, 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.

 

ABO hemolytic disease of the newborn

Main article: Hemolytic disease of the newborn (ABO)

 

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 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 glycosyltransferase—that 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.

 

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.

 

Genetics

 

There are two common O alleles, O01 and O02. These are identical to the group A allele (A01) for the first 261 nucleotides, at which point a guanosine base is deleted, resulting in a frame-shift mutation that produces a premature stop codon and failure to produce a functional A or B transferase. This deletion is found in all populations worldwide and presumably arose before humans migrated out of Africa (50,000 to 100,000 years ago). The second most common allele for group O (termed O02) is considered to be an even more ancient than the O01 allele.

 

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. 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. 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. Both theories contradict the previously held theory that type O blood evolved earliest.

 

Other blood group systems

The International Society of Blood Transfusion currently recognizes 29 blood group systems (including the ABO and Rh systems).[7] Thus, in addition to the ABO antigens and Rhesus antigens, many other antigens are expressed on the RBC surface membrane. For example, an individual can be AB RhD 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.

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 Food and Drug Administration.

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 immunological reaction, hemolysis (RBC destruction), renal failure and shock are 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 cross-matching blood, but this may be skipped when blood is required for an emergency. Cross-matching involves mixing a sample of the recipient's blood with a sample of the donor's blood and checking to see 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.

Some front-line military personnel choose to be tattooed with their blood type in case they should need an emergency blood transfusion. This was the case with frontline German Waffen-SS during the World War II; ironically this was an easy form of SS identification.[22]

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,[23] and the rarity of this blood type in the rest of the population can result in a shortage of Duffy-negative 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.[24]

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 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 group 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 of groups A or AB.

·                  Blood group B individuals have the B antigen on their 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 of groups 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 a blood transfusion is needed in a dire emergency, and the time taken to process the recipient's blood would cause a detrimental delay, O Neg blood is issued.

RBC Compatibility chartType O donors can give to A, B & AB; donors of types A & B can give to AB.

RBC Compatibility chart
Type O donors can give to A, B & AB; donors of types A & B can give to AB.

Red blood cell compatibility table[26][27]

Recipient blood type

Donor red blood cells must be:

AB+

O-

O+

A-

A+

B-

B+

AB-

AB+

AB-

O-

 

A-

 

B-

 

AB-

 

A+

O-

O+

A-

A+

 

 

 

 

A-

O-

 

A-

 

 

 

 

 

B+

O-

O+

 

 

B-

B+

 

 

B-

O-

 

 

 

B-

 

 

 

O+

O-

O+

 

 

 

 

 

 

O-

O-

 

 

 

 

 

 

 

A RhD negative patient (who has not been sensitized to RhD positive RBCs and who does not have any anti-D antibodies) can receive RhD positive blood cells, but this would cause sensitization to the RhD antigen, and a female patient would become at risk for HDN. Therefore, RhD positive blood is never given to RhD negative women of childbearing age, and is only given to other RhD negative patients in extreme circumstances, such as for a major bleed when stocks of RhD negative blood units are very low at the blood bank. If a RhD negative patient has developed anti-D antibodies, a subsequent exposure to RhD positive blood would lead to a potentially dangerous transfusion reaction. Occasionally, for transfusion of females above child-bearing age or of males, RhD positive blood is given to RhD negative individuals (who do not have atypical red cell antibodies) when it is necessary to conserve RhD negative blood stock in the blood bank in case RhD negative blood is needed for people where sensitisation to RhD antigens could cause serious medical problems.

The converse is not true; RhD positive patients do not react to RhD negative blood.

Plasma compatibility

Plasma compatibility chartPlasma from type AB can be given to A, B & O; plasma from types A & B can be given to O.

Plasma compatibility chart
Plasma from type AB can be given to A, B & O; plasma from types A & B can be given to O.

Donor-recipient compatibility for blood plasma is the reverse of that of RBCs. Plasma extracted from type AB blood can be transfused to individuals of any blood group, but type O plasma can be used only by type O recipients.

Rhesus D antibodies are uncommon, so generally neither RhD negative nor RhD positive blood contain anti-RhD antibodies. If a potential donor is found to have anti-RhD antibodies or any strong atypical blood group antibody by antibody screening in the blood bank, they would not be accepted as a donor; therefore, all donor blood plasma issued by a blood bank can be expected to be free of RhD antibodies and free of other atypical antibodies. Donor plasma issued from a blood bank would be suitable for a recipient who may be RhD positive or RhD 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 blood type O negative blood are often called universal donors, and those with type AB positive blood are called universal recipients. Although, blood donors with particularly strong anti-A, anti-B or any atypical blood group antibody are excluded from blood donation, the terms universal donor and universal recipient are an over-simplification, because they only consider possible reactions of the recipient's anti-A and anti-B antibodies to transfused red blood cells, and also possible sensitisation to RhD antigens. The possible reactions of anti-A and anti-B antibodies present in the transfused blood to the recipients RBCs are not considered, because a relitively small volume of plasma containing antibodies is transfused.

By way of example; considering the transfusion of O RhD negative blood (universal donor blood) into a recipient of blood group A RhD positive, an immune reaction between the recipient's anti-B antibodies and the transfused RBCs is not anticipated, but 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 red blood cells, but a significant reaction is unlikely because of the dilution factors. Rhesus D sensitisization 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 can be given only to O recipients, while AB plasma (which does not contain anti-A or anti-B antibodies) can be given to patients of any ABO blood group.

Importance of Type O

Different ethnic and racial groups also have different frequency of the main blood types in their populations. For example, approximately 45 percent of Caucasians are Type O, but 51 percent of African Americans and 57 percent of Hispanics are Type O. Type O is routinely in short supply and in high demand by hospitals – both because it is the most common blood type and because Type O-negative blood, in particular, is the universal type needed for emergency transfusions. Minority and diverse populations, therefore, play a critical role in meeting the constant need for blood.

Rare Blood Types

Red blood cells carry markers called antigens on their surface that determine one’s blood type. There are more than 600 known antigens besides A and B. Certain blood types are unique to specific racial and ethnic groups. Therefore it is essential that the donor diversity match the patient diversity. For example, U-negative and Duffy-negative blood types are unique to the African American community. So Sickle cell patients with these blood types must rely on donors with matching blood types in the African American community.

When blood is phenotypically matched (i.e., close blood type match), patients are at a lower risk of developing complications from transfusion therapy. For this reason, it is extremely important to increase the number of available blood donors from all ethnic groups.

Some Rare Blood Types by Ethnic Group

Ethnic Group                                          Rare Blood Type

African-American                                   U-, Fy(a-b-)

Native American, Alaskan Native           RzRz

Pacific Island, Asian                               Jk (a-b-)

Hispanic                                                 Di(b-)

East European/Russian Jews                  Dr(a-)

Caucasian                                                Kp(b-), Vel-

Blood Components

In modern medical treatments, patients may receive a pint of whole blood or just specific components of the blood needed to treat their particular condition. Up to four components can be derived from donated blood. This approach to treatment, referred to as blood component therapy, allows several patients to benefit from one pint of donated whole blood. The main transfusable blood components include:

Whole Blood

Whole blood contains red cells, white cells, and platelets (~45% of volume) suspended in plasma (~55% of volume).

Red cells

Red cells, or erythrocytes, carry oxygen from the lungs to your body’s tissue and take carbon dioxide back to your lungs to be exhaled.

Red Blood Cells (RBCs) are perhaps the most recognizable component of whole blood. RBCs contain hemoglobin, a complex protein containing iron that carries oxygen through the body. The percentage of blood volume composed of red blood cells is called the “hematocrit.” There are about one billion red blood cells in two to three drops of blood, and for every 600 red blood cells, there are about 40 platelets and one white cell.

Manufactured in the bone marrow, RBCs are continuously produced and broken down. They live for about 120 days in the circulatory system.

Red blood cells are prepared from whole blood by removing plasma, or the liquid portion of the blood, and they are used to treat anemia while minimizing an increase in blood volume. Improvements in cell preservation solutions over decades have increased the shelf-life of red blood cells from 21 to 42 days.

RBCs may be treated and frozen for an extended storage, of 10 years or more. Patients who benefit most from transfusion of red blood cells include those with chronic anemia resulting from kidney failure or gastrointestinal bleeding, and those with acute blood loss resulting from trauma.

Prestorage leukocyte-reduced red blood cells require special preparation by removing leukocytes (white blood cells) by filtration shortly after donation. This is done before storage because high numbers of leukocytes remaining in a unit of RBCs during the storage process can fragment, deteriorate, and release cytokines (chemicals that affect the inflammatory response). Leukocytes have been implicated as a cause of reactions to a current and subsequent blood transfusions in some transfusion recipients.

Platelets

Platelets, or thrombocytes, are small, colorless cell fragments in the blood whose main function is to interact with clotting proteins to stop or prevent bleeding.

Platelets are small blood components that help the clotting process by sticking to the lining of blood vessels. Platelets are made in the bone marrow and survive in the circulatory system

Platelets are prepared by using a centrifuge to separate the platelet-rich plasma from the donated unit of whole blood.

Platelets may also be obtained from a donor by a process known as apheresis, or plateletpheresis. In this process, blood is drawn from the donor into an apheresis instrument which separates the blood into its components, retains some of the platelets, and returns the remainder of the blood to the donor.

This single donor platelet product contains about six times as many platelets as a unit of platelets obtained from whole blood. Platelets are used to treat a condition called thrombocytopenia, in which there is a shortage of platelets, and they are also used to treat platelet function abnormalities. Platelets are stored at room temperature with constant agitation for 5 days.

Plasma

Plasma is a fluid, composed of about 92% water, 7% vital proteins such as albumin, gamma globulin, anti-hemophilic factor, and other clotting factors, and 1% mineral salts, sugars, fats, hormones and vitamins.

Plasma is the liquid portion of blood – a protein-salt solution in which red and white blood cells and platelets are suspended. Plasma, which is 92 percent water, constitutes 55 percent of blood volume. Plasma contains albumin (the chief protein constituent), fibrinogen (responsible, in part, for the clotting of blood) and globulins (including antibodies). Plasma serves a variety of functions, from maintaining a satisfactory blood pressure and volume to

supplying critical proteins for blood clotting and immunity. It also serves as the medium for

exchange of vital minerals such as sodium and potassium and helps to maintain a proper pH (acid-base) balance in the body, which is critical to cell function. Plasma is obtained by separating the liquid portion of blood from the cells.

Plasma is frozen quickly after donation (up to 24 hours) to preserve clotting factors, stored up to one year, and thawed shortly before use. It is commonly transfused to trauma patients and patients with severe liver disease or multiple clotting factor deficiencies.

Plasma derivatives are concentrates of specific plasma proteins prepared from pools (many donor units) of plasma. Plasma derivatives are obtained through a process known as fractionation. The derivatives are treated with heat and/or solvent detergent to kill certain viruses like those that cause HIV, hepatitis B, and hepatitis C.

Plasma derivatives include:

·       Factor VIII Concentrate

·       Factor IX Concentrate

·       Anti-Inhibitor Coagulation Complex (AICC)

·       Albumin

·       Immune Globulins, including Rh Immune Globulin

·       Anti-Thrombin III Concentrate

·       Alpha 1-Proteinase Inhibitor Concentrate

Cryoprecipitated AHF

Cryoprecipitated Antihemophilic Factor (Cryo) is a portion of plasma rich in clotting factors, including Factor VIII and fibrinogen. It is prepared by freezing and then slowly thawing the frozen plasma.

Cryoprecipitated Antihemophilic Factor (Cryo) is a portion of plasma rich in clotting factors, including Factor VIII and fibrinogen. It is prepared by freezing and then slowly thawing the frozen plasma.

White Blood Cells & Granulocytes

White Blood Cells

White blood cells (leukocytes) are one of the body’s defenses against disease. Some white cells travel throughout the body and destroy bacteria, some produce antibodies against bacteria and viruses, and others help fight malignant diseases. One’s own “leukocytes” help maintain the body’s immune function, but when present in donated blood, they serve no purpose. In fact, leukocytes may carry viruses that cause immune suppression and release toxic substances in the recipient. Leukocytes can cause a reaction when transfused, and are often removed from the transfusable blood components, a process called leuko-reduction. The majority of white blood cells are produced in the bone marrow, where they outnumber red blood cells by 2 to 1. However, in the blood stream, there are about 600 red blood cells for every white blood cell. There are several different types of white blood cells.

Granulocytes

Granulocytes are one type of several types of white blood cells that are in fact used in more specialized transfusion therapy. Granulocytes and monocytes protect against infection by surrounding and destroying invading bacteria and viruses, and lymphocytes aid in the immune defense system. Granulocytes are prepared by an automated process called apheresis, and must be transfused within 24 hours after collection. They are used for infections that are unresponsive to antibiotic therapy.

Leukemia

Leukaemia
Classification & external resources

http://upload.wikimedia.org/wikipedia/en/thumb/0/0e/Acute_leukemia-ALL.jpg/190px-Acute_leukemia-ALL.jpg

A Wright's stained bone marrow aspirate smear of patient with precursor B-cell acute lymphoblastic leukemia.

ICD-10

C91.-C95.

ICD-9

208.9

ICD-O:

9800-9940

DiseasesDB

7431

Leukemia or leukaemia (see spelling differences) is a cancer of the blood or bone marrow and is characterized by an abnormal proliferation (production by multiplication) of blood cells, usually white blood cells (leukocytes). It is part of the broad group of diseases called hematological neoplasms.

Symptoms

Damage to the bone marrow, by way of displacing the normal bone marrow cells with higher numbers of immature white blood cells, results in a lack of blood platelets, which are important in the blood clotting process. This means people with leukemia may become bruised, bleed excessively, or develop pinprick bleeds (petechiae).

White blood cells, which are involved in fighting pathogens, may be suppressed or dysfunctional, putting the patient at the risk of developing infections.

Finally, the red blood cell deficiency leads to anemia, which may cause dyspnea. All symptoms may also be attributable to other diseases; for diagnosis, blood tests and a bone marrow examination are required.

Some other related symptoms

·                  Fever, chills, and other flu-like symptoms

·                  Weakness and fatigue

·                  Loss of appetite and/or weight

·                  Swollen or bleeding gums

·                  Neurological symptoms (headache)

·                  Enlarged liver and spleen

Four major types

Leukemia is a broad term covering a spectrum of diseases.

Aleukemia

Definition: condition in which the bone marrow has an abnormally high number of cancerous white blood cells, which are not entering the bloodstream. Aleukemia occurs in about 30% of all patients with leukemia, regardless of the specific type. When a patient is aleukemic, the leukemia is not behaving in the usual way, i.e., with an overwhelming number of early white blood cells in the blood. A person with aleukemia will have a normal or low white blood count and bone marrow disorder.

Acute vs. Chronic

Leukemia is clinically and pathologically split into its acute and chronic forms.

·                  Acute leukemia is characterized by the rapid growth of immature blood cells. This crowding makes the bone marrow unable to produce healthy blood cells. Acute forms of leukemia can occur in children and young adults. (In fact, it is a more common cause of death for children in the US than any other type of malignant disease.) Immediate treatment is required in acute leukemias due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. If left untreated, the patient will die within months or even weeks.

·                  Chronic leukemia is distinguished by the excessive build up of relatively mature, but still abnormal, blood cells. Typically taking months to years to progress, the cells are produced at a much higher rate than normal cells, resulting in many abnormal white blood cells in the blood. Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group. Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy.

Causes and risk factors

There is no single known cause for all of the different types of leukemia. The different leukemias likely have different causes, and very little is certain about what causes them. Researchers have strong suspicions about four possible causes:

·                  natural or artificial ionizing radiation

·                  certain kinds of chemicals

·                  some viruses

·                  genetic predispositions

Leukemia, like other cancers, result from somatic mutations in the DNA which activate oncogenes or deactivate tumor suppressor genes, and disrupt the regulation of cell death, differentiation or division. These mutations may occur spontaneously or as a result of exposure to radiation or carcinogenic substances and are likely to be influenced by genetic factors. Cohort and case-control studies have linked exposure to petrochemicals, such as benzene, and hair dyes to the development of some forms of leukemia.

Viruses have also been linked to some forms of leukemia. For example, certain cases of ALL are associated with viral infections by either the human immunodeficiency virus (HIV, responsible for AIDS) or human T-lymphotropic virus (HTLV-1 and -2, causing adult T-cell leukemia/lymphoma).

Fanconi anemia is also a risk factor for developing acute myelogenous leukemia.

Until the cause or causes of leukemia are found, there is no way to prevent the disease.

Treatment options for leukemia by type

Acute Myelogenous Leukemia (AML)

It is most common for adults, but more men than women are affected. Many different chemotherapeutic plans are available for the treatment of AML. Overall, the strategy is to control bone marrow and systemic (whole-body) disease while offering specific treatment for the central nervous system (CNS), if involved. In general, most oncologists rely on combinations of drugs for the initial, induction phase of chemotherapy. Such combination chemotherapy usually offers the benefits of early remission (lessening of the disease) and a lower risk of disease resistance. Consolidation or "maintenance" treatments may be given to prevent disease recurrence once remission has been achieved. Consolidation treatment often entails a repetition of induction chemotherapy or the intensification chemotherapy with added drugs. By contrast, maintenance treatment involves drug doses that are lower than those administered during the induction phase.

In addition, specific treatment plans may be used, depending on the type of leukemia that has been diagnosed. Whatever the plan, it is important for the patient to understand the treatment that is being given and the decision-making process behind the choice.

Initial treatment of AML

Initial treatment of AML usually begins with induction chemotherapy using a combination of drugs such as daunorubicin (DNR), cytarabine (ara-C), idarubicin, thioguanine, etoposide, or mitoxantrone.

Follow-up treatment

Follow-up therapy for such patients may involve:

·                  supportive care, such as intravenous nutrition and treatment with oral antibiotics (e.g., ofloxacin, rifampin), especially in patients who have prolonged granulocytopenia; that is too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)

·                  injection with colony-stimulating factors such as granulocyte colony-stimulating factor (G-CSF), which may help to shorten the period of granulocytopenia that results from induction therapy

·                  transfusions with red blood cells and platelets

Patients with newly diagnosed disease also may be considered for stem cell transplantation (SCT), either from the bone marrow or other sources. Allogeneic bone marrow transplant (alloBMT) is reserved primarily for patients under 55 years of age who have a compatible family donor. Approximately half of newly diagnosed AML patients are in this age group, with 75% achieving a complete remission (CR) after induction and consolidation therapy. Allogeneic bone marrow transplant is available for about 15% of all patients with AML. Unfortunately, it is estimated that only 7% of all AML patients will be cured using this procedure.

People who receive stem cell transplantation (SCT, alloBMT) require protective isolation in the hospital, including filtered air, sterile food, and sterilization of the microorganisms in the gut, until their total white blood cell (WBC) count is above 500.

Treatment of central nervous system leukemia, if present, may involve injection of chemotherapeutic drugs (e.g., cytarabine or ara-C, methotrexate) into the areas around the brain and spinal cord.

Consolidation or maintenance therapy

Once the patient is in remission, he or she will receive consolidation or maintenance therapy, for example, consolidation therapy with high-dose ara-C (HDAC) with/without anthracycline drugs).

If, however, the AML patient has resistant disease (about 15%) or relapses (about 70%), second remissions sometimes are achieved by treating them with:

·                 conventional induction chemotherapy

·                 high-dose ara-C (HDAC), with/without other drugs

·                 etoposide or other single chemotherapeutic agents

Elderly AML patients have special treatment concerns. They may be less able to tolerate the septicemia (blood poisoning) associated with granulocytopenia, and they often have higher rates of myelodysplastic ('preleukemia') syndrome (MDS). Individuals who are over age 75 or who have significant medical conditions can be treated effectively with low-dose ara-C. High-dose post-induction chemotherapy is unlikely to be tolerated by elderly patients.

Until recently, the treatment plans and responses of children with AML did not differ much from those of adults. Yet new, more intensive induction and consolidation treatments have resulted in higher remission rates and prolonged survivals. Many induction trials have produced good results using combinations of cytarabine (ara-C) plus an anthracycline (e.g., daunorubicin, doxorubicin). In children under 3 years of age, the anthracycline used for induction should be chosen with care, since doxorubicin produces more toxicity and related deaths than daunorubicin.

Consolidation therapy is complex, but it should include at least two courses of high-dose ara-C (HDAC). Children who have hyperleukocytosis (too many white blood cells), especially monocytic M5 leukemia, have a poor prognosis.

Leukemia (American English) or leukaemia (British English) (from the Ancient Greek λευκός leukos "white", and αμα haima "blood") is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts." Leukemia is a broad term covering a spectrum of diseases. In turn, it is part of the even broader group of diseases affecting the blood, bone marrow, and lymphoid system, which are all known as hematological neoplasms.

In 2000, approximately 256,000 children and adults around the world developed some form of leukemia, and 209,000 died from it. About 90% of all leukemias are diagnosed in adults.

Classification

Four major kinds of leukemia

1.     Cell type: Lymphocytic leukemia(or "lymphoblastic"), Myelogenous leukemia (also "myeloid" or "nonlymphocytic")

2.     Acute:          Acute lymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML)    Acute lymphoblastic leukemia (ALL)  (or myeloblastic)

3.     Chronic: Chronic lymphocytic leukemia (CLL), Chronic myelogenous leukemia (CML)

Clinically and pathologically, leukemia is subdivided into a variety of large groups. The first division is between its acute and chronic forms:

Acute leukemia is characterized by a rapid increase in the number of immature blood cells. Crowding due to such cells makes the bone marrow unable to produce healthy blood cells. Immediate treatment is required in acute leukemia due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. Acute forms of leukemia are the most common forms of leukemia in children

Chronic leukemia is characterized by the excessive build up of relatively mature, but still abnormal, white blood cells. Typically taking months or years to progress, the cells are produced at a much higher rate than normal, resulting in many abnormal white blood cells. Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy. Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group.

Additionally, the diseases are subdivided according to which kind of blood cell is affected. This split divides leukemias into lymphoblastic or lymphocytic leukemias and myeloid or myelogenous leukemias:

In lymphoblastic or lymphocytic leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form lymphocytes, which are infection-fighting immune system cells. Most lymphocytic leukemias involve a specific subtype of lymphocyte, the B cell.

In myeloid or myelogenous leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form red blood cells, some other types of white cells, and platelets.

Combining these two classifications provides a total of four main categories. Within each of these four main categories, there are typically several subcategories. Finally, some rarer types are usually considered to be outside of this classification scheme.

Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in young children. This disease also affects adults, especially those age 65 and older. Standard treatments involve chemotherapy and radiotherapy. The survival rates vary by age: 85% in children and 50% in adults. Subtypes include precursor B acute lymphoblastic leukemia, precursor T acute lymphoblastic leukemia, Burkitt's leukemia, and acute biphenotypic leukemia.

Chronic lymphocytic leukemia (CLL) most often affects adults over the age of 55. It sometimes occurs in younger adults, but it almost never affects children. Two-thirds of affected people are men. The five-year survival rate is 75%. It is incurable, but there are many effective treatments. One subtype is B-cell prolymphocytic leukemia, a more aggressive disease.

Acute myelogenous leukemia (AML) occurs more commonly in adults than in children, and more commonly in men than women. AML is treated with chemotherapy. The five-year survival rate is 40%. Subtypes of AML include acute promyelocytic leukemia, acute myeloblastic leukemia, and acute megakaryoblastic leukemia.

Chronic myelogenous leukemia (CML) occurs mainly in adults; a very small number of children also develop this disease. Treatment is with imatinib (Gleevec in US, Glivec in Europe)  or other drugs. The five-year survival rate is 90%. One subtype is chronic monocytic leukemia.

Hairy cell leukemia (HCL) is sometimes considered a subset of chronic lymphocytic leukemia, but does not fit neatly into this pattern. About 80% of affected people are adult men. No cases in children have been reported. HCL is incurable, but easily treatable. Survival is 96% to 100% at ten years.

T-cell prolymphocytic leukemia (T-PLL) is a very rare and aggressive leukemia affecting adults; somewhat more men than women are diagnosed with this disease. Despite its overall rarity, it is also the most common type of mature T cell leukemia; nearly all other leukemias involve B cells. It is difficult to treat, and the median survival is measured in months.

Large granular lymphocytic leukemia may involve either T-cells or NK cells; like hairy cell leukemia, which involves solely B cells, it is a rare and indolent (not aggressive) leukemia. Adult T-cell leukemia is caused by human T-lymphotropic virus (HTLV), a virus similar to HIV. Like HIV, HTLV infects CD4+ T-cells and replicates within them; however, unlike HIV, it does not destroy them. Instead, HTLV "immortalizes" the infected T-cells, giving them the ability to proliferate abnormally. Human T cell lymphotropic virus types I and II (HTLV-I/II) are endemic in certain areas of the world.

Signs and symptoms

Common symptoms of chronic or acute leukemia

Damage to the bone marrow, by way of displacing the normal bone marrow cells with higher numbers of immature white blood cells, results in a lack of blood platelets, which are important in the blood clotting process. This means people with leukemia may easily become bruised, bleed excessively, or develop pinprick bleeds (petechiae).

White blood cells, which are involved in fighting pathogens, may be suppressed or dysfunctional. This could cause the patient's immune system to be unable to fight off a simple infection or to start attacking other body cells. Because leukemia prevents the immune system from working normally, some patients experience frequent infection, ranging from infected tonsils, sores in the mouth, or diarrhea to life-threatening pneumonia or opportunistic infections.

Finally, the red blood cell deficiency leads to anemia, which may cause dyspnea and pallor.

Some patients experience other symptoms, such as feeling sick, having fevers, chills, night sweats, feeling fatigued and other flu-like symptoms. Some patients experience nausea or a feeling of fullness due to an enlarged liver and spleen; this can result in unintentional weight loss. Blasts affected by the disease may come together and become swollen in the liver or in the lymph nodes causing pain and leading to nausea.

If the leukemic cells invade the central nervous system, then neurological symptoms (notably headaches) can occur. All symptoms associated with leukemia can be attributed to other diseases. Consequently, leukemia is always diagnosed through medical tests.

The word leukemia, which means 'white blood', is derived from the disease's namesake high white blood cell counts that most leukemia patients have before treatment. The high number of white blood cells are apparent when a blood sample is viewed under a microscope. Frequently, these extra white blood cells are immature or dysfunctional. The excessive number of cells can also interfere with the level of other cells, causing a harmful imbalance in the blood count.

Some leukemia patients do not have high white blood cell counts visible during a regular blood count. This less-common condition is called aleukemia. The bone marrow still contains cancerous white blood cells which disrupt the normal production of blood cells, but they remain in the marrow instead of entering the bloodstream, where they would be visible in a blood test. For an aleukemic patient, the white blood cell counts in the bloodstream can be normal or low. Aleukemia can occur in any of the four major types of leukemia, and is particularly common in hairy cell leukemia.

Causes

No single known cause for any of the different types of leukemia exists. The known causes, which are not generally factors within the control of the average person, account for relatively few cases. The different leukemias likely have different causes.

Leukemia, like other cancers, results from mutations in the DNA. Certain mutations can trigger leukemia by activating oncogenes or deactivating tumor suppressor genes, and thereby disrupting the regulation of cell death, differentiation or division. These mutations may occur spontaneously or as a result of exposure to radiation or carcinogenic substances.

Among adults, the known causes are natural and artificial ionizing radiation, a few viruses such as human T-lymphotropic virus, and some chemicals, notably benzene and alkylating chemotherapy agents for previous malignancies. Use of tobacco is associated with a small increase in the risk of developing acute myeloid leukemia in adults. Cohort and case-control studies have linked exposure to some petrochemicals and hair dyes to the development of some forms of leukemia. A few cases of maternal-fetal transmission have been reported. Diet has very limited or no effect, although eating more vegetables may confer a small protective benefit.

Viruses have also been linked to some forms of leukemia. Experiments on mice and other mammals have demonstrated the relevance of retroviruses in leukemia, and human retroviruses have also been identified. The first human retrovirus identified was human T-lymphotropic virus, or HTLV-1, which is known to cause adult T-cell leukemia.

Some people have a genetic predisposition towards developing leukemia. This predisposition is demonstrated by family histories and twin studies. The affected people may have a single gene or multiple genes in common. In some cases, families tend to develop the same kinds of leukemia as other members; in other families, affected people may develop different forms of leukemia or related blood cancers.

In addition to these genetic issues, people with chromosomal abnormalities or certain other genetic conditions have a greater risk of leukemia. For example, people with Down syndrome have a significantly increased risk of developing forms of acute leukemia (especially acute myeloid leukemia), and Fanconi anemia is a risk factor for developing acute myeloid leukemia.

Whether non-ionizing radiation causes leukemia has been studied for several decades. The International Agency for Research on Cancer expert working group undertook a detailed review of all data on static and extremely low frequency electromagnetic energy, which occurs naturally and in association with the generation, transmission, and use of electrical power. They concluded that there is limited evidence that high levels of ELF magnetic (but not electric) fields might cause childhood leukemia. Exposure to significant ELF magnetic fields might result in twofold excess risk for leukemia for children exposed to these high levels of magnetic fields. However, the report also says that methodological weaknesses and biases in these studies have likely caused the risk to be overstated. No evidence for a relationship to leukemia or another form of malignancy in adults has been demonstrated. Since exposure to such levels of ELFs is relatively uncommon, the World Health Organization concludes that ELF exposure, if later proven to be causative, would account for just 100 to 2400 cases worldwide each year, representing 0.2 to 4.9% of the total incidence of childhood leukemia for that year (about 0.03 to 0.9% of all leukemias).

According to a study conducted at the Center for Research in Epidemiology and Population Health in France, children born to mothers who use fertility drugs to induce ovulation are more than twice as likely to develop leukemia during their childhoods than other children.

Race is known to play a role, with some racial groups being more at risk than others. Hispanics, especially those under the age of 20, are at the highest risk for leukemia, while whites, Native Americans, Asians, and Alaska Natives are at higher risk than blacks.

In the case of gender, more men than women are diagnosed with leukemia and die from the disease. Around 31 percent more men than women live with leukemia.

Diagnosis

Diagnosis is usually based on repeated complete blood counts and a bone marrow examination following observations of the symptoms, however, in rare cases blood tests may not show if a patient has leukemia, usually this is because the leukemia is in the early stages or has entered remission. A lymph node biopsy can be performed as well in order to diagnose certain types of leukemia in certain situations.

Following diagnosis, blood chemistry tests can be used to determine the degree of liver and kidney damage or the effects of chemotherapy on the patient. When concerns arise about visible damage due to leukemia, doctors may use an X-ray, MRI, or ultrasound. These can potentially view leukemia's effects on such body parts as bones (X-ray), the brain (MRI), or the kidneys, spleen, and liver (ultrasound). Finally, CT scans are rarely used to check lymph nodes in the chest.

Despite the use of these methods to diagnose whether or not a patient has leukemia, many people have not been diagnosed because many of the symptoms are vague, unspecific, and can refer to other diseases. For this reason, the American Cancer Society predicts that at least one-fifth of the people with leukemia have not yet been diagnosed.

Mutation in SPRED1 gene has been associated with a predisposition to childhood leukemia. SPRED1 gene mutations can be diagnosed with genetic sequencing.

Treatment

Most forms of leukemia are treated with pharmaceutical medication, typically combined into a multi-drug chemotherapy regimen. Some are also treated with radiation therapy. In some cases, a bone marrow transplant is useful.

Acute lymphoblastic

Management of ALL focuses on control of bone marrow and systemic (whole-body) disease. Additionally, treatment must prevent leukemic cells from spreading to other sites, particularly the central nervous system (CNS) e.g. monthly lumbar punctures. In general, ALL treatment is divided into several phases:

Induction chemotherapy to bring about bone marrow remission. For adults, standard induction plans include prednisone, vincristine, and an anthracycline drug; other drug plans may include L-asparaginase or cyclophosphamide. For children with low-risk ALL, standard therapy usually consists of three drugs (prednisone, L-asparaginase, and vincristine) for the first month of treatment.

Consolidation therapy or intensification therapy to eliminate any remaining leukemia cells. There are many different approaches to consolidation, but it is typically a high-dose, multi-drug treatment that is undertaken for a few months. Patients with low- to average-risk ALL receive therapy with antimetabolite drugs such as methotrexate and 6-mercaptopurine (6-MP). High-risk patients receive higher drug doses of these drugs, plus additional drugs.

CNS prophylaxis (preventive therapy) to stop the cancer from spreading to the brain and nervous system in high-risk patients. Standard prophylaxis may include radiation of the head and/or drugs delivered directly into the spine.

Maintenance treatments with chemotherapeutic drugs to prevent disease recurrence once remission has been achieved. Maintenance therapy usually involves lower drug doses, and may continue for up to three years.

Alternatively, allogeneic bone marrow transplantation may be appropriate for high-risk or relapsed patients.

New therapeutic strategies for the treatment of acute lymphoblastic .

The hallmark of bone-marrow B-cell development is the ordered rearrangement of gene segments that encode the variable portion of the antibody molecule. DJH rearrangements initially occur in lymphoid progenitor cells that express CD34, CD10 and weak CD19. Pseudo-light chains (LC) CD179a and CD179b first appear in the cytoplasm of early pre-B (pro-B) cells that harbour VDJH rearrangement. The pre-B stage is heralded by the functional VDJH rearrangement (bold type), the appearance of cytoplasmic  immunoglobulin (Ig) heavy chains, and the movement of CD22 from the cytoplasm to the cell surface. The transitional pre-B cell undergoes V to JK light-chain rearrangement, and displays surface pre-B-cell receptors that are comprised of Ig complexed to LC and are non-convalently bound to CD79a and CD79b (/LC/CD79). The mature naive B-cell with functional light-chain rearrangement (bold type) is initiated with the movement of IgM to the cell surface, fully expresses / or / B-cell receptor (a complex of IgM–CD79a–CD79b), and loses terminal deoxynucleotidyl transferase (TDT). The bone-marrow-derived T-cell precursor expresses CD34, CD7 and possibly CD2, and has T-cell receptor , ,  and  genes (TCRD, TCRG, TCRA and TCRB) in germline configuration. The earliest cells committed to T-cell development, pre-T cells, are found in the outer cortical areas of thymus and express CD34, CD7, CD1a, CD2, cytoplasmic CD3 and TDT, but not CD4 or CD8 (they are double negative because of the absence of CD4 and CD8 expression). As these cell mature, they lose CD34 expression, begin to express CD4 and then CD8, and thereby become double-positive T cells that are characterized by CD7, CD2, CD5, CD4 and CD8 expression and low levels of CD3. Productive rearrangement of TCRA results in the production of TCR molecules, which combine with TCR proteins to form TCR, which in turn combine with CD3 and move to the surface of double-positive T cells. Cells with a functional receptor (TCR+, double-positive late cortical thymocytes) move into the cortico–medullary junction, and undergo positive or negative selection. Only about 2% of all double-positive cells survive and proceed through a final step of differentiation into either CD4- or CD8-positive T cells. Distinct gene-expression signatures are associated with leukaemic cell samples with recognized stages of thymocyte differentiation: LYL1+ corresponds to pre-T, HOX11+ corresponds to early cortical, and TAL1+ corresponds to late cortical

Chronic lymphocytic

Decision to treat

Pathogenesis to treatment of chronic lymphocytic leukaemia

The B cell receptor (BCR) is composed of two immunoglobulin (Ig) heavy and light chains (variable and constant regions), and CD79a and CD79b, which contain an intracellular activation motif that transmits signals to intracellular tyrosine kinases (for example, SYK and LYN). The ability of these kinases to activate downstream pathways varies in chronic lymphocytic leukaemia (CLL) subgroups and is correlated with Ig heavy chain variable region (IGHV) mutational status, zeta-associated protein 70 (ZAP70) and CD38 expression4, 40, 41. These pathways could be targeted by small molecule inhibitors, the most promising of which might be SYK inhibitors. b | Multiple epitopes on the CLL cell are targets for antibody (ab)-based therapies. c | The most common genetic lesions in CLL include deletion of 13q14 and the downregulation of death-associated protein kinase 1 (DAPK1, a stress-activated tumour suppressor protein18, 99) by DNA methylation18. miR-15a and miR-16-1 (encoded by genes located on 13q14) have been shown to target BCL2, and may increase its expression in CLL143. This pathway can be targeted at multiple levels, including through using small molecule BH3 mimetics136. d | Stromal and T cell interactions also contribute to CLL pathogenesis. Although not fully understood, some drugs (immune-modulating drugs; Imids) in use in CLL have been shown to target the interaction with T cells109. The crosstalk between CLL cells and accessory cells and soluble factors upregulates anti-apoptotic proteins, such as survivin, MCL1 and BCL2 (Refs 103, 105, 106, 144). Ag, antigen; BLNK, B cell linker protein; BTK, Bruton tyrosine kinase; CDK, cyclin-dependent kinase; CXCR4, chemokine receptor 4; HDAC, histone deacetylase; IL-4, interleukin 4; Me, methyl group; NF-κB, nuclear factor-κB; NFAT, nuclear factor of activated T cells; PLC-γ, phospholipase C-γ; SDF1, stromal cell-derived factor 1;VEGFA, vascular endothelial growth factor A.

Hematologists base CLL treatment on both the stage and symptoms of the individual patient. A large group of CLL patients have low-grade disease, which does not benefit from treatment. Individuals with CLL-related complications or more advanced disease often benefit from treatment. In general, the indications for treatment are:

Falling hemoglobin or platelet count

Progression to a later stage of disease

Painful, disease-related overgrowth of lymph nodes or spleen

An increase in the rate of lymphocyte production

Objective: Studies concerning the genetic relatedness between chronic lymphocytic leukemia and the more aggressive B-cell cancers that develop in about 10% of affected persons were reviewed. These B-cell cancers include large B-cell lymphoma (the Richter syndrome), prolymphocytic transformation, acute lymphoblastic leukemia, and multiple myeloma. Two possible relations were evaluated: development from the chronic lymphocytic leukemia clone (clonal evolution) and development of a genetically unrelated, independent second cancer.

Data Analysis: Analysis of genetic relatedness between the two cancers considered concordance for immunoglobulin gene rearrangements, for immunoglobulin isotypes and idiotypes, and for cytogenetic abnormalities.

Conclusions: In the case of large B-cell lymphoma, generally thought to arise from the chronic lymphocytic leukemia clone, approximately one half of the patients had genetically unrelated cancers. In prolymphocytic transformation, all cases studied appeared to evolve from the chronic lymphocytic leukemia clone. The few studies of acute lymphoblastic leukemia and multiple myeloma showed genetic relatedness in some cases and unrelatedness in others. These data indicate that progression to more aggressive B-cell cancers in persons with chronic lymphocytic leukemia can result from either clonal evolution or from an independent transforming event.

Transformation of one B cell to produce chronic lymphocytic leukemia is shown. Clonality is confirmed by analysis of immunoglobulin genes (Southern blotting), antibodies (anti-isotypic and anti-idiotypic), or chromosome analysis. The karyotype in the Figure shows a trisomy 12, and the Southern blot shows the same germline in the normal ( ) and the patient's ( ) peripheral blood cells (bar). A single immunoglobulin gene rearrangement is identified in the patient's cells () but not in the normal cells. Anti-idiotype antibodies are depicted as red with a green fluorescein tag and show specific reactivity with the immunoglobulin on the chronic lymphocytic leukemia cells. Determining genetic relatedness of the chronic lymphocytic leukemia clone to large B-cell lymphoma, prolymphocytic transformation, acute lymphoblastic leukemia, or multiple myeloma requires reactivity with the same anti-idiotype antibody, showing identical immunoglobulin gene rearrangements or identical karyotype.

Determining genetic relatedness of the chronic lymphocytic leukemia

Typical treatment approach

CLL is probably incurable by present treatments. The primary chemotherapeutic plan is combination chemotherapy with chlorambucil or cyclophosphamide, plus a corticosteroid such as prednisone or prednisolone. The use of a corticosteroid has the additional benefit of suppressing some related autoimmune diseases, such as immunohemolytic anemia or immune-mediated thrombocytopenia. In resistant cases, single-agent treatments with nucleoside drugs such as fludarabine,pentostatin, or cladribine may be successful. Younger patients may consider allogeneic or autologous bone marrow transplantation.

Acute myelogenous

Many different anti-cancer drugs are effective for the treatment of AML. Treatments vary somewhat according to the age of the patient and according to the specific subtype of AML. Overall, the strategy is to control bone marrow and systemic (whole-body) disease, while offering specific treatment for the central nervous system (CNS), if involved.

In general, most oncologists rely on combinations of drugs for the initial, induction phase of chemotherapy. Such combination chemotherapy usually offers the benefits of early remission and a lower risk of disease resistance. Consolidation and maintenance treatments are intended to prevent disease recurrence. Consolidation treatment often entails a repetition of induction chemotherapy or the intensification chemotherapy with additional drugs. By contrast, maintenance treatment involves drug doses that are lower than those administered during the induction phase.

Chronic myelogenous

There are many possible treatments for CML, but the standard of care for newly diagnosed patients is imatinib (Gleevec) therapy. Compared to most anti-cancer drugs, it has relatively few side effects and can be taken orally at home. With this drug, more than 90% of patients will be able to keep the disease in check for at least five years, so that CML becomes a chronic, manageable condition.

In a more advanced, uncontrolled state, when the patient cannot tolerate imatinib, or if the patient wishes to attempt a permanent cure, then an allogeneic bone marrow transplantation may be performed. This procedure involves high-dose chemotherapy and radiation followed by infusion of bone marrow from a compatible donor. Approximately 30% of patients die from this procedure.

Hairy cell

Decision to treat

 Patients with hairy cell leukemia who are symptom-free typically do not receive immediate treatment. Treatment is generally considered necessary when the patient shows signs and symptoms such as low blood cell counts (e.g., infection-fighting neutrophil count below 1.0 K/µL), frequent infections, unexplained bruises, anemia, or fatigue that is significant enough to disrupt the patient's everyday life.

Typical treatment approach

 Patients who need treatment usually receive either one week of cladribine, given daily by intravenous infusion or a simple injection under the skin, or six months of pentostatin, given every four weeks by intravenous infusion. In most cases, one round of treatment will produce a prolonged remission.

Other treatments include rituximab infusion or self-injection with Interferon-alpha. In limited cases, the patient may benefit from splenectomy (removal of the spleen). These treatments are not typically given as the first treatment because their success rates are lower than cladribine or pentostatin.

T-cell prolymphocytic

Most patients with T-cell prolymphocytic leukemia, a rare and aggressive leukemia with a median survival of less than one year, require immediate treatment.

T-cell prolymphocytic leukemia is difficult to treat, and it does not respond to most available chemotherapeutic drugs. Many different treatments have been attempted, with limited success in certain patients: purine analogues (pentostatin, fludarabine, cladribine), chlorambucil, and various forms of combination chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone CHOP, cyclophosphamide, vincristine, prednisone [COP], vincristine, doxorubicin, prednisone, etoposide, cyclophosphamide, bleomycin VAPEC-B). Alemtuzumab (Campath), a monoclonal antibody that attacks white blood cells, has been used in treatment with greater success than previous options.

Some patients who successfully respond to treatment also undergo stem cell transplantation to consolidate the response.

Juvenile myelomonocytic

Treatment for juvenile myelomonocytic leukemia can include splenectomy, chemotherapy, and bone marrow transplantation.

Epidemiology

 

In 2000, approximately 256,000 children and adults around the world developed a form of leukemia, and 209,000 died from it. This represents about 3% of the almost seven million deaths due to cancer that year, and about 0.35% of all deaths from any cause. Of the sixteen separate sites the body compared, leukemia was the 12th most common class of neoplastic disease, and the 11th most common cause of cancer-related death.

About 245,000 people in the United States are affected with some form of leukemia, including those that have achieved remission or cure. Approximately 44,270 new cases of leukemia were diagnosed in the year of 2008 in the US.[40] This represents 2.9% of all cancers (excluding simple basal cell and squamous cell skin cancers) in the United States, and 30.4% of all blood cancers.

Among children with some form of cancer, about a third have a type of leukemia, most commonly acute lymphoblastic leukemia. A type of leukemia is the second most common form of cancer in infants (under the age of 12 months) and the most common form of cancer in older children. Boys are somewhat more likely to develop leukemia than girls, and white American children are almost twice as likely to develop leukemia than black American children. Only about 3% cancer diagnoses among adults are for leukemias, but because cancer is much more common among adults, more than 90% of all leukemias are diagnosed in adults.

History

 

Leukemia was first observed by pathologist Rudolf Virchow in 1845. Observing an abnormally large number of white blood cells in a blood sample from a patient, Virchow called the condition Leukämie in German, which he formed from the two Greek words leukos (λευκός), meaning "white", and aima (αίμα), meaning "blood". Around ten years after Virchow's findings, pathologist Franz Ernst Christian Neumann found that one deceased leukemia patient's bone marrow was colored "dirty green-yellow" as opposed to the normal red. This finding allowed Neumann to conclude that a bone marrow problem was responsible for the abnormal blood of leukemia patients.

By 1900 leukemia was viewed as a family of diseases as opposed to a single disease. By 1947 Boston pathologist Sydney Farber believed from past experiments that aminopterin, a folic acid mimic, could potentially cure leukemia in children. The majority of the children with ALL who were tested showed signs of improvement in their bone marrow, but none of them were actually cured. This, however, led to further experiments.

In 1962, researchers Emil J. Freireich Jr. and Emil Frei III used combination chemotherapy to attempt to cure leukemia. The tests were successful with some patients surviving long after the tests.

Research directions

Significant research into the causes, prevalence, diagnosis, treatment, and prognosis of leukemia is being performed. Hundreds of clinical trials are being planned or conducted at any given time. Studies may focus on effective means of treatment, better ways of treating the disease, improving the quality of life for patients, or appropriate care in remission or after cures.

In general, there are two types of leukemia research: clinical or translational research and basic research. Clinical/translational research focuses on studying the disease in a defined and generally immediately patient-applicable way, such as testing a new drug in patients. By contrast, basic science research studies the disease process at a distance, such as seeing whether a suspected carcinogen can cause leukemic changes in isolated cells in the laboratory or how the DNA changes inside leukemia cells as the disease progresses. The results from basic research studies are generally less immediately useful to patients with the disease.

Treatment through gene therapy is currently being pursued. One such approach turns T cells into cancer-targeting attackers. As of August 2011, a year after treatment, two of the three patients are cancer-free.

Society and culture

Leukemias are often romanticized in 20th century fiction. It is presented as a pure, clean disease, whose innocent, beautiful, and spiritually sensitive victims tragically die young. As such, it is the cultural successor to tuberculosis, which held this cultural position until tuberculosis was discovered to be an infectious disease. The 1970 romance novel Love Story is an example of this romanticization of leukemia.

In pregnancy

Leukemia is rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women. How it is handled depends primarily on the type of leukemia. Nearly all leukemias appearing in pregnant women are acute leukemias. Acute leukemias normally require prompt, aggressive treatment, despite significant risks of pregnancy loss and birth defects, especially if chemotherapy is given during the developmentally sensitive first trimester. Chronic myelogenous leukemia can be treated with relative safety at any time during pregnancy with Interferon-alpha hormones. Treatment for chronic lymphocytic leukemias, which are rare in pregnant women, can often be postponed until after the end of the pregnancy.

The occurrence of leukemia during pregnancy is very rare with an estimated incidence of one per 100,000 pregnancies annually. It has been estimated that during pregnancy most leukemias are acute: two thirds are myeloid (AML) and one third are lymphatic (ALL). Chronic myeloid leukemia (CML) is found in less than 10% of leukemias during pregnancy  and chronic lymphocytic leukemia (CLL) is extremely rare.

The survival of pregnant and non-pregnant women with acute leukemia has improved with the availability of modern chemotherapy and supportive care. Remission rates of 70-75% and median survival time of 6 to12 months are currently reported for pregnant women. These figures are not different from those achieved in non-pregnant women with acute leukemia.

Acute leukemia can affect pregnancy and the fetus.

Intrauterine growth retardation has been reported in mothers not treated with chemotherapy.

 

In addition, preterm labor, induced and spontaneous abortion as well as still birth are common in acute leukemia.

 

Although there is an estimated teratogenic risk rate of 10% when chemotherapy is administered in the first trimester, no fetal malformations and no late side effects have been reported in children born to mothers who were treated for acute leukemia during early pregnancy .

Pregnancy in Chronic Myeloid Leukemia

Treatment

It is generally believed that pregnant women should be treated as non-pregnant women.

Therapeutic abortion should be considered in early gestation, but if the woman decides to continue the pregnancy certain drugs, like methotrexate, should be replaced. Standard anti-leukemic treatment can be safely administered during the second and third trimesters. Delivery should be accomplished when fetal survival can be ensured and the mother is in complete remission. There are rare reports of leukemia blasts infiltrating the placenta  and a single case of infantile acute monocytic leukemia caused by vertical transmission of the mother's leukemia cells.

 Five cases of relapse of ALL in pregnancy have been reported in the  medical literature. The mechanisms attributable to the immunologic and hormonal changes of pregnancy have been postulated. All five patients were treated between 2 weeks and 4.5 months with cytotoxic chemotherapy with the fetus still in utero. Four out of five patients delivered healthy and normal infants and an elective abortion was reported. Unfortunately, all mothers except one died of their disease in under 2 years.

Chronic myeloid leukemia during pregnancy should be treated as in the nongestational patients. Since the disease has an initial chronic phase, it is usually managed conservatively during pregnancy, while an aggressive approach, such as bone marrow transplantation, may be considered after delivery. A limited number of cases described successful treatment modalities of CML during pregnancy including leukapheresis,  hydroxyurea and interferon.

 

Pregnancy complicated by hairy cell leukemia is extremely rare. Splenectomy is a safe and effective treatment option during the second trimester for this rare condition  Single cases have been treated with interferon during pregnancy.

Prevention

Folate supplements taken by pregnant women may also protect babies from leukemia.

A new study, suggests that women who eat more vegetables, fruit and foods containing protein before pregnancy may have a lower risk of having a child who develops leukemia, the most common childhood cancer in the United States.

The study, published in the August 2004 issue of Cancer Causes and Control, is the first time researchers have conducted a systematic survey of a woman's diet and linked it to childhood leukemia risk.

 

Within the fruit and vegetable food groups, certain foods - including carrots, string beans and cantaloupe - stood out as having stronger links to lower childhood leukemia risk. The researchers point to the benefits of nutrients, such as carotenoids, in those foods as potential protective factors.

 

The researchers looked further and found that glutathione was the nutrient in the protein group with a strong link to lower cancer risk. Glutathione is an antioxidant found in both meat and legumes, and it plays a role in the synthesis and repair of DNA, as well as the detoxification of certain harmful compounds. National guidelines recommend that people eat at least five servings of fruits and vegetables every day, and two to three servings of foods from the protein group.

B-cell chronic lymphocytic leukemia

Peripheral blood smear showing CLL cells

B-cell chronic lymphocytic leukemia (B-CLL), also known as chronic lymphoid leukemia (CLL), is the most common type of leukemia. Leukemias are cancers of the white blood cells (leukocytes). CLL affects B cell lymphocytes. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by producing antibodies. In CLL, B cells grow out of control and accumulate in the bone marrow and blood, where they crowd out healthy blood cells. CLL is a stage of small lymphocytic lymphoma (SLL), a type of B-cell lymphoma, which presents primarily in the lymph nodes. CLL and SLL are considered the same underlying disease, just with different appearances.

CLL is a disease of adults, but, in rare cases, it can occur in teenagers and occasionally in children (inherited). Most (>75%) people newly diagnosed with CLL are over the age of 50, and the majority are men.

Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count, but, as it advances, CLL results in swollen lymph nodes, spleen, and liver, and eventually anemia and infections. Early CLL is not treated, and late CLL is treated with chemotherapy and monoclonal antibodies.

DNA analysis has distinguished two major types of CLL, with different survival times. CLL that is positive for the marker ZAP-70 has an average survival of 8 years. CLL that is negative for ZAP-70 has an average survival of more than 25 years. Many patients, especially older ones, with slowly progressing disease can be reassured and may not need any treatment in their lifetimes.

Symptoms and signs

Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count. Less commonly, CLL may present with enlarged lymph nodes without a high white blood cell count or no evidence of the disease in the blood. This is referred to as small lymphocytic lymphoma. In some individuals the disease comes to light only after the neoplastic cells overwhelm the bone marrow resulting in anemia producing tiredness or weakness.

Diagnosis

Micrograph of a lymph node affected by B-CLL showing a characteristic proliferation center (right of image), composed of larger, lighter staining, cells. H&E stain.

CLL is usually first suspected by the presence of a lymphocytosis, an increase in one type of white blood cell, on a complete blood count (CBC) test. This frequently is an incidental finding on a routine physician visit. Most often the lymphocyte count is greater than 4000 cells per microliter (µl) of blood, but can be much higher. The presence of a lymphocytosis in an elderly individual should raise strong suspicion for CLL, and a confirmatory diagnostic test, in particular flow cytometry, should be performed unless clinically unnecessary.

The diagnosis of CLL is based on the demonstration of an abnormal population of B lymphocytes in the blood, bone marrow, or tissues that display an unusual but characteristic pattern of molecules on the cell surface. This atypical molecular pattern includes the coexpression of cells surface markers cluster of differentiation 5 (CD5) and cluster of differentiation 23 (CD23). In addition, all the CLL cells within one individual are clonal, that is, genetically identical. In practice, this is inferred by the detection of only one of the mutually exclusive antibody light chains, kappa or lambda, on the entire population of the abnormal B cells. Normal B lymphocytes consist of a stew of different antibody-producing cells, resulting in a mixture of both kappa and lambda expressing cells. The lack of the normal distribution of kappa and lambda producing B cells is one basis for demonstrating clonality, the key element for establishing a diagnosis of any B cell malignancy (B cell non-Hodgkin lymphoma).

The combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by flow cytometry to confirm clonality and marker molecule expression is needed to establish the diagnosis of CLL. Both are easily accomplished on a small amount of blood. A flow cytometer is an instrument that can examine the expression of molecules on individual cells in fluids. This requires the use of specific antibodies to marker molecules with fluorescent tags recognized by the instrument. In CLL, the lymphocytes are genetically clonal, of the B cell lineage (expressing marker molecules cluster of differentiation 19 (CD19) and CD20), and characteristically express the marker molecules CD5 and CD23. These B cells resemble normal lymphocytes under the microscope, although slightly smaller, and are fragile when smeared onto a glass slide, giving rise to many broken cells, which are called smudge, or smear cells.

Childhood Leukemia

Childhood leukemia, the most common type of cancer in children and teens, is a cancer of the white blood cells. Abnormal white blood cells form in the bone marrow. They quickly travel through the bloodstream and crowd out healthy cells. This increases the body's chances of infection and other problems.

As tough as it is for a child to have cancer, it's good to know that most children and teens with childhood leukemia can be successfully treated.

Description of Evidence

Incidence and Mortality An estimated 12,200 new cervical cancers and 4,210 cervical cancer deaths will occur in the United States in 2010.An additional 1,250,000 women will be diagnosed with precancers annually by cytology using the Papanicolaou (Pap) smear. A continuum of pathologic changes may be diagnosed, ranging from atypical squamous cells of undetermined significance to low-grade squamous intraepithelial lesions (LSIL) to high-grade squamous intraepithelial lesions (HSIL) to invasive...

Risk Factors for Childhood Leukemia

Doctors don't know exactly what causes most cases of childhood leukemia. But certain factors may increase the chances of getting it. Keep in mind, though, that having a risk factor does not necessarily mean a child will get leukemia. In fact, most children with leukemia don't have any known risk factors.

The risk for childhood leukemia increases if your child has:

·                            An inherited disorder such as Li-Fraumeni syndrome, Down syndrome, or Klinefelter syndrome

·                            An inherited immune system problem such as ataxia telangiectasia

·                            A brother or sister with leukemia, especially an identical twin

·                            A history of being exposed to high levels of radiation, chemotherapy, or chemicals such as benzene (a solvent)

·                            A history of immune system suppression, such as for an organ transplant

Although the risk is small, doctors advise that children with known risk factors have regular checkups to spot any problems early.

Types of Childhood Leukemia

Almost all cases of childhood leukemia are acute, which means they develop rapidly. A tiny number are chronic and develop slowly.

Types of childhood leukemia include:

·                            Acute lymphoblastic leukemia (ALL), also called acute lymphocytic leukemia. ALL accounts for three out of every four cases of childhood leukemia.

·                            Acute myelogenous leukemia (AML). AML is the next most common type of childhood leukemia.

·                            Hybrid or mixed lineage leukemia. This is a rare leukemia with features of both ALL and AML.

·                            Chronic myelogenous leukemia (CML). CML is rare in children.

·                            Chronic lymphocytic leukemia (CLL). CLL is very rare in children.

·                            Juvenile myelomonocytic leukemia (JMML). This is a rare type that is neither chronic nor acute and occurs most often in children under age 4.

 

Symptoms of Childhood Leukemia

Symptoms of leukemia often prompt a visit to the doctor. This is a good thing because it means the disease may be found earlier than it otherwise would. Early diagnosis can lead to more successful treatment.

Many signs and symptoms of childhood leukemia occur when leukemia cells crowd out normal cells.

Common symptoms include:

·                            Fatigue or pale skin

·                            Infections and fever

·                            Easy bleeding or bruising

·                            Extreme fatigue or weakness

·                            Shortness of breath

·                            Coughing 

Other symptoms may include:

·                            Bone or joint pain

·                            Swelling in the abdomen, face, arms, underarms, sides of neck, or groin

·                            Swelling above the collarbone

·                            Loss of appetite or weight loss

·                            Headaches, seizures, balance problems, or abnormal vision

·                            Vomiting

·                            Rashes

·                            Gum problems

Diagnosing Childhood Leukemia

To diagnose childhood leukemia, the doctor will take a thorough medical history and perform a physical exam. Tests are used to diagnose childhood leukemia as well as classify its type.

Initial tests may include:

·                            Blood tests to measure the number of blood cells and see how they appear.

·                            Bone marrow aspiration and biopsy, usually taken from the pelvic bone, to confirm a diagnosis of leukemia.

·                            Lumbar puncture, or spinal tap, to check for spread of leukemia cells in the fluid that bathes the brain and spinal cord.

A pathologist examines cells from the blood tests under a microscope. This specialist also checks bone marrow samples for the number of blood-forming cells and fat cells.

Other tests may be done to help determine which type of leukemia your child may have. These tests also help the doctors know how likely the leukemia is to respond to treatment.

Certain tests may be repeated later to see how your child responds to treatment.

Treatments for Childhood Leukemia

Have a "heart-to-heart" talk with your child's doctor and other members of the cancer care team about the best options for your child. Treatment depends mainly upon the type of leukemia as well as other factors.

The good news is the survival rates for most types of childhood leukemia have increased over time. And treatment at special centers for children and teens provides the advantages of specialized care. In addition, childhood cancers tend to respond to treatment better than adult cancers do, and children's bodies often tolerate treatment better.

Before cancer treatment begins, sometimes a child needs treatment to address illness complications. For example, changes in blood cells can lead to infections or severe bleeding and may affect the amount of oxygen reaching the body's tissues. Treatment may involve antibiotics, blood transfusions, or other measures to fight infection.

Chemotherapy is the main treatment for childhood leukemia. Your child will receive anticancer drugs by mouth, or into a vein, a muscle, or the spinal fluid. To keep leukemia from returning, maintenance therapy occurs in cycles over a period of two or three years.

Targeted therapy is also sometimes used for leukemia. This therapy targets specific parts of cancer cells, working differently than standard chemotherapy. Effective for certain types of childhood leukemia, targeted therapy often has less severe side effects.

Other types of treatment may include radiation therapy, which uses high-energy radiation to kill cancer cells and shrink tumors. It may be used to help prevent or treat the spread of leukemia to other parts of the body. Surgery is rarely used to treat childhood leukemia.

If standard treatment is likely to be less effective, a stem cell transplant may be the best option. It involves a transplant of blood-forming stem cells after whole body radiation combined with high-dose chemotherapy to first destroy the child's bone marrow.

VIDEO

Blood Groups

Diseases of Blood

 

Literature:

1. Àäàì÷èê Ì.Â. Âåëèêèé àíãëî-óêðà¿íñüêèé ñëîâíèê. – Êè¿â, 2007.

2. Àíãë³éñüêà ìîâà çà ïðîôåñ³éíèì ñïðÿìóâàííÿì: Ìåäèöèíà: íàâ÷. ïîñ³á. äëÿ ñòóä. âèù. íàâ÷. çàêë. IV ð³âíÿ àêðåäèòàö³¿ / ². À. Ïðîêîï, Â. ß. Ðàõëåöüêà, Ã. ß. Ïàâëèøèí ; Òåðíîï. äåðæ. ìåä. óí-ò ³ì. ². ß. Ãîðáà÷åâñüêîãî. –  Òåðíîï³ëü: ÒÄÌÓ : Óêðìåäêíèãà, 2010. – 576 ñ.

3. Áàëëà Ì.²., Ïîäâåçüêî Ì.Ë. Àíãëî-óêðà¿íñüêèé ñëîâíèê. – Êè¿â: Îñâ³òà, 2006. – Ò. 1,2.

4. Hansen J. T. Netter’s Anatomy Coloring Book. – Saunders Elsevier, 2010. – 121 p.

5. Henderson B., Dorsey J. L. Medical Terminology for Dummies. – Willey Publishing, 2009. – P. 189-211.