Dengue and dengue haemorrhagic fever

KEY FACTS

 Dengue is a mosquito-borne infection that causes a severe flu-like illness, and sometimes a
potentially lethal complication called dengue haemorrhagic fever.
 Global incidence of dengue has grown dramatically in recent decades.
 About two fifths of the world's population are now at risk.
 Dengue is found in tropical and sub-tropical climates worldwide, mostly in urban and semi-urban
areas.
 Dengue haemorrhagic fever is a leading cause of serious illness and death among children in
some Asian countries.
 There is no specific treatment for dengue, but appropriate medical care frequently saves the lives
of patients with the more serious dengue haemorrhagic fever.
 The only way to prevent dengue virus transmission is to combat the disease-carrying mosquitoes.

Dengue is a mosquito-borne infection that in recent decades has become a major international public
health concern. Dengue is found in tropical and sub-tropical regions around the world, predominantly in
urban and semi-urban areas.

Dengue haemorrhagic fever (DHF), a potentially lethal complication, was first recognized in the 1950s
during dengue epidemics in the Philippines and Thailand. Today DHF affects most Asian countries and has
become a leading cause of hospitalization and death among children in the region.

There are four distinct, but closely related, viruses that cause dengue. Recovery from infection by one
provides lifelong immunity against that virus but confers only partial
and transient protection against subsequent infection by the other Related links
three viruses. There is good evidence that sequential infection
increases the risk of developing DHF.
:: Dengue/dengue haemorrhagic
fever
Global burden of dengue
:: Dengue haemorrhagic fever:
The incidence of dengue has grown dramatically around the world in diagnosis, treatment, prevention
recent decades. Some 2.5 billion people – two fifths of the world's and control
population – are now at risk from dengue. WHO currently estimates
there may be 50 million dengue infections worldwide every year. :: Dengue (Special Programme
for Research and Training in
Tropical Diseases, TDR)
In 2007 alone, there were more than 890 000 reported cases of
dengue in the Americas, of which 26 000 cases were DHF.

The disease is now endemic in more than 100 countries in Africa, the Americas, the Eastern
Mediterranean, South-east Asia and the Western Pacific. South-east Asia and the Western Pacific are the
most seriously affected. Before 1970 only nine countries had experienced DHF epidemics, a number that
had increased more than four-fold by 1995.

Not only is the number of cases increasing as the disease is spreading to new areas, but explosive
outbreaks are occurring. In 2007, Venezuela reported over 80 000 cases, including more than 6 000 cases
of DHF.

Some other statistics:

 During epidemics of dengue, infection rates among those who have not been previously exposed
to the virus are often 40% to 50%, but can reach 80% to 90%.
 An estimated 500 000 people with DHF require hospitalization each year, a very large proportion
of whom are children. About 2.5% of those affected die.
 Without proper treatment, DHF fatality rates can exceed 20%. Wider access to medical care from
health providers with knowledge about DHF - physicians and nurses who recognize its symptoms
and know how to treat its effects - can reduce death rates to less than 1%.

The spread of dengue is attributed to expanding geographic distribution of the four dengue viruses and
their mosquito vectors, the most important of which is the predominantly urban species Aedes aegypti. A
rapid rise in urban mosquito populations is bringing ever greater numbers of people into contact with this
vector, especially in areas that are favourable for mosquito breeding, e.g. where household water storage
is common and where solid waste disposal services are inadequate.

DengueNet: WHO surveillance

Transmission

Dengue viruses are transmitted to humans through the bites of

infective female Aedes mosquitoes. Mosquitoes generally acquire the
virus while feeding on the blood of an infected person. After virus
incubation for eight to 10 days, an infected mosquito is capable,

WHO/TDR/Stammers
during probing and blood feeding, of transmitting the virus for the rest of its life. Infected female
mosquitoes may also transmit the virus to their offspring by transovarial (via the eggs) transmission, but
the role of this in sustaining transmission of the virus to humans has not yet been defined.

Infected humans are the main carriers and multipliers of the virus, serving as a source of the virus for
uninfected mosquitoes. The virus circulates in the blood of infected humans for two to seven days, at
approximately the same time that they have a fever; Aedes mosquitoes may acquire the virus when they
feed on an individual during this period. Some studies have shown that monkeys in some parts of the
world play a similar role in transmission.

Characteristics

Dengue fever is a severe, flu-like illness that affects infants, young children and adults, but seldom causes
death.

The clinical features of dengue fever vary according to the age of the patient. Infants and young children
may have a fever with rash. Older children and adults may have either a mild fever or the classical
incapacitating disease with abrupt onset and high fever, severe headache, pain behind the eyes, muscle
and joint pains, and rash.

Dengue haemorrhagic fever (DHF) is a potentially deadly complication that is characterized by high fever,
often with enlargement of the liver, and in severe cases circulatory failure. The illness often begins with a
sudden rise in temperature accompanied by facial flush and other flu-like symptoms. The fever usually
continues for two to seven days and can be as high as 41°C, possibly with convulsions and other
complications.

In moderate DHF cases, all signs and symptoms abate after the fever subsides. In severe cases, the
patient's condition may suddenly deteriorate after a few days of fever; the temperature drops, followed by
signs of circulatory failure, and the patient may rapidly go into a critical state of shock and die within 12 to
24 hours, or quickly recover following appropriate medical treatment (see below).

Treatment

There is no specific treatment for dengue fever.

For DHF, medical care by physicians and nurses experienced with the effects and progression of the
complicating haemorrhagic fever can frequently save lives - decreasing mortality rates from more than
20% to less than 1%. Maintenance of the patient's circulating fluid volume is the central feature of DHF
care.

Immunization

There is no vaccine to protect against dengue. Although progress is underway, developing a vaccine
against the disease - in either its mild or severe form - is challenging.

 With four closely related viruses that can cause the disease, the vaccine must immunize against
all four types to be effective.
 There is limited understanding of how the disease typically behaves and how the virus interacts
with the immune system.
 There is a lack of laboratory animal models available to test immune responses to potential
vaccines.

Despite these challenges, two vaccine candidates have advanced to evaluation in human subjects in
countries with endemic disease, and several potential vaccines are in earlier stages of development. WHO
provides technical advice and guidance to countries and private partners to support vaccine research and
evaluation.

More on vaccine research

Prevention and control

At present, the only method of controlling or preventing dengue virus transmission is to combat the vector
mosquitoes.

In Asia and the Americas, Aedes aegypti breeds primarily in man-made containers like earthenware jars,
metal drums and concrete cisterns used for domestic water storage, as well as discarded plastic food
containers, used automobile tyres and other items that collect
rainwater. In Africa the mosquito also breeds extensively in natural
habitats such as tree holes, and leaves that gather to form "cups"
and catch water.

In recent years, Aedes albopictus, a secondary dengue vector in

Asia, has become established in the United States, several Latin
American and Caribbean countries, parts of Europe and Africa. The
rapid geographic spread of this species is largely attributed to the
international trade in used tyres, a breeding habitat.

WHO/TDR/Crump
Vector control is implemented using environmental management
and chemical methods. Proper solid waste disposal and improved water storage practices, including
 covering containers to prevent access by egg-laying female mosquitoes are among methods that are
encouraged through community-based programmes.

The application of appropriate insecticides to larval habitats, particularly those that are useful in
households, e.g. water storage vessels, prevents mosquito breeding for several weeks but must be re-
applied periodically. Small, mosquito-eating fish and copepods (tiny crustaceans) have also been used
with some success.

During outbreaks, emergency vector control measures can also include broad application of insecticides as
space sprays using portable or truck-mounted machines or even aircraft. However, the mosquito-killing
effect is transient, variable in its effectiveness because the aerosol droplets may not penetrate indoors to
microhabitats where adult mosquitoes are sequestered, and the procedure is costly and operationally
difficult. Regular monitoring of the vectors' susceptibility to widely used insecticides is necessary to ensure
the appropriate choice of chemicals. Active monitoring and surveillance of the natural mosquito population
should accompany control efforts to determine programme effectiveness.

Coagulation factors and related substancesNumber and/or nameFunctionI (fibrinogen)Forms clot (fibrin)II (prothrombin)Its
active form (IIa) activates I, V, VII, XIII, protein C, plateletsTissue factorCo-factor of VIIa (formerly known as factor
III)CalciumRequired for coagulation factors to bind to phospholipid (formerly known as factor IV)V (proaccelerin, labile
factor)Co-factor of X with which it forms the prothrombinase complexVIUnassigned – old name of Factor VaVII (stable
factor)Activates IX, XVIII (antihemophilic factor)Co-factor of IX with which it forms the tenase complexIX (Christmas
factor)Activates X: forms tenase complex with factor VIIIX (Stuart-Prower factor)Activates II:
froms prothrombinase complex with factor VXI (plasma thromboplastin antecedent)Activates XII, IX and
prekallikreinXII (Hageman factor)Activates prekallikrein and fibrinolysisXIII (fibrin-stabilizing factor)Crosslinks fibrinvon
Willebrand factorBinds to VIII, mediates platelet adhesionprekallikreinActivates XII and prekallikrein; cleaves HMWKhigh
molecular weight kininogen(HMWK)Supports reciprocal activation of XII, XI, and prekallikreinfibronectinMediates cell
adhesionantithrombin IIIInhibits IIa, Xa, and other proteases;heparin cofactor IIInhibits IIa, cofactor for heparin
and dermatan sulfate ("minor antithrombin")protein CInactivates Va and VIIIaprotein SCofactor for activated protein C
(APC, inactive when bound to C4b-binding protein)protein ZMediates thrombin adhesion to phospholipids and stimulates
degradation of factor X by ZPIProtein Z-related protease inhibitor(ZPI)Degrades factors X (in presence of protein Z) and
XI (independently)plasminogenConverts to plasmin, lyses fibrin and other proteinsalpha 2-antiplasminInhibits
plasmintissue plasminogen activator (tPA)Activates plasminogenurokinaseActivates plasminogenplasminogen activator
inhibitor-1(PAI1)Inactivates tPA & urokinase (endothelial PAI)plasminogen activator inhibitor-2(PAI2)Inactivates tPA &
urokinase (placental PAI)cancer procoagulantPathological factor X activator linked to thrombosis in cancer

Coagulation

From Wikipedia, the free encyclopedia

This article is about the clotting of blood. For other uses, see Coagulation (disambiguation).

Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis (the cessation of

blood loss from a damaged vessel), wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing

clot to stop bleeding and begin repair of the damaged vessel. Disorders of coagulation can lead to an increased risk of

bleeding (hemorrhage) or clotting (thrombosis).

Coagulation is highly conserved throughout biology; in all mammals, coagulation involves both a cellular (platelet) and

a protein (coagulation factor) component. The system in humans has been the most extensively researched and,

therefore, the best-understood.

Coagulation begins almost instantly after an injury to the blood vessel has damaged the endothelium (lining of the vessel),

this releasesphospholipid components called tissue factor and fibrinogen that initiate a chain

reaction. Platelets immediately form a plug at the site of injury; this is called primary hemostasis. Secondary

hemostasis occurs simultaneously: Proteins in the blood plasma, called coagulation factors orclotting factors, respond in a

complex cascade to form fibrin strands, which strengthen the platelet plug.[1]

[edit]Physiology

[edit]Platelet activation

Damage to blood vessel walls exposes subendothelium proteins, most notably von Willebrand factor (vWF), present

under the endothelium. vWF is a protein secreted by healthy endothelium, forming a layer between the endothelium and

underlying basement membrane. When the endothelium is damaged, the normally-isolated, underlying vWF is exposed to

blood and recruits Factor VIII, collagen, and other clotting factors. Circulating platelets bind to collagen with surface

collagen-specific glycoprotein Ia/IIa receptors. This adhesion is strengthened further by additional circulating proteins

vWF), which forms additional links between the platelets glycoprotein Ib/IX/V and the collagen fibrils. These adhesions

activate the platelets.

Activated platelets release the contents of stored granules into the blood plasma. The granules

include ADP, serotonin, platelet-activating factor(PAF), vWF, platelet factor 4, and thromboxane A2 (TXA2), which, in turn,

activate additional platelets. The granules' contents activate a Gq-linked protein receptor cascade, resulting in increased

calcium concentration in the platelets' cytosol. The calcium activates protein kinase C, which, in turn,

activates phospholipase A2 (PLA2). PLA2 then modifies the integrin membrane glycoprotein IIb/IIIa, increasing its affinity to

bind fibrinogen. The activated platelets change shape from spherical to stellate, and the fibrinogen cross-links with

glycoprotein IIb/IIIa aid in aggregation of adjacent platelets.

[edit]The coagulation cascade

The coagulation cascade.

The coagulation cascade of secondary hemostasis has two pathways, the contact activation pathway (formerly known as

the intrinsic pathway), and the tissue factor pathway (formerly known as the extrinsic pathway), which lead

to fibrin formation. It was previously thought that the coagulation cascade consisted of two pathways of equal importance

joined to a common pathway. It is now known that the primary pathway for the initiation of blood coagulation is the tissue

factor pathway. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine

proteaseand its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in

the cascade, ultimately resulting in cross-linked fibrin. Coagulation factors are generally indicated by Roman numerals,

with a lowercase aappended to indicate an active form.

The coagulation factors are generally serine proteases (enzymes). There are some exceptions. For example, FVIII and

FV are glycoproteins, and Factor XIII is a transglutaminase. Serine proteases act by cleaving other proteins at specific

sites. The coagulation factors circulate as inactive zymogens. The coagulation cascade is classically divided into three

pathways. The tissue factor and contact activation pathways both activate the "final common pathway" of factor X,

thrombin and fibrin.

[edit]Tissue factor pathway (extrinsic)

The main role of the tissue factor pathway is to generate a "thrombin burst," a process by which thrombin, the most

important constituent of the coagulation cascade in terms of its feedback activation roles, is released instantaneously.

FVIIa circulates in a higher amount than any other activated coagulation factor.

 Following damage to the blood vessel, FVII leaves the circulation and comes into contact with tissue factor (TF)

expressed on tissue-factor-bearing cells (stromal fibroblasts and leukocytes), forming an activated complex (TF-

FVIIa).

 TF-FVIIa activates FIX and FX.

 FVII is itself activated by thrombin, FXIa, plasmin, FXII and FXa.

 The activation of FXa by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor (TFPI).

 FXa and its co-factor FVa form the prothrombinase complex, which activates prothrombin to thrombin.

 Thrombin then activates other components of the coagulation cascade, including FV and FVIII (which activates

FXI, which, in turn, activates FIX), and activates and releases FVIII from being bound to vWF.

 FVIIIa is the co-factor of FIXa, and together they form the "tenase" complex, which activates FX; and so the

cycle continues. ("Tenase" is a contraction of "ten" and the suffix "-ase" used for enzymes.)

[edit]Contact activation pathway (intrinsic)

The contact activation pathway begins with formation of the primary complex on collagen by high-molecular-weight

kininogen (HMWK),prekallikrein, and FXII (Hageman factor). Prekallikrein is converted to kallikrein and FXII becomes

FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex,

which activates FX to FXa. The minor role that the contact activation pathway has in initiating clot formation can be

illustrated by the fact that patients with severe deficiencies of FXII, HMWK, and prekallikrein do not have a bleeding

disorder.

[edit]Final common pathway

Thrombin has a large array of functions. Its primary role is the conversion of fibrinogen to fibrin, the building block of a

hemostatic plug. In addition, it activates Factors VIII and V and their inhibitor protein C (in the presence

of thrombomodulin), and it activates Factor XIII, which formscovalent bonds that crosslink the fibrin polymers that form

from activated monomers.

Following activation by the contact factor or tissue factor pathways, the coagulation cascade is maintained in a

prothrombotic state by the continued activation of FVIII and FIX to form the tenase complex, until it is down-regulated by

the anticoagulant pathways.

[edit]Cofactors

Various substances are required for the proper functioning of the coagulation cascade:

 Calcium and phospholipid (a platelet membrane constituent) are required for the tenase and prothrombinase

complexes to function. Calcium mediates the binding of the complexes via the terminal gamma-carboxy residues on

FXa and FIXa to the phospholipid surfaces expressed by platelets, as well as procoagulant microparticles

or microvesicles shed from them. Calcium is also required at other points in the coagulation cascade.

 Vitamin K is an essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxyl group

to glutamic acid residues on factors II, VII, IX and X, as well as Protein S, Protein C and Protein Z. In adding the

gamma-carboxyl group to glutamate residues on the immature clotting factors Vitamin K is itself oxidized. Another

enzyme, Vitamin K epoxide reductase, (VKORC) reduces vitamin K back to its active form. Vitamin K epoxide

reductase is pharmacologically important as a target for anticoagulant drugs warfarin and related coumarins such

as acenocoumarol, phenprocoumon, and dicumarol. These drugs create a deficiency of reduced vitamin K by

blocking VKORC, thereby inhibiting maturation of clotting factors. Other deficiencies of vitamin K (e.g.,

in malabsorption), or disease (hepatocellular carcinoma) impairs the function of the enzyme and leads to the

formation of PIVKAs (proteins formed in vitamin K absence); this causes partial or non-gamma carboxylation, and

affects the coagulation factors' ability to bind to expressed phospholipid.

[edit]Regulators

Five mechanisms keep platelet activation and the coagulation cascade in check. Abnormalities can lead to an increased

tendency toward thrombosis:

 Protein C is a major physiological anticoagulant. It is a vitamin K-dependent serine protease enzyme that is

activated by thrombin into activated protein C (APC). Protein C is activated in a sequence that starts with Protein C

and thrombin binding to a cell surface proteinthrombomodulin. Thrombomodulin binds these proteins in such a way
 that it activates Protein C. The activated form, along with protein S and a phospholipid as cofactors, degrades FVa

and FVIIIa. Quantitative or qualitative deficiency of either may lead to thrombophilia (a tendency to develop

thrombosis). Impaired action of Protein C (activated Protein C resistance), for example by having the "Leiden" variant

of Factor V or high levels of FVIII also may lead to a thrombotic tendency.

 Antithrombin is a serine protease inhibitor (serpin) that degrades the serine proteases: thrombin, FIXa, FXa,

FXIa, and FXIIa. It is constantly active, but its adhesion to these factors is increased by the presence of heparan

sulfate (a glycosaminoglycan) or the administration ofheparins (different heparinoids increase affinity to FXa,

thrombin, or both). Quantitative or qualitative deficiency of antithrombin (inborn or acquired, e.g., in proteinuria) leads

to thrombophilia.

 Tissue factor pathway inhibitor (TFPI) limits the action of tissue factor (TF). It also inhibits excessive TF-

mediated activation of FIX and FX.

 Plasmin is generated by proteolytic cleavage of plasminogen, a plasma protein synthesized in the liver. This

cleavage is catalyzed by tissue plasminogen activator (t-PA), which is synthesized and secreted by endothelium.

Plasmin proteolytically cleaves fibrin into fibrin degradation products that inhibit excessive fibrin formation.

 Prostacyclin (PGI2) is released by endothelium and activates platelet Gs protein-linked receptors. This, in turn,

activates adenylyl cyclase, which synthesizes cAMP. cAMP inhibits platelet activation by counteracting the actions

that result from increased cytosolic levels of calcium and, by doing so, inhibits the release of granules that would

lead to activation of additional platelets and the coagulation cascade.

[edit]Fibrinolysis

Main article: Fibrinolysis

Eventually, blood clots are reorganised and resorbed by a process termed fibrinolysis. The main enzyme responsible for

this process (plasmin) is regulated by various activators and inhibitors.

[edit]Testing of coagulation

Numerous tests are used to assess the function of the coagulation system:

 Common: aPTT, PT (also used to determine INR), fibrinogen testing (often by the Clauss

method), platelet count, platelet function testing (often by PFA-100).

 Other: TCT, bleeding time, mixing test (whether an abnormality corrects if the patient's plasma is mixed with

normal plasma), coagulation factor assays, antiphosholipid antibodies, D-dimer, genetic tests (eg. factor V

Leiden, prothrombin mutation G20210A), dilute Russell's viper venom time (dRVVT), miscellaneous platelet function

tests, thromboelastography (TEG or Sonoclot), euglobulin lysis time (ELT), .

The contact activation pathway is initiated by activation of the "contact factors" of plasma, and can be measured by

the activated partial thromboplastin time (aPTT) test.

The tissue factor pathway is initiated by release of tissue factor (a specific cellular lipoprotein), and can be measured by

the prothrombin time(PT) test. PT results are often reported as ratio (INR value) to monitor dosing of oral anticoagulants

such as warfarin.

The quantitative and qualitative screening of fibrinogen is measured by the thrombin clotting time (TCT). Measurement of

the exact amount of fibrinogen present in the blood is generally done using the Clauss method for fibrinogen testing. Many

analysers are capable of measuring a "derived fibrinogen" level from the graph of the Prothrombin time clot.

If a coagulation factor is part of the contact activation or tissue factor pathway, a deficiency of that factor will affect only

one of the tests: Thushemophilia A, a deficiency of factor VIII, which is part of the contact activation pathway, results in an

abnormally prolonged aPTT test but a normal PT test. The exceptions are prothrombin, fibrinogen, and some variants of

FX that can be detected only by either aPTT or PT. If an abnormal PT or aPTT is present, additional testing will occur to

determine which (if any) factor is present as aberrant concentrations.

Deficiencies of fibrinogen (quantitative or qualitative) will affect all screening tests.

[edit]Role in disease

Problems with coagulation may dispose to hemorrhage, thrombosis, and occasionally both, depending on the nature of

the pathology.

[edit]Platelet disorders

Platelet conditions may be inborn or acquired. Some inborn platelet pathologies are Glanzmann's

thrombasthenia, Bernard-Soulier syndrome(abnormal glycoprotein Ib-IX-V complex), gray platelet

syndrome (deficient alpha granules), and delta storage pool deficiency (deficient dense granules). Most are rare

conditions. Most inborn platelet pathologies predispose to hemorrhage. Von Willebrand disease is due to deficiency or

abnormal function of von Willebrand factor, and leads to a similar bleeding pattern; its milder forms are relatively common.

Decreased platelet numbers may be due to various causes, including insufficient production (e.g., in myelodysplastic

syndrome or other bone marrow disorders), destruction by the immune system (immune thrombocytopenic purpura/ITP),

and consumption due to various causes (thrombotic thrombocytopenic purpura/TTP, hemolytic-uremic

syndrome/HUS, paroxysmal nocturnal hemoglobinuria/PNH, disseminated intravascular coagulation/DIC, heparin-induced

thrombocytopenia/HIT). Most consumptive conditions lead to platelet activation, and some are associated with

thrombosis.

[edit]Disease and clinical significance of thrombosis

The best-known coagulation factor disorders are the hemophilias. The three main forms are hemophilia A (factor VIII

deficiency), hemophilia B(factor IX deficiency or "Christmas disease") and hemophilia C (factor XI deficiency, mild

bleeding tendency). Hemophilia A and B are X-linked recessive disorders, whereas Hemophilia C is much more rare

autosomal recessive disorder most commonly seen in Ashkenazi Jews.

Von Willebrand disease (which behaves more like a platelet disorder except in severe cases), is the most common

hereditary bleeding disorder and is characterized as being inherited autosomal recessive or dominant. In this disease,

there is a defect in von Willebrand factor (vWF), which mediates the binding of glycoprotein Ib (GPIb) to collagen. This

binding helps mediate the activation of platelets and formation of primary hemostasis.

Bernard-Soulier syndrome is a defect or deficiency in GPIb. GPIb, the receptor for vWF, can be defective and lead to lack

of primary clot formation (primary hemostasis) and increased bleeding tendency. This is an autosomal recessive inherited

disorder.

Thrombasthenia of Glanzman and Naegeli (Glanzmann thrombasthenia) is extremely rare. It is characterized by a defect

in GPIIb/IIIa fibrinogen receptor complex. When GPIIb/IIIa receptor is dysfunctional, fibrinogen cannot cross-link platelets,

which inhibits primary hemostasis. This is an autosomal recessive inherited disorder. In liver failure (acute and chronic

forms), there is insufficient production of coagulation factors by the liver; this may increase bleeding risk.

Deficiency of Vitamin K may also contribute to bleeding disorders because clotting factor maturation depends on Vitamin

K.

Thrombosis is the pathological development of blood clots. These clots may break free and become mobile, forming

an embolus or grow to such a size that occludes the vessel in which it developed. An embolism is said to occur when

the thrombus (blood clot) becomes a mobile embolus and migrates to another part of the body, interfering with blood

circulation and hence impairing organ function downstream of the occlusion. This causes ischemia and often leads to

ischemic necrosis of tissue. Most cases of thrombosis are due to acquired extrinsic problems

(surgery, cancer, immobility, obesity, economy class syndrome), but a small proportion of people harbor predisposing

conditions known collectively as thrombophilia (e.g., antiphospholipid syndrome, factor V Leiden, and various other rarer

genetic disorders).

Mutations in factor XII have been associated with an asymptomatic prolongation in the clotting time and possibly a

tendency towardthrombophlebitis. Other mutations have been linked with a rare form of hereditary angioedema (type III).
[edit]Pharmacology

[edit]Procoagulants

The use of adsorbent chemicals, such as zeolites, and other hemostatic agents are also used for use in sealing severe

injuries quickly (such as in traumatic bleeding secondary to gunshot wounds). Thrombin and fibrin glue are used surgically

to treat bleeding and to thrombose aneurysms.

Desmopressin is used to improve platelet function by activating arginine vasopressin receptor 1A.

Coagulation factor concentrates are used to treat hemophilia, to reverse the effects of anticoagulants, and to treat

bleeding in patients with impaired coagulation factor synthesis or increased consumption. Prothrombin complex

concentrate, cryoprecipitate and fresh frozen plasma are commonly-used coagulation factor products. Recombinant

activated human factor VII is increasingly popular in the treatment of major bleeding.

Tranexamic acid and aminocaproic acid inhibit fibrinolysis, and lead to a de facto reduced bleeding rate. Before its

withdrawal, aprotinin was used in some forms of major surgery to decrease bleeding risk and need for blood products.

[edit]Anticoagulants

Main articles: Antiplatelet drug and Anticoagulant

Anticoagulants and anti-platelet agents are amongst the most commonly used medicines. Anti-platelet

agents include aspirin, clopidogrel,dipyridamole and ticlopidine; the parenteral glycoprotein IIb/IIIa inhibitors are used

during angioplasty.

Of the anticoagulants, warfarin (and related coumarins) and heparin are the most commonly used. Warfarin affects the

vitamin K-dependent clotting factors (II, VII, IX,X) , whereas heparin and related compounds increase the action of

antithrombin on thrombin and factor Xa. A newer class of drugs, the direct thrombin inhibitors, is under development;

some members are already in clinical use (such as lepirudin). Also under development are other small molecular

compounds that interfere directly with the enzymatic action of particular coagulation factors (e.g.,rivaroxaban).

[edit]Coagulation factors

Coagulation factors and related substances

Number and/or name Function

I (fibrinogen) Forms clot (fibrin)

II (prothrombin) Its active form (IIa) activates I, V, VII, VIII, XI, XIII, protein C, platelets

Tissue factor Co-factor of VIIa (formerly known as factor III)

Required for coagulation factors to bind to phospholipid (formerly known as factor

Calcium
IV)

V (proaccelerin, labile factor) Co-factor of X with which it forms the prothrombinase complex

VI Unassigned – old name of Factor Va

VII (stable factor) Name: Pro Convertin - Activates IX, X

VIII (Anti Hemophilic factor A) Co-factor of IX with which it forms the tenase complex
IX (Anti Hemophilic Factor B or Christmas
Activates X: forms tenase complex with factor VIII
factor)

X (Stuart-Prower factor) Activates II: forms prothrombinase complex with factor V

XI (plasma thromboplastin antecedent) Activates IX

XII (Hageman factor) Activates factor XI and prekallikrein

XIII (fibrin-stabilizing factor) Crosslinks fibrin

von Willebrand factor Binds to VIII, mediates platelet adhesion

prekallikrein Activates XII and prekallikrein; cleaves HMWK

high-molecular-weight kininogen (HMWK) Supports reciprocal activation of XII, XI, and prekallikrein

fibronectin Mediates cell adhesion

antithrombin III Inhibits IIa, Xa, and other proteases;

heparin cofactor II Inhibits IIa, cofactor for heparin and dermatan sulfate ("minor antithrombin")

protein C Inactivates Va and VIIIa

protein S Cofactor for activated protein C (APC, inactive when bound to C4b-binding protein)

Mediates thrombin adhesion to phospholipids and stimulates degradation of factor X

protein Z
by ZPI

Protein Z-related protease inhibitor (ZPI) Degrades factors X (in presence of protein Z) and XI (independently)

plasminogen Converts to plasmin, lyses fibrin and other proteins

alpha 2-antiplasmin Inhibits plasmin

tissue plasminogen activator (tPA) Activates plasminogen

urokinase Activates plasminogen

plasminogen activator inhibitor-1 (PAI1) Inactivates tPA & urokinase (endothelial PAI)

plasminogen activator inhibitor-2 (PAI2) Inactivates tPA & urokinase (placental PAI)

cancer procoagulant Pathological factor X activator linked to thrombosis in cancer

[edit]History

[edit]Initial discoveries

Theories on the coagulation of blood have existed since antiquity. Physiologist Johannes Müller (1801-1858) described

fibrin, the substance of a thrombus. Its soluble precursor, fibrinogen, was thus named by Rudolf Virchow (1821-1902), and

isolated chemically by Prosper Sylvain Denis(1799-1863). Alexander Schmidt suggested that the conversion from

fibrinogen to fibrin is the result of an enzymatic process, and labeled the hypothetical enzyme "thrombin" and its precursor

"prothrombin".[2][3] Arthus discovered in 1890 that calcium was essential in coagulation.[4][5]Platelets were identified in 1865,

and their function was elucidated by Giulio Bizzozero in 1882.[6]

The theory that thrombin is generated by the presence of tissue factor was consolidated by Paul Morawitz in 1905.[7] At

this stage, it was known that thrombokinase/thromboplastin (factor III) is released by damaged tissues, reacting

with prothrombin (II), which, together withcalcium (IV), forms thrombin, which converts fibrinogen into fibrin (I).[8]

[edit]Coagulation factors

The remainder of the biochemical factors in the process of coagulation were largely discovered in the 20th century.

A first clue as to the actual complexity of the system of coagulation was the discovery of proaccelerin (initially and later

called Factor V) by Paul Owren (1905-1990) in 1947. He also postulated its function to be the generation of accelerin

(Factor VI), which later turned out to be the activated form of V (or Va); hence, VI is not now in active use.[8]

Factor VII (also known as serum prothrombin conversion accelerator or proconvertin, precipitated by barium sulfate) was

discovered in a young female patient in 1949 and 1951 by different groups.

Factor VIII turned out to be deficient in the clinically recognised but etiologically elusive hemophilia A; it was identified in

the 1950s and is alternatively called antihemophilic globulin due to its capability to correct hemophilia A.[8]

Factor IX was discovered in 1952 in a young patient with hemophilia B named Stephen Christmas (1947-1993). His

deficiency was described by Dr. Rosemary Biggs and Professor R.G. MacFarlane in Oxford, UK. The factor is, hence,

called Christmas Factor or Christmas Eve Factor. Christmas lived in Canada, and campaigned for blood transfusion safety

until succumbing to transfusion-related AIDS at age 46. An alternative name for the factor is plasma thromboplastin

component, given by an independent group in California.[8]

Hageman factor, now known as factor XII, was identified in 1955 in an asymptomatic patient with a prolonged bleeding

time named of John Hageman. Factor X, or Stuart-Prower factor, followed, in 1956. This protein was identified in a Ms.

Audrey Prower of London, who had a lifelong bleeding tendency. In 1957, an American group identified the same factor in

a Mr. Rufus Stuart. Factors XI and XIII were identified in 1953 and 1961, respectively.[8]

The view that the coagulation process is a "cascade" or "waterfall" was enunciated almost simultaneously by

MacFarlane[9] in the UK and by Davie and Ratnoff[10] in the USA, respectively.

[edit]Nomenclature

The usage of Roman numerals rather than eponyms or systematic names was agreed upon during annual conferences

(starting in 1955) of hemostasis experts. In 1962, consensus was achieved on the numbering of factors I-XII. [11] This

committee evolved into the present-day International Committee on Thrombosis and Hemostasis (ICTH). Assignment of

numerals ceased in 1963 after the naming of Factor XIII. The names Fletcher Factor and Fitzgerald Factor were given to

further coagulation-related proteins, namely prekallikrein and high-molecular-weight kininogen, respectively.[8]

Factors III and VI are unassigned, as thromboplastin was never identified, and actually turned out to consist of ten further

factors, and accelerin was found to be activated Factor V.

[edit]Other species

All mammals have an extremely closely related blood coagulation process, using a combined cellular and serine protease

process. In fact, it is possible for any mammalian coagulation factor to "cleave" its equivalent target in any other mammal.

The only nonmammalian animal known to use serine proteases for blood coagulation is the horseshoe crab.

[edit] Coagulation

From Wikipedia, the free encyclopedia

This article is about the clotting of blood. For other uses, see Coagulation (disambiguation).

Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis (the cessation of

blood loss from a damaged vessel), wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing

clot to stop bleeding and begin repair of the damaged vessel. Disorders of coagulation can lead to an increased risk of

bleeding (hemorrhage) or clotting (thrombosis).

Coagulation is highly conserved throughout biology; in all mammals, coagulation involves both a cellular (platelet) and

a protein (coagulation factor) component. The system in humans has been the most extensively researched and,

therefore, the best-understood.

Coagulation begins almost instantly after an injury to the blood vessel has damaged the endothelium (lining of the vessel),

this releasesphospholipid components called tissue factor and fibrinogen that initiate a chain

reaction. Platelets immediately form a plug at the site of injury; this is called primary hemostasis. Secondary

hemostasis occurs simultaneously: Proteins in the blood plasma, called coagulation factors orclotting factors, respond in a

complex cascade to form fibrin strands, which strengthen the platelet plug.[1]
 Contents

[hide]

1 Physiology

o 1.1 Platelet activation

o 1.2 The coagulation cascade

 1.2.1 Tissue factor pathway (extrinsic)

 1.2.2 Contact activation pathway (intrinsic)

 1.2.3 Final common pathway

o 1.3 Cofactors

o 1.4 Regulators

o 1.5 Fibrinolysis

2 Testing of coagulation

3 Role in disease

o 3.1 Platelet disorders

o 3.2 Disease and clinical significance of thrombosis

4 Pharmacology

o 4.1 Procoagulants

o 4.2 Anticoagulants

5 Coagulation factors

6 History

o 6.1 Initial discoveries

o 6.2 Coagulation factors

o 6.3 Nomenclature

7 Other species

8 References

9 External links

o 9.1 3D structures

[edit]Physiology

[edit]Platelet activation

Damage to blood vessel walls exposes subendothelium proteins, most notably von Willebrand factor (vWF), present

under the endothelium. vWF is a protein secreted by healthy endothelium, forming a layer between the endothelium and

underlying basement membrane. When the endothelium is damaged, the normally-isolated, underlying vWF is exposed to

blood and recruits Factor VIII, collagen, and other clotting factors. Circulating platelets bind to collagen with surface

collagen-specific glycoprotein Ia/IIa receptors. This adhesion is strengthened further by additional circulating proteins

vWF), which forms additional links between the platelets glycoprotein Ib/IX/V and the collagen fibrils. These adhesions

activate the platelets.

Activated platelets release the contents of stored granules into the blood plasma. The granules

include ADP, serotonin, platelet-activating factor(PAF), vWF, platelet factor 4, and thromboxane A2 (TXA2), which, in turn,

activate additional platelets. The granules' contents activate a Gq-linked protein receptor cascade, resulting in increased

calcium concentration in the platelets' cytosol. The calcium activates protein kinase C, which, in turn,

activates phospholipase A2 (PLA2). PLA2 then modifies the integrin membrane glycoprotein IIb/IIIa, increasing its affinity to

bind fibrinogen. The activated platelets change shape from spherical to stellate, and the fibrinogen cross-links with

glycoprotein IIb/IIIa aid in aggregation of adjacent platelets.

[edit]The coagulation cascade

The coagulation cascade.

The coagulation cascade of secondary hemostasis has two pathways, the contact activation pathway (formerly known as

the intrinsic pathway), and the tissue factor pathway (formerly known as the extrinsic pathway), which lead

to fibrin formation. It was previously thought that the coagulation cascade consisted of two pathways of equal importance

joined to a common pathway. It is now known that the primary pathway for the initiation of blood coagulation is the tissue

factor pathway. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine

proteaseand its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in

the cascade, ultimately resulting in cross-linked fibrin. Coagulation factors are generally indicated by Roman numerals,

with a lowercase aappended to indicate an active form.

The coagulation factors are generally serine proteases (enzymes). There are some exceptions. For example, FVIII and

FV are glycoproteins, and Factor XIII is a transglutaminase. Serine proteases act by cleaving other proteins at specific

sites. The coagulation factors circulate as inactive zymogens. The coagulation cascade is classically divided into three

pathways. The tissue factor and contact activation pathways both activate the "final common pathway" of factor X,

thrombin and fibrin.

[edit]Tissue factor pathway (extrinsic)

The main role of the tissue factor pathway is to generate a "thrombin burst," a process by which thrombin, the most

important constituent of the coagulation cascade in terms of its feedback activation roles, is released instantaneously.

FVIIa circulates in a higher amount than any other activated coagulation factor.

 Following damage to the blood vessel, FVII leaves the circulation and comes into contact with tissue factor (TF)

expressed on tissue-factor-bearing cells (stromal fibroblasts and leukocytes), forming an activated complex (TF-

FVIIa).

 TF-FVIIa activates FIX and FX.

 FVII is itself activated by thrombin, FXIa, plasmin, FXII and FXa.

 The activation of FXa by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor (TFPI).

 FXa and its co-factor FVa form the prothrombinase complex, which activates prothrombin to thrombin.

 Thrombin then activates other components of the coagulation cascade, including FV and FVIII (which activates

FXI, which, in turn, activates FIX), and activates and releases FVIII from being bound to vWF.

 FVIIIa is the co-factor of FIXa, and together they form the "tenase" complex, which activates FX; and so the

cycle continues. ("Tenase" is a contraction of "ten" and the suffix "-ase" used for enzymes.)
[edit]Contact activation pathway (intrinsic)

The contact activation pathway begins with formation of the primary complex on collagen by high-molecular-weight

kininogen (HMWK),prekallikrein, and FXII (Hageman factor). Prekallikrein is converted to kallikrein and FXII becomes

FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex,

which activates FX to FXa. The minor role that the contact activation pathway has in initiating clot formation can be

illustrated by the fact that patients with severe deficiencies of FXII, HMWK, and prekallikrein do not have a bleeding

disorder.

[edit]Final common pathway

Thrombin has a large array of functions. Its primary role is the conversion of fibrinogen to fibrin, the building block of a

hemostatic plug. In addition, it activates Factors VIII and V and their inhibitor protein C (in the presence

of thrombomodulin), and it activates Factor XIII, which formscovalent bonds that crosslink the fibrin polymers that form

from activated monomers.

Following activation by the contact factor or tissue factor pathways, the coagulation cascade is maintained in a

prothrombotic state by the continued activation of FVIII and FIX to form the tenase complex, until it is down-regulated by

the anticoagulant pathways.

[edit]Cofactors

Various substances are required for the proper functioning of the coagulation cascade:

 Calcium and phospholipid (a platelet membrane constituent) are required for the tenase and prothrombinase

complexes to function. Calcium mediates the binding of the complexes via the terminal gamma-carboxy residues on

FXa and FIXa to the phospholipid surfaces expressed by platelets, as well as procoagulant microparticles

or microvesicles shed from them. Calcium is also required at other points in the coagulation cascade.

 Vitamin K is an essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxyl group

to glutamic acid residues on factors II, VII, IX and X, as well as Protein S, Protein C and Protein Z. In adding the

gamma-carboxyl group to glutamate residues on the immature clotting factors Vitamin K is itself oxidized. Another

enzyme, Vitamin K epoxide reductase, (VKORC) reduces vitamin K back to its active form. Vitamin K epoxide

reductase is pharmacologically important as a target for anticoagulant drugs warfarin and related coumarins such

as acenocoumarol, phenprocoumon, and dicumarol. These drugs create a deficiency of reduced vitamin K by

blocking VKORC, thereby inhibiting maturation of clotting factors. Other deficiencies of vitamin K (e.g.,

in malabsorption), or disease (hepatocellular carcinoma) impairs the function of the enzyme and leads to the

formation of PIVKAs (proteins formed in vitamin K absence); this causes partial or non-gamma carboxylation, and

affects the coagulation factors' ability to bind to expressed phospholipid.

[edit]Regulators

Five mechanisms keep platelet activation and the coagulation cascade in check. Abnormalities can lead to an increased

tendency toward thrombosis:

 Protein C is a major physiological anticoagulant. It is a vitamin K-dependent serine protease enzyme that is

activated by thrombin into activated protein C (APC). Protein C is activated in a sequence that starts with Protein C

and thrombin binding to a cell surface proteinthrombomodulin. Thrombomodulin binds these proteins in such a way

that it activates Protein C. The activated form, along with protein S and a phospholipid as cofactors, degrades FVa

and FVIIIa. Quantitative or qualitative deficiency of either may lead to thrombophilia (a tendency to develop

thrombosis). Impaired action of Protein C (activated Protein C resistance), for example by having the "Leiden" variant

of Factor V or high levels of FVIII also may lead to a thrombotic tendency.

 Antithrombin is a serine protease inhibitor (serpin) that degrades the serine proteases: thrombin, FIXa, FXa,

FXIa, and FXIIa. It is constantly active, but its adhesion to these factors is increased by the presence of heparan

sulfate (a glycosaminoglycan) or the administration ofheparins (different heparinoids increase affinity to FXa,
 thrombin, or both). Quantitative or qualitative deficiency of antithrombin (inborn or acquired, e.g., in proteinuria) leads

to thrombophilia.

 Tissue factor pathway inhibitor (TFPI) limits the action of tissue factor (TF). It also inhibits excessive TF-

mediated activation of FIX and FX.

 Plasmin is generated by proteolytic cleavage of plasminogen, a plasma protein synthesized in the liver. This

cleavage is catalyzed by tissue plasminogen activator (t-PA), which is synthesized and secreted by endothelium.

Plasmin proteolytically cleaves fibrin into fibrin degradation products that inhibit excessive fibrin formation.

 Prostacyclin (PGI2) is released by endothelium and activates platelet Gs protein-linked receptors. This, in turn,

activates adenylyl cyclase, which synthesizes cAMP. cAMP inhibits platelet activation by counteracting the actions

that result from increased cytosolic levels of calcium and, by doing so, inhibits the release of granules that would

lead to activation of additional platelets and the coagulation cascade.

[edit]Fibrinolysis

Main article: Fibrinolysis

Eventually, blood clots are reorganised and resorbed by a process termed fibrinolysis. The main enzyme responsible for

this process (plasmin) is regulated by various activators and inhibitors.

[edit]Testing of coagulation

Numerous tests are used to assess the function of the coagulation system:

 Common: aPTT, PT (also used to determine INR), fibrinogen testing (often by the Clauss

method), platelet count, platelet function testing (often by PFA-100).

 Other: TCT, bleeding time, mixing test (whether an abnormality corrects if the patient's plasma is mixed with

normal plasma), coagulation factor assays, antiphosholipid antibodies, D-dimer, genetic tests (eg. factor V

Leiden, prothrombin mutation G20210A), dilute Russell's viper venom time (dRVVT), miscellaneous platelet function

tests, thromboelastography (TEG or Sonoclot), euglobulin lysis time (ELT), .

The contact activation pathway is initiated by activation of the "contact factors" of plasma, and can be measured by

the activated partial thromboplastin time (aPTT) test.

The tissue factor pathway is initiated by release of tissue factor (a specific cellular lipoprotein), and can be measured by

the prothrombin time(PT) test. PT results are often reported as ratio (INR value) to monitor dosing of oral anticoagulants

such as warfarin.

The quantitative and qualitative screening of fibrinogen is measured by the thrombin clotting time (TCT). Measurement of

the exact amount of fibrinogen present in the blood is generally done using the Clauss method for fibrinogen testing. Many

analysers are capable of measuring a "derived fibrinogen" level from the graph of the Prothrombin time clot.

If a coagulation factor is part of the contact activation or tissue factor pathway, a deficiency of that factor will affect only

one of the tests: Thushemophilia A, a deficiency of factor VIII, which is part of the contact activation pathway, results in an

abnormally prolonged aPTT test but a normal PT test. The exceptions are prothrombin, fibrinogen, and some variants of

FX that can be detected only by either aPTT or PT. If an abnormal PT or aPTT is present, additional testing will occur to

determine which (if any) factor is present as aberrant concentrations.

Deficiencies of fibrinogen (quantitative or qualitative) will affect all screening tests.

[edit]Role in disease

Problems with coagulation may dispose to hemorrhage, thrombosis, and occasionally both, depending on the nature of

the pathology.

[edit]Platelet disorders
Platelet conditions may be inborn or acquired. Some inborn platelet pathologies are Glanzmann's

thrombasthenia, Bernard-Soulier syndrome(abnormal glycoprotein Ib-IX-V complex), gray platelet

syndrome (deficient alpha granules), and delta storage pool deficiency (deficient dense granules). Most are rare

conditions. Most inborn platelet pathologies predispose to hemorrhage. Von Willebrand disease is due to deficiency or

abnormal function of von Willebrand factor, and leads to a similar bleeding pattern; its milder forms are relatively common.

Decreased platelet numbers may be due to various causes, including insufficient production (e.g., in myelodysplastic

syndrome or other bone marrow disorders), destruction by the immune system (immune thrombocytopenic purpura/ITP),

and consumption due to various causes (thrombotic thrombocytopenic purpura/TTP, hemolytic-uremic

syndrome/HUS, paroxysmal nocturnal hemoglobinuria/PNH, disseminated intravascular coagulation/DIC, heparin-induced

thrombocytopenia/HIT). Most consumptive conditions lead to platelet activation, and some are associated with

thrombosis.

[edit]Disease and clinical significance of thrombosis

The best-known coagulation factor disorders are the hemophilias. The three main forms are hemophilia A (factor VIII

deficiency), hemophilia B(factor IX deficiency or "Christmas disease") and hemophilia C (factor XI deficiency, mild

bleeding tendency). Hemophilia A and B are X-linked recessive disorders, whereas Hemophilia C is much more rare

autosomal recessive disorder most commonly seen in Ashkenazi Jews.

Von Willebrand disease (which behaves more like a platelet disorder except in severe cases), is the most common

hereditary bleeding disorder and is characterized as being inherited autosomal recessive or dominant. In this disease,

there is a defect in von Willebrand factor (vWF), which mediates the binding of glycoprotein Ib (GPIb) to collagen. This

binding helps mediate the activation of platelets and formation of primary hemostasis.

Bernard-Soulier syndrome is a defect or deficiency in GPIb. GPIb, the receptor for vWF, can be defective and lead to lack

of primary clot formation (primary hemostasis) and increased bleeding tendency. This is an autosomal recessive inherited

disorder.

Thrombasthenia of Glanzman and Naegeli (Glanzmann thrombasthenia) is extremely rare. It is characterized by a defect

in GPIIb/IIIa fibrinogen receptor complex. When GPIIb/IIIa receptor is dysfunctional, fibrinogen cannot cross-link platelets,

which inhibits primary hemostasis. This is an autosomal recessive inherited disorder. In liver failure (acute and chronic

forms), there is insufficient production of coagulation factors by the liver; this may increase bleeding risk.

Deficiency of Vitamin K may also contribute to bleeding disorders because clotting factor maturation depends on Vitamin

K.

Thrombosis is the pathological development of blood clots. These clots may break free and become mobile, forming

an embolus or grow to such a size that occludes the vessel in which it developed. An embolism is said to occur when

the thrombus (blood clot) becomes a mobile embolus and migrates to another part of the body, interfering with blood

circulation and hence impairing organ function downstream of the occlusion. This causes ischemia and often leads to

ischemic necrosis of tissue. Most cases of thrombosis are due to acquired extrinsic problems

(surgery, cancer, immobility, obesity, economy class syndrome), but a small proportion of people harbor predisposing

conditions known collectively as thrombophilia (e.g., antiphospholipid syndrome, factor V Leiden, and various other rarer

genetic disorders).

Mutations in factor XII have been associated with an asymptomatic prolongation in the clotting time and possibly a

tendency towardthrombophlebitis. Other mutations have been linked with a rare form of hereditary angioedema (type III).

[edit]Pharmacology

[edit]Procoagulants

The use of adsorbent chemicals, such as zeolites, and other hemostatic agents are also used for use in sealing severe

injuries quickly (such as in traumatic bleeding secondary to gunshot wounds). Thrombin and fibrin glue are used surgically

to treat bleeding and to thrombose aneurysms.

Desmopressin is used to improve platelet function by activating arginine vasopressin receptor 1A.

Coagulation factor concentrates are used to treat hemophilia, to reverse the effects of anticoagulants, and to treat

bleeding in patients with impaired coagulation factor synthesis or increased consumption. Prothrombin complex

concentrate, cryoprecipitate and fresh frozen plasma are commonly-used coagulation factor products. Recombinant

activated human factor VII is increasingly popular in the treatment of major bleeding.

Tranexamic acid and aminocaproic acid inhibit fibrinolysis, and lead to a de facto reduced bleeding rate. Before its

withdrawal, aprotinin was used in some forms of major surgery to decrease bleeding risk and need for blood products.

[edit]Anticoagulants

Main articles: Antiplatelet drug and Anticoagulant

Anticoagulants and anti-platelet agents are amongst the most commonly used medicines. Anti-platelet

agents include aspirin, clopidogrel,dipyridamole and ticlopidine; the parenteral glycoprotein IIb/IIIa inhibitors are used

during angioplasty.

Of the anticoagulants, warfarin (and related coumarins) and heparin are the most commonly used. Warfarin affects the

vitamin K-dependent clotting factors (II, VII, IX,X) , whereas heparin and related compounds increase the action of

antithrombin on thrombin and factor Xa. A newer class of drugs, the direct thrombin inhibitors, is under development;

some members are already in clinical use (such as lepirudin). Also under development are other small molecular

compounds that interfere directly with the enzymatic action of particular coagulation factors (e.g.,rivaroxaban).

[edit]Coagulation factors

Coagulation factors and related substances

Number and/or name Function

I (fibrinogen) Forms clot (fibrin)

II (prothrombin) Its active form (IIa) activates I, V, VII, VIII, XI, XIII, protein C, platelets

Tissue factor Co-factor of VIIa (formerly known as factor III)

Required for coagulation factors to bind to phospholipid (formerly known as factor

Calcium
IV)

V (proaccelerin, labile factor) Co-factor of X with which it forms the prothrombinase complex

VI Unassigned – old name of Factor Va

VII (stable factor) Name: Pro Convertin - Activates IX, X

VIII (Anti Hemophilic factor A) Co-factor of IX with which it forms the tenase complex

IX (Anti Hemophilic Factor B or Christmas

Activates X: forms tenase complex with factor VIII
factor)

X (Stuart-Prower factor) Activates II: forms prothrombinase complex with factor V

XI (plasma thromboplastin antecedent) Activates IX

XII (Hageman factor) Activates factor XI and prekallikrein

XIII (fibrin-stabilizing factor) Crosslinks fibrin

von Willebrand factor Binds to VIII, mediates platelet adhesion

prekallikrein Activates XII and prekallikrein; cleaves HMWK

high-molecular-weight kininogen (HMWK) Supports reciprocal activation of XII, XI, and prekallikrein

fibronectin Mediates cell adhesion

antithrombin III Inhibits IIa, Xa, and other proteases;

heparin cofactor II Inhibits IIa, cofactor for heparin and dermatan sulfate ("minor antithrombin")

protein C Inactivates Va and VIIIa

protein S Cofactor for activated protein C (APC, inactive when bound to C4b-binding protein)

Mediates thrombin adhesion to phospholipids and stimulates degradation of factor X

protein Z
by ZPI

Protein Z-related protease inhibitor (ZPI) Degrades factors X (in presence of protein Z) and XI (independently)

plasminogen Converts to plasmin, lyses fibrin and other proteins

alpha 2-antiplasmin Inhibits plasmin

tissue plasminogen activator (tPA) Activates plasminogen

urokinase Activates plasminogen

plasminogen activator inhibitor-1 (PAI1) Inactivates tPA & urokinase (endothelial PAI)

plasminogen activator inhibitor-2 (PAI2) Inactivates tPA & urokinase (placental PAI)

cancer procoagulant Pathological factor X activator linked to thrombosis in cancer

[edit]History

[edit]Initial discoveries
Theories on the coagulation of blood have existed since antiquity. Physiologist Johannes Müller (1801-1858) described

fibrin, the substance of a thrombus. Its soluble precursor, fibrinogen, was thus named by Rudolf Virchow (1821-1902), and

isolated chemically by Prosper Sylvain Denis(1799-1863). Alexander Schmidt suggested that the conversion from

fibrinogen to fibrin is the result of an enzymatic process, and labeled the hypothetical enzyme "thrombin" and its precursor

"prothrombin".[2][3] Arthus discovered in 1890 that calcium was essential in coagulation.[4][5]Platelets were identified in 1865,

and their function was elucidated by Giulio Bizzozero in 1882.[6]

The theory that thrombin is generated by the presence of tissue factor was consolidated by Paul Morawitz in 1905.[7] At

this stage, it was known that thrombokinase/thromboplastin (factor III) is released by damaged tissues, reacting

with prothrombin (II), which, together withcalcium (IV), forms thrombin, which converts fibrinogen into fibrin (I).[8]

[edit]Coagulation factors

The remainder of the biochemical factors in the process of coagulation were largely discovered in the 20th century.

A first clue as to the actual complexity of the system of coagulation was the discovery of proaccelerin (initially and later

called Factor V) by Paul Owren (1905-1990) in 1947. He also postulated its function to be the generation of accelerin

(Factor VI), which later turned out to be the activated form of V (or Va); hence, VI is not now in active use.[8]

Factor VII (also known as serum prothrombin conversion accelerator or proconvertin, precipitated by barium sulfate) was

discovered in a young female patient in 1949 and 1951 by different groups.

Factor VIII turned out to be deficient in the clinically recognised but etiologically elusive hemophilia A; it was identified in

the 1950s and is alternatively called antihemophilic globulin due to its capability to correct hemophilia A.[8]

Factor IX was discovered in 1952 in a young patient with hemophilia B named Stephen Christmas (1947-1993). His

deficiency was described by Dr. Rosemary Biggs and Professor R.G. MacFarlane in Oxford, UK. The factor is, hence,

called Christmas Factor or Christmas Eve Factor. Christmas lived in Canada, and campaigned for blood transfusion safety

until succumbing to transfusion-related AIDS at age 46. An alternative name for the factor is plasma thromboplastin

component, given by an independent group in California.[8]

Hageman factor, now known as factor XII, was identified in 1955 in an asymptomatic patient with a prolonged bleeding

time named of John Hageman. Factor X, or Stuart-Prower factor, followed, in 1956. This protein was identified in a Ms.

Audrey Prower of London, who had a lifelong bleeding tendency. In 1957, an American group identified the same factor in

a Mr. Rufus Stuart. Factors XI and XIII were identified in 1953 and 1961, respectively.[8]

The view that the coagulation process is a "cascade" or "waterfall" was enunciated almost simultaneously by

MacFarlane[9] in the UK and by Davie and Ratnoff[10] in the USA, respectively.

[edit]Nomenclature

The usage of Roman numerals rather than eponyms or systematic names was agreed upon during annual conferences

(starting in 1955) of hemostasis experts. In 1962, consensus was achieved on the numbering of factors I-XII. [11] This

committee evolved into the present-day International Committee on Thrombosis and Hemostasis (ICTH). Assignment of

numerals ceased in 1963 after the naming of Factor XIII. The names Fletcher Factor and Fitzgerald Factor were given to

further coagulation-related proteins, namely prekallikrein and high-molecular-weight kininogen, respectively.[8]

Factors III and VI are unassigned, as thromboplastin was never identified, and actually turned out to consist of ten further

factors, and accelerin was found to be activated Factor V.

[edit]Other species

All mammals have an extremely closely related blood coagulation process, using a combined cellular and serine protease

process. In fact, it is possible for any mammalian coagulation factor to "cleave" its equivalent target in any other mammal.

The only nonmammalian animal known to use serine proteases for blood coagulation is the horseshoe crab.
[edit]
 ABO Blood Types

The most well known and medically important blood types are in the ABO
group. They were discovered in 1900 and 1901 at the University of Vienna by Karl
Landsteiner in the process of trying to learn why blood transfusions sometimes
cause death and at other times save a patient. In 1930, he belatedly received the
Nobel Prize for this discovery.

All humans and many other primates can be typed for the ABO blood group. There Karl Landsteiner
are four principal types: A, B, AB, and O. There are two antigens and two antibodies (1868-1943)
that are mostly responsible for the ABO types. The specific combination of these
four components determines an individual's type in most cases. The table below shows the possible permutations of
antigens and antibodies with the corresponding ABO type ("yes" indicates the presence of a component and "no"
indicates its absence in the blood of an individual).

ABO
Blood Type Antigen Antigen Antibody Antibody
A B anti-A Anti-B

A yes no no yes
B no yes yes no
O no no yes yes
AB yes yes no no

For example, people with type A blood will have the A antigen on the surface of their red cells (as shown in the table
below). As a result, anti-A antibodies will not be produced by them because they would cause the destruction of their own
blood. However, if B type blood is injected into their systems, anti-B antibodies in their plasma will recognize it as alien
and burst or agglutinate the introduced red cells in order to cleanse the blood of alien protein.

ABO
Blood Type Antibody
Antigen Antigen Antibody
Anti-B
A B anti-A

A yes no no yes
B no yes yes no
O no no yes yes
AB yes yes no no

Individuals with type O blood do not produce ABO antigens. Therefore, their blood normally will not be rejected when it is
given to others with different ABO types. As a result, type O people are universal donors for transfusions, but they can
receive only type O blood themselves. Those who have type AB blood do not make any ABO antibodies. Their blood
does not discriminate against any other ABO type. Consequently, they are universal receivers for transfusions, but their
blood will be agglutinated when given to people with every other type because they produce both kinds of antigens.

ABO
Blood Type Antibody
Antigen Antigen Antibody
Anti-B
A B anti-A

A yes no no yes
B no yes yes no
O no no yes yes
AB yes yes no no

It is easy and inexpensive to determine an individual's ABO type from a few drops of blood. A serum containing anti-A
antibodies is mixed with some of the blood. Another serum with anti-B antibodies is mixed with the remaining sample.
Whether or not agglutination occurs in either sample indicates the ABO type. It is a simple process of elimination of the
possibilities. For instance, if an individual's blood sample is agglutinated by the anti-A antibody, but not the anti-B
antibody, it means that the A antigen is present but not the B antigen. Therefore, the blood type is A.

Blood Typing Workshop Activity--hands-on simulation of blood typing.

This link takes you to an external website maintained by Nobel e-Museum.
To return here, you must click the "back" button on your browser program.

Genetic Inheritance Patterns

ABO blood types are inherited through genes on chromosome 9, and they do not change as a result of environmental
influences during life. An individual's ABO type is determined by the inheritance of 1 of 3 alleles (A, B, or O) from each
parent. The possible outcomes are shown below:

Parent Alleles
A B O

AA AB AO
A
(A) (AB) (A)

AB BB BO
B
(AB) (B) (B)

AO BO OO
O
(A) (B) (O)

The possible ABO alleles for one parent are in the top row and the alleles of the
other are in the left column. Offspring genotypes are shown in black.
Phenotypes are red.

Both A and B alleles are dominant over O. As a result, individuals who have an AO genotype will have an A phenotype.
People who are type O have OO genotypes. In other words, they inherited a recessive O allele from both parents. The A
and B alleles are codominant. Therefore, if an A is inherited from one parent and a B from the other, the phenotype will be
AB. Agglutination tests will show that these individuals have the characteristics of both type A and type B blood.

CAUTION: the inheritance of ABO blood types does not always follow such straightforward rules of inheritance. If you
wish to explore the reason why this is true, select the Bombay Phenotype button below.

Bombay Phenotype

ABO Blood type antigens are not only found on the surface of red cells. They are also normally secreted by some people
in their body fluids, including saliva, tears, and urine. Whether someone is able to secrete them is genetically controlled.
Police agencies now routinely use this so-called secretor system data to identify potential victims and criminals when
blood samples are not available.

Despite the fact that the blood types of children are solely determined by inheritance from their parents, paternity in the
U.S. and many other nations can no longer be legally established based on conventional blood typing. To do that, it is
necessary to compareHLA types and/or DNA sequences. The use of DNA is more accurate in determining paternity, but it
is also more expensive than HLA typing.

Antibodies to alien antigens in the ABO group are usually present in our plasma prior to the first contact with blood of a
different ABO type. This may be partly explained by the fact that these antigens are also produced by certain bacteria and
possibly some plants. When we come in contact with them, our bodies may develop long-term active immunity to their
antigens and subsequently to the same antigens on the surface of red blood cells. This usually occurs to babies within
the first six months following their birth.

Environmental Factors

While blood types are 100% genetically inherited, the environment potentially can determine which blood types in a
population will be passed on more frequently to the next generation. It does this through natural selection. Specific ABO
blood types are thought to be linked with increased or decreased susceptibility to particular diseases. For instance,
individuals with type A blood are at a somewhat higher risk of contracting smallpox and developing cancer of the
esophagus, pancreas, and stomach. People who are type O are at a higher risk for contracting cholera and plague as
well as developing duodenal and peptic ulcers. Research suggests that they are also more tasty to mosquitoes. That
could be a significant factor in contracting malaria.

NOTE: A small number of people have two different ABO blood types. They are not simply AB codominant. Apparently,

most of these blood chimera individuals shared a blood supply with their non-identical twin before birth. In some
cases, people are unaware that they had a twin because he or she died early in gestation and was spontaneously
aborted. As many as 8% of non-identical twins may have chimeric blood. Some people are microchimeric--they have a
small amount of blood of a different type in their system that has persisted from a blood transfusion or passed across the
placental barrier from their mother before birth. Likewise, fetal blood can pass into a mother's system. This fact has led
some researchers to suggest that the significantly higher frequency of autoimmune disorders in women is a result of the
presence of foreign white blood cells that had come from their unborn children during pregnancy.

NEWS: An international team of researchers led by Henrick Clausen of the University of Copenhagen, Denmark have
discovered a bacterial enzyme that can convert red blood cells of types A, B, and AB into O by stripping away their
identifying surface antigens. This has the potential for dramatically improving the safety of blood transfusions. Clinical
trials of thistechnique are now underway. ("Bacterial Glycosidases for the Production of Universal Red Blood
Cells", published online inNature Biotechnology, April 1, 2007).

Blood type

From Wikipedia, the free encyclopedia

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 bloodbased on the presence or absence

of inherited antigenic substances on the surface of red blood cells (RBCs). These antigens may

beproteins, 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.[1]

Blood types are inherited and represent contributions from both parents. A total of 30 human blood group systems are

now recognized by the International Society of Blood Transfusion(ISBT).[2]

Many pregnant women carry a fetus with a different blood type from their own, and the mother can form antibodies

against fetal RBCs. Sometimes these maternal antibodies are IgG, a small immunoglobulin, which can cross the placenta

and cause hemolysisof fetal RBCs, which in turn can lead to hemolytic disease of the newborn, an illness of low fetal

blood counts which ranges from mild to severe.[3]

 Contents

[hide]

1 Serology

2 ABO and Rh blood grouping

3 Blood group systems

o 3.1 ABO blood group system

o 3.2 Rhesus blood group system

o 3.3 ABO and Rh distribution by country

o 3.4 Other blood group systems

4 Clinical significance

o 4.1 Blood transfusion

o 4.2 Hemolytic disease of the newborn (HDN)

5 Compatibility

o 5.1 Blood products

o 5.2 Red blood cell compatibility

o 5.3 Plasma compatibility

o 5.4 Universal donors and universal recipients

6 Conversion

7 History

8 Cultural beliefs and pseudoscience

9 References

10 Further reading

11 External links

[edit]Serology

If an individual is exposed to a blood group antigen that is not recognized 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. When IgM antibodies bind to the transfused cells, the transfused

cells can clump. It is vital that compatible blood is selected for transfusions and that compatible tissue is selected

for organ transplantation. Transfusion reactions involving minor antigens or weak antibodies may lead to minor problems.

However, more serious incompatibilities can lead to a more vigorous immune response with massive RBC

destruction, low blood pressure, and evendeath.

[edit]ABO and Rh blood grouping

Agglutination of blood cells tested with antibodies for determination of blood type in the laboratory. The discovery of this

type of agglutination was an important medical breakthrough.[4]

Anti-A and Anti-B, the common IgM antibodies to the RBC surface antigens of the ABO blood group system, are

sometimes described as being "naturally occurring"; however, this is a misnomer, because these antibodies are formed in
infancy by sensitization in the same way as other antibodies. The theory that explains how these antibodies are

developed states that antigens similar to the A and B antigens occur in nature, including in food, plants, and bacteria. After

birth an infant's gut becomes colonized with normal flora that express these A-like and B-like antigens, causing the

immune system to make antibodies to those antigens that the red blood cells do not possess. People who are blood type

A will have Anti-B antibodies, blood type B will have Anti-A antibodies, blood type O will have both Anti-A and Anti-B

antibodies, and blood type AB will have neither. Because of these so called "naturally occurring" and expected antibodies,

it is important to correctly determine a patient's blood type prior to transfusion of any blood component. These naturally

occurring antibodies are of the IgM class, which have the capability of agglutinating (clumping) and damaging red blood

cells within the blood vessels, possibly leading to death. It is not necessary to determine any other blood groups because

almost all other red blood cell antibodies can develop only through active immunization, which can occur only through

either previous blood transfusion or pregnancy. A test called the Antibody Screen is always performed on patients who

may require red blood cell transfusion, and this test will detect most clinically significant red blood cell antibodies.

The RhD antigen is also important in determining a person's blood type. The terms "positive" or "negative" refer to either

the presence or absence of the RhD antigen irrespective of the presence or absence of the other antigens of the Rhesus

system. Anti-RhD is not usually a naturally occurring antibody as the Anti-A and Anti-B antibodies are. Cross-matching for

the RhD antigen is extremely important, because the RhD antigen is immunogenic, meaning that a person who is RhD

negative is very likely to make Anti-RhD when exposed to the RhD antigen (perhaps through either transfusion or

pregnancy). Once an individual is sensitized to RhD antigens, his or her blood will contain RhD IgG antibodies, which can

bind to RhD positive RBCs and may cross the placenta.[5]

[edit]Blood group systems

A total of 30 human blood group systems are now recognized by the International Society of Blood Transfusion (ISBT).[2] A

complete blood type would describe a full set of 30 substances on the surface of RBCs, and an individual's blood type is

one of the many possible combinations of blood-group antigens. Across the 30 blood groups, over 600 different blood-

group antigens have been found,[6] but many of these are very rare or are mainly found in certain ethnic groups.

Almost always, an individual has the same blood group for life, but very rarely an individual's blood type changes through

addition or suppression of an antigen in infection, malignancy, or autoimmune disease.[7][8][9][10] An example of this rare

phenomenon is the case of Demi-Lee Brennan, an Australian citizen, whose blood group changed after a liver transplant.
[11][12]
Another more common cause in blood-type change is a bone marrow transplant. Bone-marrow transplants are

performed for many leukemias and lymphomas, among other diseases. If a person receives bone marrow from someone

who is a different ABO type (eg, a type A patient receives a type O bone marrow), the patient's blood type will eventually

convert to the donor's type.

Some blood types are associated with inheritance of other diseases; for example, the Kell antigen is sometimes

associated with McLeod syndrome.[13] Certain blood types may affect susceptibility to infections, an example being the

resistance to specific malaria species seen in individuals lacking the Duffy antigen.[14] The Duffy antigen, presumably as a

result of natural selection, is less common in ethnic groups from areas with a high incidence of malaria.[15]

[edit]ABO blood group system

ABO blood group system - diagram showing the carbohydrate chains that determine the ABO blood group
Main article: ABO blood group system

The ABO system is the most important blood-group system in human-blood transfusion. The associated anti-

A antibodies and anti-B antibodies are usually "Immunoglobulin M", abbreviated IgM, antibodies. ABO IgM antibodies are

produced in the first years of life by sensitization to environmental substances such as food, bacteria, and viruses. The

"O" in ABO is often called "0" (zero/null) in other languages. [16]

Phenotype Genotype

A AA or AO

B BB or BO

AB AB

O OO

[edit]Rhesus blood group system

Main article: 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 pregnancy or

occasionally a blood transfusion with RhD positive RBCs.[5] Rh disease can develop in these cases.[17]

[edit]ABO and Rh distribution by country

ABO and Rh blood type distribution by nation (population averages)

Country Population[18] O+ A+ B+ AB+ O- A- B- AB-

Australia[19] 21262641 40% 31% 8% 2% 9% 7% 2% 1%

Austria[20] 8210281 30% 33% 12% 6% 7% 8% 3% 1%

Belgium[21] 10414336 38% 34% 8.5% 4.1% 7% 6% 1.5% 0.8%

Brazil[22] 198739269 36% 34% 8% 2.5% 9% 8% 2% 0.5%

Canada[23] 33487208 39% 36% 7.6% 2.5% 7% 6% 1.4% 0.5%

Denmark[24] 5500510 35% 37% 8% 4% 6% 7% 2% 1%

Estonia[25] 1299371 30% 31% 20% 6% 4.5% 4.5% 3% 1%

Finland[26] 5250275 27% 38% 15% 7% 4% 6% 2% 1%

France[27] 62150775 36% 37% 9% 3% 6% 7% 1% 1%

Germany[28] 82329758 35% 37% 9% 4% 6% 6% 2% 1%

Hong Kong SAR[29] 7055071 40% 26% 27% 7% 0.31% 0.19% 0.14% 0.05%

Iceland[30] 306694 47.6% 26.4% 9.3% 1.6% 8.4% 4.6% 1.7% 0.4%

India[31] 1166079217 36.5% 22.1% 30.9% 6.4% 2.0% 0.8% 1.1% 0.2%

Ireland[32] 4203200 47% 26% 9% 2% 8% 5% 2% 1%

Israel[33] 7233701 32% 34% 17% 7% 3% 4% 2% 1%

New Zealand[34] 4213418 38% 32% 9% 3% 9% 6% 2% 1%

Norway[35] 4660539 34% 42.5% 6.8% 3.4% 6% 7.5% 1.2% 0.6%

Poland[36] 38482919 31% 32% 15% 7% 6% 6% 2% 1%

Portugal[37] 10707924 36.2% 39.8% 6.6% 2.9% 6.0% 6.6% 1.1% 0.5%

Saudi Arabia[38] 28686633 48% 24% 17% 4% 4% 2% 1% 0.23%

South Africa[39] 49320000 39% 32% 12% 3% 7% 5% 2% 1%

Spain[40] 40525002 36% 34% 8% 2.5% 9% 8% 2% 0.5%

Sweden[41] 9059651 32% 37% 10% 5% 6% 7% 2% 1%

Netherlands[42] 16715999 39.5% 35% 6.7% 2.5% 7.5% 7% 1.3% 0.5%

Turkey[43] 76805524 29.8% 37.8% 14.2% 7.2% 3.9% 4.7% 1.6% 0.8%

United Kingdom[44] 61113205 37% 35% 8% 3% 7% 7% 2% 1%

United States[45] 307212123 37.4% 35.7% 8.5% 3.4% 6.6% 6.3% 1.5% 0.6%

Population-weighted mean (total population = 2261025244) 36.44% 28.27% 20.59% 5.06% 4.33% 3.52% 1.39% 0.45%

[show]Racial & Ethnic Distribution of ABO (without Rh) Blood Types [46]
(This table has more entries than the table above but does not distinguish between Rh types.)

Blood group B has its highest frequency in Northern India and neighboring Central Asia, and its incidence diminishes both

towards the west and the east, falling to single digit percentages in Spain.[47][48] It is believed to have been entirely absent

from Native American and Australian Aboriginal populations prior to the arrival of Europeans in those areas. [48][49]

Blood group A is associated with high frequencies in Europe, especially in Scandinavia and Central Europe, although its

highest frequencies occur in some Australian Aborigine populations and the Blackfoot Indians of Montana. [50][51]

[edit]Other blood group systems

Main article: Human blood group systems

The International Society of Blood Transfusion currently recognizes 30 blood-group systems (including the ABO and Rh

systems).[2] Thus, in addition to the ABO antigens and 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.

[edit]Clinical significance

[edit]Blood transfusion

Main article: Blood transfusion

Transfusion medicine is a specialized branch of hematology that is concerned with the study of blood groups, along with

the work of a blood bank to provide a transfusion service for blood and other blood products. Across the world, blood

products must be prescribed by a medical doctor (licensed physician or surgeon) in a similar way as medicines. In the

USA, blood products are tightly regulated by the U.S. Food and Drug Administration.

Main symptoms of acute hemolytic reaction due to blood type mismatch.[52][53]

Much of the routine work of a blood bank involves testing blood from both donors and recipients to ensure that every

individual recipient is given blood that is compatible and is as safe as possible. If a unit of incompatible blood

is transfused between a donor and recipient, a severe acute hemolytic reaction with hemolysis (RBC destruction), renal

failure and shock is likely to occur, and death is a possibility. Antibodies can be highly active and can attack RBCs and

bind components of thecomplement 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 serum with a sample of the donor's red blood cells

and checking if the mixtureagglutinates, or forms clumps. If agglutination is not obvious by direct vision, blood bank

technicians usually check for agglutination with a microscope. If agglutination occurs, that particular donor's blood cannot

be transfused to that particular recipient. In a blood bank it is vital that all blood specimens are correctly identified, so

labeling has been standardized using a barcode system known as ISBT 128.

The blood group may be included on identification tags or on tattoos worn by military personnel, in case they should need

an emergency blood transfusion. Frontline German Waffen-SS had blood group tattoos during World War II.

Rare blood types can cause supply problems for blood banks and hospitals. For example Duffy-negative blood occurs

much more frequently in people of African origin,[54] and the rarity of this blood type in the rest of the population can result

in a shortage of 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.[55]

[edit]Hemolytic disease of the newborn (HDN)

Main article: Hemolytic disease of the newborn

A pregnant woman can make IgG blood group antibodies if her fetus has a blood group antigen that she does not have.

This can happen if some of the fetus' blood cells pass into the mother's blood circulation (e.g. a small

fetomaternal hemorrhage at the time of childbirth or obstetric intervention), or sometimes after a therapeutic blood

transfusion. This can cause Rh disease or other forms of hemolytic disease of the newborn(HDN) in the current

pregnancy and/or subsequent pregnancies. If a pregnant woman is known to have anti-RhD antibodies, the RhD blood

type of a fetus can be tested by analysis of fetal DNA in maternal plasma to assess the risk to the fetus of Rh disease.
[56]
One of the major advances of twentieth century medicine was to prevent this disease by stopping the formation of Anti-

RhD antibodies by RhD negative mothers with an injectable medication called Rho(D) immune globulin.[57][58] Antibodies

associated with some blood groups can cause severe HDN, others can only cause mild HDN and others are not known to

cause HDN.[3]

[edit]Compatibility

[edit]Blood products

In order to provide maximum benefit from each blood donation and to extend shelf-life, blood banks fractionate some

whole blood into several products. The most common of these products are packed

RBCs, plasma, platelets, cryoprecipitate, and fresh frozen plasma (FFP). FFP is quick-frozen to retain the labile clotting

factors V and VIII, which are usually administered to patients who have a potentially fatal clotting problem caused by a

condition such as advanced liver disease, overdose of anticoagulant, or disseminated intravascular coagulation (DIC).

Units of packed red cells are made by removing as much of the plasma as possible from whole blood units.

Clotting factors synthesized by modern recombinant methods are now in routine clinical use for hemophilia, as the risks of

infection transmission that occur with pooled blood products are avoided.

[edit]Red blood cell compatibility

 Blood group AB individuals have both A and B antigens on the surface of their RBCs, and their blood

serum does not contain any antibodies against either A or B antigen. Therefore, an individual with type AB blood can

receive blood from any group (with AB being preferable), but can donate blood only to another type AB individual.

 Blood group A individuals have the A antigen on the surface of their RBCs, and blood serum

containing IgM antibodies against the B antigen. Therefore, a group A individual can receive blood only from

individuals of groups A or O (with A being preferable), and can donate blood to individuals with type A or AB.

 Blood group B individuals have the B antigen on the surface of their RBCs, and blood serum containing IgM

antibodies against the A antigen. Therefore, a group B individual can receive blood only from individuals of groups B

or O (with B being preferable), and can donate blood to individuals with type B or AB.

 Blood group O (or blood group zero in some countries) individuals do not have either A or B antigens on the

surface of their RBCs, but their blood serum contains IgM anti-A antibodies and anti-B antibodies against the A and B

blood group antigens. Therefore, a group O individual can receive blood only from a group O individual, but can

donate blood to individuals of any ABO blood group (ie A, B, O or AB). If anyone needs a blood transfusion in a dire

emergency, and if the time taken to process the recipient's blood would cause a detrimental delay, O Negative blood

can be issued.

RBC Compatibility chart

In addition to donating to the same blood group; type O blood donors can give to A, B
and AB; blood donors of types A and B can give to AB.

Red blood cell compatibility table[59][60]

Recipient[1] Donor[1]

O− O+ A− A+ B− B+ AB− AB+

O−

O+

A−

A+
 B−

B+

AB−

AB+

Table note

1. Assumes absence of atypical antibodies that would cause an incompatibility between donor and recipient blood, as is

usual for blood selected by cross matching.

A RhD-negative patient who does not have any anti-RhD antibodies (never being previously sensitized to RhD-positive

RBCs) can receive a transfusion of RhD-positive blood once, but this would cause sensitization to the RhD antigen, and a

female patient would become at risk forhemolytic disease of the newborn. If an RhD-negative patient has developed anti-

RhD antibodies, a subsequent exposure to RhD-positive blood would lead to a potentially dangerous transfusion reaction.

RhD-positive blood should never be given to RhD-negative women of child bearing age or to patients with RhD

antibodies, so blood banks must conserve Rhesus-negative blood for these patients. In extreme circumstances, such as

for a major bleed when stocks of RhD-negative blood units are very low at the blood bank, RhD-positive blood might be

given to RhD-negative females above child-bearing age or to Rh-negative males, providing that they did not have anti-

RhD antibodies, to conserve RhD-negative blood stock in the blood bank. The converse is not true; RhD-positive patients

do not react to RhD negative blood.

[edit]Plasma compatibility

Plasma compatibility chart

In addition to donating to the same blood group; plasma from type AB can be given to A, B and O; plasma from types A

and B can be given to O.

Recipients can receive plasma of the same blood group, but otherwise the donor-recipient compatibility forblood

plasma is
the converse of that of RBCs: plasma extracted from type AB blood can be
transfused to individuals of any blood group; individuals of blood group O can receive
plasma from any blood group; and type O plasma can be used only by type O recipients.
 Plasma compatibility table[60]

Recipient Donor[1]

O A B AB

AB

Table note

1. Assumes absence of strong atypical antibodies in donor plasma

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 (or in some blood banks the blood would be

drawn but the product would need to be appropriately labeled); therefore, donor blood plasma issued by a blood bank can

be selected to be free of RhD antibodies and free of other atypical antibodies, and such donor plasma issued from a blood

bank would be suitable for a recipient who may be RhD positive or RhD negative, as long as blood plasma and the

recipient are ABO compatible.

[edit]Universal donors and universal recipients

With regard to transfusions of whole blood or packed red blood cells, individuals with type O Rh(D) negative blood are

often called universal donors, and those with type AB Rh(D) positive blood are called universal recipients; however, these

terms are only generally true with respect to possible reactions of the recipient's anti-A and anti-B antibodies to transfused

red blood cells, and also possible sensitization to RhD antigens. Exceptions include individuals with hh antigen

system (also known as the Bombay blood group) who can only receive blood safely from other hh donors, because they

form antibodies against the H substance.[61][62]

Blood donors with particularly strong anti-A, anti-B or any atypical blood group antibody are excluded from blood donation.

The possible reactions of anti-A and anti-B antibodies present in the transfused blood to the recipients RBCs need not be

considered, because a relatively small volume of plasma containing antibodies is transfused.

By way of example: considering the transfusion of O 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. However, the relatively small amount of plasma in the transfused blood contains anti-A antibodies, which

could react with the A antigens on the surface of the recipients RBCs, but a significant reaction is unlikely because of the

dilution factors. Rhesus D sensitization is not anticipated.

Additionally, red blood cell surface antigens other than A, B and Rh D, might cause adverse reactions and sensitization, if

they can bind to the corresponding antibodies to generate an immune response. Transfusions are further complicated

because platelets and white blood cells(WBCs) have their own systems of surface antigens, and sensitization to platelet

or WBC antigens can occur as a result of transfusion.

With regard to transfusions of plasma, this situation is reversed. Type O plasma, containing both anti-A and anti-B

antibodies, can only be given to O recipients. The antibodies will attack the antigens on any other blood type. Conversely,

AB plasma can be given to patients of any ABO blood group due to not containing any anti-A or anti-B antibodies.

[edit]Conversion

In April 2007 a method was discovered to convert blood types A, B, and AB to O, using enzymes. This method is still

experimental and the resulting blood has yet to undergo human trials.[63][64] The method specifically removes or converts

antigens on the red blood cells, so other antigens and antibodies would remain. This does not help plasma compatibility,

but that is a lesser concern since plasma has much more limited clinical utility in transfusion and is much easier to

preserve.

[edit]History

The two most significant blood group systems were discovered by Karl Landsteiner during early experiments with blood

transfusion: the ABO group in 1901[65] and in co-operation with Alexander S. Wiener the Rhesus group in 1937.
[66]
Development of the Coombs test in 1945,[67] the advent of transfusion medicine, and the understanding of hemolytic

disease of the newborn led to discovery of more blood groups, and now 30human blood group systems are recognized by

the International Society of Blood Transfusion (ISBT),[2] and across the 30 blood groups, over 600 different blood group

antigens have been found,[6] many of these are very rare or are mainly found in certain ethnic groups. Blood types have

been used in forensic science and in paternity testing, but both of these uses are being replaced by genetic fingerprinting,

which provides greater certainty [68].

[edit]Cultural beliefs and pseudoscience

The Japanese blood type theory of personality is a popular belief that a person's ABO blood type is predictive of

their personality, character, andcompatibility with others. This belief is also widespread in South Korea.[69] Deriving from

ideas of historical scientific racism, the theory reached Japan in a 1927 psychologist's report, and the militarist

government of the time commissioned a study aimed at breeding better soldiers. [69] The fad faded in the 1930s due to its

unscientific basis. The theory has long since been rejected by the scientists[citation needed], but it was revived in the 1970s

by Masahiko Nomi, a broadcaster who had no medical background.[69]

The blood type diet is a diet advocated by Peter D'Adamo, a naturopathic physician, and outlined in his book Eat Right 4

Your Type. D'Adamo's claim is that ABO blood type is the most important factor in determining a healthy diet, and he

promotes distinct diets for people with O, A, B, and AB blood types. This is viewed skeptically by most scientists and

physicians (e.g.,http://www.earthsave.org/news/bloodtyp.htm).