Coagulation, also known as clotting, is the process by which
blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in th ...
changes from a
liquid
A liquid is a nearly incompressible fluid that conforms to the shape of its container but retains a (nearly) constant volume independent of pressure. As such, it is one of the four fundamental states of matter (the others being solid, gas, an ...
to a
gel, forming a
blood clot. It potentially results in
hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism of coagulation involves
activation
Activation, in chemistry and biology, is the process whereby something is prepared or excited for a subsequent reaction.
Chemistry
In chemistry, "activation" refers to the reversible transition of a molecule into a nearly identical chemical ...
,
adhesion
Adhesion is the tendency of dissimilar particles or surfaces to cling to one another ( cohesion refers to the tendency of similar or identical particles/surfaces to cling to one another).
The forces that cause adhesion and cohesion can b ...
and aggregation of
platelets, as well as deposition and maturation of
fibrin
Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with pla ...
.
Coagulation begins almost instantly after an injury to the
endothelium
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...
lining a
blood vessel
Blood vessels are the structures of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away from ...
. Exposure of blood to the subendothelial space initiates two processes: changes in platelets, and the exposure of subendothelial
tissue factor to plasma
factor VII, which ultimately leads to cross-linked fibrin formation. Platelets immediately form a plug at the site of injury; this is called ''primary hemostasis. Secondary hemostasis'' occurs simultaneously: additional coagulation (clotting) factors beyond factor VII (
listed below) respond in a cascade to form fibrin strands, which strengthen the
platelet plug
The platelet plug, also known as the hemostatic plug or platelet thrombus, is an aggregation of platelets formed during early stages of hemostasis in response to one or more injuries to blood vessel walls. After platelets are recruited and begin ...
.
Disorders of coagulation are disease states which can result in problems with
hemorrhage
Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...
,
bruising, or
thrombosis.
Coagulation is highly
conserved throughout biology. In all
mammals, coagulation involves both cellular components (platelets) and
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
aceous components (here,
coagulation factors).
The pathway in humans has been the most extensively researched and is the best understood.
Physiology
Platelet activation
When the endothelium is damaged, the normally isolated underlying collagen is exposed to circulating platelets, which bind directly to collagen with collagen-specific
glycoprotein Ia/IIa surface receptors. This adhesion is strengthened further by
von Willebrand factor (vWF), which is released from the endothelium and from platelets; vWF forms additional links between the platelets'
glycoprotein Ib/IX/V and A1 domain. This localization of platelets to the extracellular matrix promotes collagen interaction with platelet
glycoprotein VI. Binding of collagen to
glycoprotein VI triggers a signaling cascade that results in activation of platelet integrins. Activated integrins mediate tight binding of platelets to the extracellular matrix. This process adheres platelets to the site of injury.
Activated platelets release the contents of stored granules into the blood plasma. The granules include
ADP
Adp or ADP may refer to:
Aviation
* Aéroports de Paris, airport authority for the Parisian region in France
* Aeropuertos del Perú, airport operator for airports in northern Peru
* SLAF Anuradhapura, an airport in Sri Lanka
* Ampara Air ...
,
serotonin,
platelet-activating factor (PAF),
vWF,
platelet factor 4, and
thromboxane A2 (TXA
2), 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 (PLA
2). PLA
2 then modifies the
integrin membrane
glycoprotein IIb/IIIa, increasing its affinity to bind
fibrinogen
Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood ...
. The activated platelets change shape from spherical to stellate, and the
fibrinogen
Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood ...
cross-links with
glycoprotein IIb/IIIa aid in aggregation of adjacent platelets (completing primary hemostasis).
Coagulation cascade
The coagulation cascade of secondary hemostasis has two initial pathways which lead to ''
fibrin
Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with pla ...
'' formation. These are the ''contact activation pathway'' (also known as the intrinsic pathway), and the ''tissue factor pathway'' (also known as the extrinsic pathway), which both lead to the same fundamental reactions that produce fibrin. It was previously thought that the two pathways of coagulation cascade were of equal importance, but it is now known that the primary pathway for the initiation of blood coagulation is the ''tissue factor'' (extrinsic) pathway. The pathways are a series of reactions, in which a
zymogen
In biochemistry, a zymogen (), also called a proenzyme (), is an inactive precursor of an enzyme. A zymogen requires a biochemical change (such as a hydrolysis reaction revealing the active site, or changing the configuration to reveal the acti ...
(inactive enzyme precursor) of a
serine protease
Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site.
They are found ubiquitously in both eukaryotes and prokaryotes. S ...
and its
glycoprotein
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as g ...
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 numeral
Roman numerals are a numeral system that originated in ancient Rome and remained the usual way of writing numbers throughout Europe well into the Late Middle Ages. Numbers are written with combinations of letters from the Latin alphabet, eac ...
s, with a lowercase ''a'' appended to indicate an active form.
The coagulation factors are generally
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s called
serine protease
Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site.
They are found ubiquitously in both eukaryotes and prokaryotes. S ...
s, which act by cleaving downstream proteins. The exceptions are tissue factor, FV, FVIII, FXIII. Tissue factor, FV and FVIII are glycoproteins, and Factor XIII is a
transglutaminase.
The coagulation factors circulate as inactive
zymogens.
The coagulation cascade is therefore classically divided into three pathways. The ''tissue factor'' and ''contact activation'' pathways both activate the "final common pathway" of factor X, thrombin and fibrin.
Tissue factor pathway (extrinsic)
The main role of the
tissue factor (TF) 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 very rapidly. FVIIa circulates in a higher amount than any other activated coagulation factor. The process includes the following steps:
# Following damage to the blood vessel, FVII leaves the circulation and comes into contact with tissue factor 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, FXII, and FXa.
# The activation of FX (to form 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 forms a complex with 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.)
Contact activation pathway (intrinsic)
The
contact activation pathway
In the contact activation system or CAS, three proteins in the blood, factor XII (FXII), prekallikrein (PK) and high molecular weight kininogen (HK), bind to a surface and cause blood coagulation and inflammation. FXII and PK are proteases and HK ...
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 individuals with severe deficiencies of FXII, HMWK, and
prekallikrein do not have a bleeding disorder. Instead, contact activation system seems to be more involved in inflammation,
and innate immunity.
Despite this, interference with the pathway may confer protection against thrombosis without a significant bleeding risk.
[
]
Final common pathway
The division of coagulation in two pathways is arbitrary, originating from laboratory tests in which clotting times were measured either after the clotting was initiated by glass, the intrinsic pathway; or clotting was initiated by thromboplastin (a mix of tissue factor and phospholipids), the extrinsic pathway.
Further, the final common pathway scheme implies that prothrombin is converted to thrombin only when acted upon by the intrinsic or extrinsic pathways, which is an oversimplification. In fact, thrombin is generated by activated platelets at the initiation of the platelet plug, which in turn promotes more platelet activation.
Thrombin functions not only to convert fibrinogen
Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood ...
to fibrin, it also activates Factors VIII and V and their inhibitor protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIX, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and cell death and maintain ...
(in the presence of thrombomodulin); and it activates Factor XIII, which forms covalent bonds that crosslink the fibrin polymers that form from activated monomers.
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.
Cell-based scheme of coagulation
A newer model of coagulation mechanism explains the intricate combination of cellular and biochemical events that occur during the coagulation process ''in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
''. Along with the procoagulant and anticoagulant plasma proteins, normal physiologic coagulation requires the presence of two cell types for formation of coagulation complexes: cells that express tissue factor (usually extravascular) and platelets.
The coagulation process occurs in two phases. First is the initiation phase, which occurs in tissue-factor-expressing cells. This is followed by the propagation phase, which occurs on activated platelets. The initiation phase, mediated by the tissue factor exposure, proceeds via the classic extrinsic pathway and contributes to about 5% of thrombin production. The amplified production of thrombin occurs via the classic intrinsic pathway in the propagation phase; about 95% of thrombin generated will be during this second phase.
Cofactors
Various substances are required for the proper functioning of the coagulation cascade:
Calcium and phospholipids
Calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
and phospholipid
Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids ty ...
s (constituents of platelet membrane) are required for the tenase and prothrombinase complexes to function. Calcium mediates the binding of the complexes via the terminal gamma-carboxy residues on Factor Xa and Factor IXa 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. Calcium ions play a major role in the regulation of coagulation cascade that is paramount in the maintenance of hemostasis. Other than platelet activation, calcium ions are responsible for complete activation of several coagulation factors, including coagulation Factor XIII.
Vitamin K
Vitamin K
Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulat ...
is an essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxyl
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyl ...
group to glutamic acid
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
residues on factors II, VII, IX and X, as well as Protein S
Protein S (also known as PROS) is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In ...
, Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIX, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and cell death and maintain ...
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
Vitamin K epoxide reductase (VKOR) is an enzyme () that reduces vitamin K after it has been oxidised in the carboxylation of glutamic acid residues in blood coagulation enzymes. VKOR is a member of a large family of predicted enzymes that are p ...
'' (VKORC), reduces vitamin K back to its active form. Vitamin K epoxide reductase is pharmacologically important as a target of anticoagulant drugs warfarin and related coumarin
Coumarin () or 2''H''-chromen-2-one is an aromatic organic chemical compound with formula . Its molecule can be described as a benzene molecule with two adjacent hydrogen atoms replaced by a lactone-like chain , forming a second six-membered ...
s such as acenocoumarol, phenprocoumon, and dicumarol. These drugs create a deficiency of reduced vitamin K by blocking VKORC, thereby inhibiting maturation of clotting factors. Vitamin K deficiency from other causes (e.g., in malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a variety ...
) or impaired vitamin K metabolism in disease (e.g., in liver failure) lead to the formation of PIVKAs (proteins formed in vitamin K absence), which are partially or totally non-gamma carboxylated, affecting the coagulation factors' ability to bind to phospholipid.
Regulators
Five mechanisms keep platelet activation and the coagulation cascade in check. Abnormalities can lead to an increased tendency toward thrombosis:
Protein C
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIX, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and cell death and maintain ...
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 protein thrombomodulin. 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 (protein C or protein S) 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
Antithrombin is a serine protease inhibitor
Serpins are a superfamily of proteins with similar structures that were first identified for their protease inhibition activity and are found in all kingdoms of life. The acronym serpin was originally coined because the first serpins to be id ...
(serpin
Serpins are a superfamily of proteins with similar structures that were first identified for their protease inhibition activity and are found in all kingdoms of life. The acronym serpin was originally coined because the first serpins to be ide ...
) 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 of heparin
Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the trea ...
s (different heparinoids increase affinity to FXa, thrombin, or both). Quantitative or qualitative deficiency of antithrombin (inborn or acquired, e.g., in proteinuria
Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy (although this symptom ma ...
) leads to thrombophilia.
Tissue factor pathway inhibitor (TFPI)
Tissue factor pathway inhibitor (TFPI) limits the action of tissue factor (TF). It also inhibits excessive TF-mediated activation of FVII and FX.
Plasmin
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
Prostacyclin (PGI2) is released by endothelium and activates platelet Gs protein-linked receptors. This, in turn, activates adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
, which synthesizes cAMP. cAMP inhibits platelet activation by decreasing 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.
Fibrinolysis
Eventually, blood clots are reorganized and resorbed by a process termed '' fibrinolysis''. The main enzyme responsible for this process ( plasmin) is regulated by various activators and inhibitors.
Role in immune system
The coagulation system overlaps with the immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...
. Coagulation can physically trap invading microbes in blood clots. Also, some products of the coagulation system can contribute to the innate immune system
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is th ...
by their ability to increase vascular permeability and act as chemotactic agent
Chemotaxis (from ''chemical substance, chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell organism, single-cell or multicellular organisms direct their ...
s for phagocytic cell
Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek ', "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek ...
s. In addition, some of the products of the coagulation system are directly antimicrobial
An antimicrobial is an agent that kills microorganisms or stops their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. For example, antibiotics are used against bacteria, and antifungals ...
. For example, beta-lysine, an amino acid produced by platelets during coagulation, can cause lysis
Lysis ( ) is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ''lysate''. In molecular bio ...
of many Gram-positive bacteria
In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall.
Gram-positive bact ...
by acting as a cationic detergent.[Immunology – Chapter One: Innate (non-specific) immunity]
Gene Mayer, Ph.D. Immunology Section of Microbiology and Immunology On-line. University of South Carolina Many acute-phase proteins of inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
are involved in the coagulation system. In addition, pathogenic bacteria may secrete agents that alter the coagulation system, e.g. coagulase
Coagulase is a protein enzyme produced by several microorganisms that enables the conversion of fibrinogen to fibrin. In the laboratory, it is used to distinguish between different types of '' Staphylococcus'' isolates. Importantly, '' S. aureu ...
and streptokinase
Streptokinase (SK) is a thrombolytic medication activating plasminogen by nonenzymatic mechanism. As a medication it is used to break down clots in some cases of myocardial infarction (heart attack), pulmonary embolism, and arterial thromboembo ...
.
Assessment
Numerous tests are used to assess the function of the coagulation system:
* Common: aPTT
The partial thromboplastin time (PTT), also known as the activated partial thromboplastin time (aPTT or APTT), is a blood test that characterizes coagulation of the blood. A historical name for this measure is the kaolin-cephalin clotting time ...
, PT (also used to determine INR), fibrinogen
Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood ...
testing (often by the Clauss method), platelet count, platelet function testing (often by PFA-100
The PFA-100 (Platelet Function Assay or Platelet Function Analyser120 seconds) may indicate
the following;
* Anemia (hematocrit <0.28)
* Thrombocytopenia (platelet count < 100 x 10/L)
* A significant platelet function defect other than aspirin
Once ...
), thrombodynamics test.
* Other: TCT, bleeding time, mixing test (whether an abnormality corrects if the patient's plasma is mixed with normal plasma), coagulation factor assays, antiphospholipid antibodies, D-dimer, genetic tests (e.g. 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 (intrinsic) 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 (extrinsic) 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: Thus hemophilia A
Haemophilia A (or hemophilia A) is a genetic deficiency in clotting factor VIII, which causes increased bleeding and usually affects males. In the majority of cases it is inherited as an X-linked recessive trait, though there are cases which aris ...
, 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.
Role in disease
Coagulation defects may cause hemorrhage or thrombosis, and occasionally both, depending on the nature of the defect.
Platelet disorders
Platelet disorders are either congenital or acquired. Examples of congenital platelet disorders 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. They 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 (thrombocytopenia) is due to insufficient production (e.g., myelodysplastic syndrome or other bone marrow disorders), destruction by the immune system ( immune thrombocytopenic purpura), or consumption (e.g., thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, paroxysmal nocturnal hemoglobinuria, disseminated intravascular coagulation, heparin-induced thrombocytopenia). An increase in platelet count leading to elevated risk of thrombosis is called thrombocytosis, which may lead to formation of thromboembolisms.
Coagulation factor disorders
The best-known coagulation factor disorders are the hemophilias. The three main forms are hemophilia A
Haemophilia A (or hemophilia A) is a genetic deficiency in clotting factor VIII, which causes increased bleeding and usually affects males. In the majority of cases it is inherited as an X-linked recessive trait, though there are cases which aris ...
(factor VIII deficiency), hemophilia B (factor IX deficiency or "Christmas disease") and hemophilia C (factor XI deficiency, mild bleeding tendency).
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.
In acute or chronic liver failure, there is insufficient production of coagulation factors, possibly increasing risk of bleeding during surgery.
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
Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dig ...
of tissue. Most cases of venous thrombosis are due to acquired states (older age, surgery, cancer, immobility) or inherited thrombophilias (e.g., antiphospholipid syndrome
Antiphospholipid syndrome, or antiphospholipid antibody syndrome (APS or APLS), is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS provokes blood clots ( thrombosis) in both arteries and veins as well as pregna ...
, factor V Leiden, and various other genetic deficiencies or variants).
Pharmacology
Procoagulants
The use of adsorbent chemicals, such as zeolites, and other hemostatic agents are also used for sealing severe injuries quickly (such as in traumatic bleeding secondary to gunshot wounds). Thrombin and fibrin glue
Adhesive, also known as glue, cement, mucilage, or paste, is any non-metallic substance applied to one or both surfaces of two separate items that binds them together and resists their separation.
The use of adhesives offers certain advant ...
are used surgically to treat bleeding and to thrombose aneurysms. Hemostatic Powder Spray TC-325
Hemostatic Powder Spray TC-325 (Hemospray or TC-325) is an inert, highly absorptive mineral agent which is used for the treatment of gastrointestinal bleeding. Applied during endoscopy to bleeding lesions, TC-325 is derived from bentonite, and is ...
is used to treated gastrointestinal bleeding.
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 people 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 the need for blood products.
Anticoagulants
Anticoagulants and anti-platelet agents are amongst the most commonly used medications. Anti-platelet agents include aspirin
Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat in ...
, dipyridamole
Dipyridamole (trademarked as Persantine and others) is a nucleoside transport inhibitor and a PDE3 inhibitor medication that inhibits blood clot formation when given chronically and causes blood vessel dilation when given at high doses over a ...
, ticlopidine, clopidogrel, ticagrelor and prasugrel; the parenteral glycoprotein IIb/IIIa inhibitors are used during angioplasty. Of the anticoagulants, warfarin (and related coumarin
Coumarin () or 2''H''-chromen-2-one is an aromatic organic chemical compound with formula . Its molecule can be described as a benzene molecule with two adjacent hydrogen atoms replaced by a lactone-like chain , forming a second six-membered ...
s) and heparin
Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the trea ...
are the most commonly used. Warfarin affects the vitamin K-dependent clotting factors (II, VII, IX, X) and protein C and protein S, 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 in clinical use are other small molecular compounds that interfere directly with the enzymatic action of particular coagulation factors (the directly acting oral anticoagulants: dabigatran
Dabigatran, sold under the brand name Pradaxa among others, is an anticoagulant used to treat and prevent blood clots and to prevent stroke in people with atrial fibrillation. Specifically it is used to prevent blood clots following hip or ...
, rivaroxaban, apixaban, and edoxaban).
List of coagulation factors
History
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
Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood ...
, was thus named by Rudolf Virchow
Rudolf Ludwig Carl Virchow (; or ; 13 October 18215 September 1902) was a German physician, anthropologist, pathologist, prehistorian, biologist, writer, editor, and politician. He is known as "the father of modern pathology" and as the founde ...
(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". Arthus discovered in 1890 that calcium was essential in coagulation. Platelets were identified in 1865, and their function was elucidated by Giulio Bizzozero in 1882.
The theory that thrombin is generated by the presence of tissue factor was consolidated by Paul Morawitz in 1905. At this stage, it was known that ''thrombokinase/thromboplastin'' (factor III) is released by damaged tissues, reacting with ''prothrombin'' (II), which, together with calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
(IV), forms ''thrombin'', which converts fibrinogen into ''fibrin'' (I).
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 (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.[
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 recognized but etiologically elusive ]hemophilia A
Haemophilia A (or hemophilia A) is a genetic deficiency in clotting factor VIII, which causes increased bleeding and usually affects males. In the majority of cases it is inherited as an X-linked recessive trait, though there are cases which aris ...
; it was identified in the 1950s and is alternatively called ''antihemophilic globulin'' due to its capability to correct hemophilia A.[
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. 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.][
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.][
The view that the coagulation process is a "cascade" or "waterfall" was enunciated almost simultaneously by MacFarlane] in the UK and by Davie and Ratnoff in the US, respectively.
Nomenclature
The usage of Roman numeral
Roman numerals are a numeral system that originated in ancient Rome and remained the usual way of writing numbers throughout Europe well into the Late Middle Ages. Numbers are written with combinations of letters from the Latin alphabet, eac ...
s 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. 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.[
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.
]
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 non-mammalian animal known to use serine proteases for blood coagulation is the horseshoe crab.
See also
* Agglutination (biology)
* Post-vaccination embolic and thrombotic events
References
Further reading
*
*
External links
*
{{Authority control
Coagulation system
Blood