Coagulation

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel,
forming a blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel,
followed by repair. The process of coagulation involves activation, adhesion and aggregation of
platelets, as well as deposition and maturation of fibrin.

Coagulation begins almost instantly after an injury Coagulation

to the endothelium that lines a blood vessel.
Exposure of blood to the subendothelial space
initiates two processes: changes in platelets, and
the exposure of subendothelial platelet tissue factor
to coagulation 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
Blood coagulation pathways in vivo showing
simultaneously: additional coagulation factors
the central role played by thrombin
beyond factor VII (listed below) respond in a
cascade to form fibrin strands, which strengthen the Health Beneficial
platelet plug.[1]

Coagulation is highly conserved throughout biology. In all mammals, coagulation involves both cellular
components (platelets) and proteinaceous components (coagulation or clotting factors).[2][3] The
pathway in humans has been the most extensively researched and is the best understood.[4] Disorders
of coagulation can result in problems with hemorrhage, bruising, or thrombosis.[5]

List of coagulation factors

There are 13 traditional clotting factors, as named below,[6] and other substances necessary for
coagulation:
Coagulation factors and related substances

Type of
Number/Name Synonym(s) Function Associated genetic disorders Source Pathway(s)
molecule

Common
Forms fibrin Congenital afibrinogenemia pathway;
Factor I Fibrinogen threads in Plasma protein Liver
Familial renal amyloidosis converted
blood clots
into fibrin

Its active form

Common
(IIa) activates Thrombophilia pathway;
platelets,
Factor II* Prothrombin Prothrombin thrombophilia Plasma protein Liver converted
factors I, V, VII,
(Prothrombin G20210A)[7] into
VIII, XI, XIII,
thrombin
protein C

Co-factor of
Tissue factor factor VIIa, Damaged
Lipoprotein
Factor IIIII tissue which was cells and Extrinsic
mixture
thromboplastin formerly known platelets
as factor III

Required for
coagulation
Calcium factors to bind Diet,
Entire
to Inorganic ions platelets,
Factor IV Calcium ions process of
phospholipids, in plasma bone
coagulation
Ca2+ ions which were matrix
formerly known
as factor IV

Co-factor of
Proaccelerin factor X with
Extrinsic
which it forms Liver,
Factor V labile factor Activated protein C resistance Plasma protein and
the platelets
intrinsic
Ac-globulin prothrombinase
complex

Unassigned –
old name of
factor Va
(activated
Factor VI form of factor N/A N/A N/A

V)

accelerin
(formerly)

Factor VII* Proconvertin Activates Congenital factor VII Plasma protein Liver Extrinsic
factors IX, X; deficiency
 Serum increases rate
Prothrombin of catalytic
Conversion conversion of
Accelerator prothrombin
(SPCA) into thrombin

Stable factor

Antihemophilic
factor A Co-factor of
Platelets
factor IX with
Antihemophilic Plasma protein and
Factor VIII which it forms Hemophilia A Intrinsic
factor (AHF) factor endothelial
the tenase
cells
Antihemophilic complex
globulin (AHG)

Antihemophilic
factor B

Christmas Activates factor

factor X, forms tenase
Factor IX* Hemophilia B Plasma protein Liver Intrinsic
complex with
plasma
factor VIII
thromboplastin
component
(PTC)

Activates factor
Stuart-Prower II, forms Extrinsic
Factor X* factor prothrombinase Congenital Factor X deficiency Protein Liver and

Stuart factor complex with intrinsic

factor V

Plasma
thromboplastin
antecedent Activates factor
Factor XI (PTA) Hemophilia C Plasma protein Liver Intrinsic
IX

Antihemophilic
factor C

Intrinsic;
Activates XI, initiates
VII, prekallikrein clotting in
Factor XII Hageman factor Hereditary angioedema type III Plasma protein Liver
and vitro; also
plasminogen activates
plasmin

Factor XIII Fibrin-stabilizing Crosslinks Congenital factor XIIIa/b Plasma protein Liver, Common
factor fibrin threads deficiency platelets pathway;
stabilizes
fibrin;
 slows
down
fibrinolysis

Essential factor
to the hepatic
gamma-
glutamyl
carboxylase Gut
that adds a Phytyl- microbiota
carboxyl group substituted (e.g. E.
Vitamin K Clotting vitamin Vitamin K deficiency Extrinsic[10]
to glutamic naphthoquinone coli[9]),
acid residues derivative dietary
on factors II, sources
VII, IX and X, as
well as Protein
S, Protein C and
Protein Z[8]

Blood
Binds to VIII,
vessels'
von Willebrand mediates Blood
von Willebrand disease endothelia,
factor platelet glycoprotein
bone
adhesion
marrow[11]

Activates XII
and Prekallikrein/Fletcher factor
Prekallikrein Fletcher factor
prekallikrein; deficiency
cleaves HMWK

Activates
Kallikrein
plasminogen

Supports
High- Fitzgerald reciprocal
molecular- factor activation of
Kininogen deficiency
weight factors XII, XI,
kininogen HMWK and
prekallikrein

Mediates cell Glomerulopathy with

Fibronectin
adhesion fibronectin deposits

Inhibits factors
Antithrombin
IIa, Xa, IXa, XIa, Antithrombin III deficiency
III
and XIIa

Heparin Inhibits factor Heparin cofactor II deficiency

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

Inactivates
Protein C factors Va and Protein C deficiency
VIIIa

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

Mediates
thrombin
adhesion to
Protein Z phospholipids Protein Z deficiency
and stimulates
degradation of
factor X by ZPI

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

Converts to
plasmin, lyses Plasminogen deficiency type I
Plasminogen
fibrin and other (ligneous conjunctivitis)
proteins

α2-Antiplasmin Inhibits plasmin Antiplasmin deficiency

Inhibits
α 2- plasmin,
Macroglobulin kallikrein, and
thrombin

Tissue Familial hyperfibrinolysis

Activates
plasminogen t-PA or TPA
plasminogen Thrombophilia
activator

Activates
Urokinase Quebec platelet disorder
plasminogen

Plasminogen Inactivates tPA

Plasminogen activator
activator PAI-1 and urokinase
inhibitor-1 deficiency
inhibitor-1 (endothelial PAI
Plasminogen
Inactivates tPA Plasminogen activator
activator PAI-2
and urokinase inhibitor-1 deficiency
inhibitor-2

Pathological
activator of
Cancer factor X; linked
procoagulant to thrombosis
in various
cancers[12]

* Vitamin K is required for biosynthesis of these clotting factors[8]

Physiology

The interaction of vWF and GP1b alpha. The GP1b

receptor on the surface of platelets allows the
platelet to bind to vWF, which is exposed upon
damage to vasculature. The vWF A1 domain
(yellow) interacts with the extracellular domain of
GP1ba (blue).

Physiology of blood coagulation is based on hemostasis, the normal bodily process that stops
bleeding. Coagulation is a part of an integrated series of haemostatic reactions, involving plasma,
platelet, and vascular components.[13]

Hemostasis consists of four main stages:

Vasoconstriction (vasospasm or vascular spasm): Here, this refers to contraction of smooth

muscles in the tunica media layer of endothelium (blood vessel wall).

Activation of platelets and platelet plug formation:

Platelet activation: Platelet activators, such as platelet activating factor and thromboxane A2,[14]
activate platelets in the bloodstream, leading to attachment of platelets' membrane receptors
 (e.g. glycoprotein IIb/IIIa[15]) to extracellular matrix[16] proteins (e.g. von Willebrand factor[17]) on
cell membranes of damaged endothelial cells and exposed collagen at the site of injury.[18]

Platelet plug formation: The adhered platelets aggregate and form a temporary plug to stop
bleeding. This process is often called "primary hemostasis".[19]

Coagulation cascade: It is a series of enzymatic reactions that lead to the formation of a stable
blood clot. The endothelial cells release substances like tissue factor, which triggers the extrinsic
pathway of the coagulation cascade. This is called as "secondary hemostasis".[20]

Fibrin clot formation: Near the end of the extrinsic pathway, after thrombin completes conversion of
fibrinogen into fibrin,[21] factor XIIIa (plasma transglutaminase;[21] activated form of fibrin-stabilizing
factor) promotes fibrin cross-linking, and subsequent stabilization of fibrin, leading to the formation
of a fibrin clot (final blood clot), which temporarily seals the wound to allow wound healing until its
inner part is dissolved by fibrinolytic enzymes, while the clot's outer part is shed off.

After the fibrin clot is formed, clot retraction occurs and then clot resolution starts, and these two
process are together called "tertiary hemostasis". Activated platelets contract their internal actin and
myosin fibrils in their cytoskeleton, which leads to shrinkage of the clot volume. Plasminogen
activators, such as tissue plasminogen activator (t-PA), activate plasminogen into plasmin, which
promotes lysis of the fibrin clot; this restores the flow of blood in the damaged/obstructed blood
vessels.[22]

Vasoconstriction

When there is an injury to a blood vessel, the endothelial cells can release various vasoconstrictor
substances, such as endothelin[23] and thromboxane,[24] to induce the constriction of the smooth
muscles in the vessel wall. This helps reduce blood flow to the site of injury and limits bleeding.

Platelet activation and platelet plug formation

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.[25]
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, forming a platelet plug and thereby completing primary
hemostasis).[26]

Coagulation cascade

The classical blood coagulation pathway[27]

 Modern coagulation pathway. Hand-
drawn composite from similar
drawings presented by Professor
Dzung Le, MD, PhD, at UCSD Clinical
Chemistry conferences on 14 and 21
October 2014. Original schema from
Introduction to Hematology by
Samuel I. Rapaport. 2nd ed.;
Lippencott: 1987. Dr Le added the
factor XI portion based on a paper
from about year 2000. Dr. Le's similar
drawings presented the development
of this cascade over 6 frames, like a
comic.

The coagulation cascade of secondary hemostasis has two initial pathways which lead to fibrin
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 (inactive enzyme precursor) of a serine protease and 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
a appended to indicate an active form.[27]

The coagulation factors are generally enzymes called serine proteases, which act by cleaving
downstream proteins. The exceptions are tissue factor, FV, FVIII, FXIII.[28] Tissue factor, FV and FVIII
are glycoproteins, and Factor XIII is a transglutaminase.[27] 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.[29]

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:[27]

1. 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).

2. TF-FVIIa activates FIX and FX.

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

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

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

6. 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.

7. 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 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 blood 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,[27] and innate
immunity.[30] Despite this, interference with the pathway may confer protection against thrombosis
without a significant bleeding risk.[30]

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.[31]

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.[32]

Thrombin functions not only to convert fibrinogen to fibrin, it also activates Factors VIII and V and their
inhibitor protein C (in the presence of thrombomodulin). By activating Factor XIII, covalent bonds are
formed that crosslink the fibrin polymers that form from activated monomers.[27] This stabilizes the
fibrin network.[33]

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.[27]

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. 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.[34]

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.[35]

Fibrinolysis

Eventually, blood clots are reorganized and resorbed by a process termed fibrinolysis. The main
enzyme responsible for this process is plasmin, which is regulated by plasmin activators and plasmin
inhibitors.[36]

Role in immune system

The coagulation system overlaps with the immune system. Coagulation can physically trap invading
microbes in blood clots. Also, some products of the coagulation system can contribute to the innate
immune system by their ability to increase vascular permeability and act as chemotactic agents for
phagocytic cells. In addition, some of the products of the coagulation system are directly
antimicrobial. For example, beta-lysine, an amino acid produced by platelets during coagulation, can
cause lysis of many Gram-positive bacteria by acting as a cationic detergent.[37] Many acute-phase
proteins of inflammation are involved in the coagulation system. In addition, pathogenic bacteria may
secrete agents that alter the coagulation system, e.g. coagulase and streptokinase.[38]

Immunohemostasis is the integration of immune activation into adaptive clot formation.

Immunothrombosis is the pathological result of crosstalk between immunity, inflammation, and
coagulation. Mediators of this process include damage-associated molecular patterns and pathogen-
associated molecular patterns, which are recognized by toll-like receptors, triggering procoagulant and
proinflammatory responses such as formation of neutrophil extracellular traps.[39]

Cofactors

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

Calcium and phospholipids

Calcium and phospholipids (constituents of platelet membrane) are required for the tenase and
prothrombinase complexes to function.[40] 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.[41] 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.[42]

Vitamin K

Vitamin K is an essential factor to the 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 of
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. Vitamin K deficiency from other causes (e.g., in malabsorption) 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.[43]
Regulators

Coagulation with arrows for negative and positive feedback.

Several mechanisms keep platelet activation and the coagulation cascade in check.[44] Abnormalities
can lead to an increased tendency toward thrombosis:

Protein C and Protein S

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 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.[44]

Antithrombin

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 of heparins (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.[44]
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.[45]

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, 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.[36]

Medical assessment

Numerous medical tests are used to assess the function of the coagulation system:[3][46]

Common: aPTT, PT (also used to determine INR), fibrinogen testing (often by the Clauss fibrinogen
assay),[47] platelet count, platelet function testing (often by PFA-100), 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 activation system,
and can be measured by the activated partial thromboplastin time (aPTT) test.[48]

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.[49] PT results are often reported
as ratio (INR value) to monitor dosing of oral anticoagulants such as warfarin.[50]

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 fibrinogen assay.[47] 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, 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.
Deficiencies of common pathway factors prothrombin, fibrinogen, FX, and FV will prolong both aPTT
and 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 prolong PT, aPTT, thrombin time, and
reptilase time.

Role in disease

Coagulation defects may cause hemorrhage or thrombosis, and occasionally both, depending on the
nature of the defect.[51]
 The GP1b-IX receptor
complex. This protein
receptor complex is found
on the surface of platelets,
and in conjunction with
GPV allows for platelets to
adhere to the site of injury.
Mutations in the genes
associated with the
glycoprotein Ib-IX-V
complex are characteristic
of Bernard–Soulier
syndrome.

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).[52] An increase in platelet count is called
thrombocytosis, which may lead to formation of thromboembolisms; however, thrombocytosis may be
associated with increased risk of either thrombosis or hemorrhage in patients with myeloproliferative
neoplasm.[53]

Coagulation factor disorders

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).[54]

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.[55]

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 venous thrombosis are due to acquired states (older age, surgery, cancer, immobility).
Unprovoked venous thrombosis may be related to inherited thrombophilias (e.g., factor V Leiden,
antithrombin deficiency, and various other genetic deficiencies or variants), particularly in younger
patients with family history of thrombosis; however, thrombotic events are more likely when acquired
risk factors are superimposed on the inherited state.[56]

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 are used surgically to treat bleeding and to thrombose aneurysms.
Hemostatic Powder Spray TC-325 is used to treated gastrointestinal bleeding.

Desmopressin is used to improve platelet function by activating arginine vasopressin receptor 1A.[57]

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 sometimes used 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.

Rivaroxaban drug bound to the coagulation factor

Xa. The drug prevents this protein from activating
the coagulation pathway by inhibiting its enzymatic
activity.

Anticoagulants

Anticoagulants and anti-platelet agents (together "antithrombotics") are amongst the most commonly
used medications. Anti-platelet agents include aspirin, dipyridamole, ticlopidine, clopidogrel, ticagrelor
and prasugrel; 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) 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, argatroban, bivalirudin and dabigatran). 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, rivaroxaban, apixaban, and edoxaban).[58]
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, 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".[59][60] Arthus discovered in 1890 that calcium was essential in coagulation.[61][62]
Platelets were identified in 1865, and their function was elucidated by Giulio Bizzozero in 1882.[63]

The theory that thrombin is generated by the presence of tissue factor was consolidated by Paul
Morawitz in 1905.[64] At this stage, it was known that thrombokinase/thromboplastin (factor III) is
released by damaged tissues, reacting with prothrombin (II), which, together with calcium (IV), forms
thrombin, which converts fibrinogen into fibrin (I).[65]

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.[65]

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;
it was identified in the 1950s and is alternatively called antihemophilic globulin due to its capability to
correct hemophilia A.[65]

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.[65]

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.[65]

The view that the coagulation process is a "cascade" or "waterfall" was enunciated almost
simultaneously by MacFarlane[66] in the UK and by Davie and Ratnoff[67] in the US, respectively.

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.[68] 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.[65]

Factor VI is unassigned, as 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. 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.[69] Exemplifying the close links between
coagulation and inflammation, the horseshoe crab has a primitive response to injury, carried out by
cells known as amoebocytes (or hemocytes) which serve both hemostatic and immune
functions.[39][70]

See also

Agglutination (biology)
Medicine portal
Antihemorrhagic

Post-vaccination embolic and thrombotic events

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Further reading

Hoffman, Maureane; Monroe, Dougald (2001). "A Cell-based Model of Hemostasis". Thrombosis and
Haemostasis. 85 (6): 958–965. doi:10.1055/s-0037-1615947 (https://doi.org/10.1055%2Fs-0037-16
15947) . PMID 11434702 (https://pubmed.ncbi.nlm.nih.gov/11434702) .

Hoffman M, Monroe DM (February 2007). "Coagulation 2006: a modern view of hemostasis".

Hematology/Oncology Clinics of North America. 21 (1): 1–11. doi:10.1016/j.hoc.2006.11.004 (http
s://doi.org/10.1016%2Fj.hoc.2006.11.004) . PMID 17258114 (https://pubmed.ncbi.nlm.nih.gov/17
258114) .

External links

Media related to Coagulation at Wikimedia Commons