Coagulation factor XII, also known as Hageman factor, is a
plasma
Plasma or plasm may refer to:
Science
* Plasma (physics), one of the four fundamental states of matter
* Plasma (mineral), a green translucent silica mineral
* Quark–gluon plasma, a state of matter in quantum chromodynamics
Biology
* Blood pla ...
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, respo ...
. It is the
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 active ...
form of factor XIIa, an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
() of the
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. ...
(or serine endopeptidase) class. In humans, factor XII is encoded by the ''F12''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Structure
Human Factor XII is 596
amino acids
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
long and consists of two chains, the heavy chain (353
residues) and light chain (243 residues) held together by a
disulfide bond
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
. It is 80,000 daltons. Its heavy chain contains two
fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
-type domains (type I and II), two
epidermal growth factor
Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-k Da and has 53 amino acid residues and three intramolecular disulfide bonds.
EGF was originally descr ...
-like domains, a kringle domain, and a proline-rich region, and its light chain contains the protease domain. The structure of the FnI-EGF-like tandem
domain
Domain may refer to:
Mathematics
*Domain of a function, the set of input values for which the (total) function is defined
**Domain of definition of a partial function
**Natural domain of a partial function
**Domain of holomorphy of a function
* Do ...
of coagulation factor XII has been solved by
X-ray crystallography
X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
.
Crystal structures of the FXII light chain has also been determined unbound (β-FXII) and bound (β-FXIIa) to
inhibitors.
Factor XII (FXII, Hageman factor) is a plasma glycoprotein of approximately 90 kDa molecular weight is part of the
coagulation
Coagulation, also known as clotting, is the process by which blood changes from a liquid 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 o ...
cascade and activates
factor XI
Factor XI or plasma thromboplastin antecedent is the zymogen form of factor XIa, one of the enzymes of the coagulation cascade. Like many other coagulation factors, it is a serine protease. In humans, Factor XI is encoded by the ''F11'' gene.
...
and
prekallikrein
Prekallikrein (PK), also known as Fletcher factor, is an 85,000 Mr serine protease that complexes with high-molecular-weight kininogen. PK is the precursor of plasma kallikrein, which is a serine protease that activates kinins. PK is cleaved to pr ...
in vitro. Factor XII itself is activated to factor XIIa by negatively charged surfaces, such as glass. This is the starting point of the intrinsic pathway. Factor XII can also be used to start coagulation cascades in laboratory diagnostic coagulation assays called activated partial thromboplastin times (aPTT).
In vivo, factor XII is activated by binding (contact) to
polyanions
Polyelectrolytes are polymers whose repeating units bear an electrolyte group. Polycations and polyanions are polyelectrolytes. These groups dissociate in aqueous solutions (water), making the polymers charged. Polyelectrolyte properties are th ...
termed contact-activation. Multiple polymers, the white clay material kaolin and glass are non-physiological factor XII contact activators. Activated platelets release inorganic polymers,
polyphosphate
Polyphosphates are salts or esters of polymeric oxyanions formed from tetrahedral PO4 (phosphate) structural units linked together by sharing oxygen atoms. Polyphosphates can adopt linear or a cyclic ring structures. In biology, the polyphosphate e ...
s. Contact to polyphosphates activates factor XII and initiates
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 platele ...
formation by the intrinsic pathway of coagulation with critical importance for
thrombus
A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of c ...
formation and the factor XII-activated pro inflammatory kallikrein kinin-system. Targeting polyphosphates with
phosphatase
In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...
s interfered with procoagulant activity of activated
platelet
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
s and blocked platelet-induced thrombosis in mice. Addition of polyphosphates restored defective plasma clotting of
Hermansky–Pudlak syndrome
Heřmanský–Pudlák syndrome (often written Hermansky–Pudlak syndrome or abbreviated HPS) is an extremely rare autosomal recessive disorder which results in oculocutaneous albinism (decreased pigmentation), bleeding problems due to a platelet ...
patients, indicating that the inorganic polymer is the endogenous factor XII activator in vivo. Platelet polyphosphate-driven factor XII activation provides the link from primary hemostasis (formation of a
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 to ...
) to secondary hemostasis (fibrin meshwork formation).
Polyphosphate exerts differential effects on plasma clotting in test tubes ex vivo, depending on polymer size and it was shown in vitro that platelet-size soluble polyphosphates induce little activaton of factor XII in solution but that they are accelerators of thrombin-induced activation of factor XI. The mystery was solved upon the discovery that short chain polyphosphate forms insoluble calcium-rich nanoparticles in vivo. These aggregates accumulate on the platelet surface and activate factor XII independently of the chain length go the individual polymer.
Regulation of polyphosphates in platelets has remained poorly understood. Combinations of systems biology, genetics and functional analyses has identified the phosphate-exporter XPR1 as important regulator of polyphosphates in platelets. Targeting XPR1 increases polyphosphate content and leads to accelerated arterial and venous thrombosis in mouse models.
Based on the seminar role of factor XII in thrombosis while sparing haemostats, targeting the protease has emerged as a promising drug traget for safe anticoagulant drugs that in contrast to currently used anticoagulants, do not increase bleeding. Multiple factor XII inhibitors have been developed and some of them are in clinical trials
Genetics
The
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
for factor XII is located on the tip of the long arm of the fifth
chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
(5q33-qter).
Role in disease
Factor XII deficiency is a rare disorder that is inherited in an
autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
manner.
Unlike other clotting factor deficiencies, factor XII deficiency is totally asymptomatic and does not cause excess bleeding.
Mice lacking the gene for factor XII, however, are less susceptible to
thrombosis
Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...
. The protein seems to be involved in the later stages of clot formation rather than the first occlusion of damages in the blood vessel wall.
Factor XII does play an important role in clot formation during ''in vitro'' measurements of the
partial thromboplastin time
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 ( ...
, which causes these measurements to be markedly prolonged in patients with factor XII deficiency, usually well beyond even what is seen in hemophilia A, hemophilia B, or factor XI deficiency.
As a result, the main concern related to factor XII deficiency is the unnecessary testing, delay in care, worry, etc. that may be prompted by the abnormal lab result.
All of this, including the mechanism of inheritance, also holds true for the other contact factors,
prekallikrein
Prekallikrein (PK), also known as Fletcher factor, is an 85,000 Mr serine protease that complexes with high-molecular-weight kininogen. PK is the precursor of plasma kallikrein, which is a serine protease that activates kinins. PK is cleaved to pr ...
(Fletcher factor) and high molecular weight
kininogen Kininogens are precursor proteins for kinins, biologically active polypeptides involved in blood coagulation, vasodilation, smooth muscle contraction, inflammatory regulation, and the regulation of the cardiovascular and renal systems.
Types o ...
.
Excess levels of factor XII can predispose individuals towards greater risk of
venous thrombosis
Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...
due to factor XII's role as one of the catalysts for conversion of plasminogen to its active fibrinolytic form of
plasmin
Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is encoded ...
.
Factor XII is also activated by
endotoxin
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer ...
s, especially
lipid A
Lipid A is a lipid component of an endotoxin held responsible for the toxicity of gram-negative bacteria. It is the innermost of the three regions of the lipopolysaccharide (LPS), also called endotoxin molecule, and its hydrophobic nature allows it ...
in vitro.
Experimental mouse models have suggested a role of FXII in multiple sclerosis.
History
Hageman factor was first discovered in 1955 when a routine preoperative
blood sample
In medicine, sampling is gathering of matter from the body to aid in the process of a medical diagnosis and/or evaluation of an indication for treatment, further medical tests or other procedures. In this sense, the sample is the gathered matter ...
of the 37-year-old railroad brakeman John Hageman (1918) was found to have prolonged clotting time in test tubes, even though he had no
hemorrhagic symptoms. Hageman was then examined by hematologist
Oscar Ratnoff, who found that Hageman lacked a previously unidentified clotting factor.
Ratnoff later found that the Hageman factor deficiency is an
autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
disorder, after examining several related people who had the deficiency. Paradoxically,
pulmonary embolism
Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain p ...
contributed to Hageman's death after an occupational accident in 1968. Since then, case studies and clinical studies identified an association between
thrombosis
Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...
and Factor XII deficiency.
Hepatocytes
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, b ...
express blood coagulation factor XII.
Currently produced
QuikClot
QuikClot is a brand of hemostatic wound dressing, that contains an agent that promotes blood clotting. It is primarily used by militaries and law enforcement to treat hemorrhaging from trauma.
History
Using zeolite as a clotting agent was ...
products, produced and marketed primarily for use in
battlefield medicine
Battlefield medicine, also called field surgery and later combat casualty care, is the treatment of wounded combatants and non-combatants in or near an area of combat. Civilian medicine has been greatly advanced by procedures that were first ...
to treat penetrating trauma (such as
gunshot wounds
A gunshot wound (GSW) is a penetrating injury caused by a projectile (e.g. a bullet) from a gun (typically firearm or air gun). Damages may include bleeding, bone fractures, organ damage, wound infection, loss of the ability to move part ...
and
stab wounds
A stab wound is a specific form of penetrating trauma to the skin that results from a knife or a similar pointed object. While stab wounds are typically known to be caused by knives, they can also occur from a variety of implements, including bro ...
), and other injuries that are known to commonly cause
exsanguination
Exsanguination is death caused by loss of blood. Depending upon the health of the individual, people usually die from losing half to two-thirds of their blood; a loss of roughly one-third of the blood volume is considered very serious. Even a sing ...
(such as
blast injury
A blast injury is a complex type of physical trauma resulting from direct or indirect exposure to an explosion. Blast injuries occur with the detonation of high-order explosives as well as the deflagration of low order explosives. These injurie ...
), are used with the overarching goal of increasing the time between the blood loss occurring, and the patient succumbing to the blood loss. The purpose of increasing this time is so that the patient may reaching a higher level of medical care before succumbing from their injuries. These products use a
Kaolinite
Kaolinite ( ) is a clay mineral, with the chemical composition Al2 Si2 O5( OH)4. It is an important industrial mineral. It is a layered silicate mineral, with one tetrahedral sheet of silica () linked through oxygen atoms to one octahedral ...
-based coating, applied to the bandages by the manufacturer before packaging and sale. This coating, when applied to an open wound via the application of the bandages, directly promotes blood clotting by activating Factor XII in the coagulation cascade.
Also, due to the active ingredient nature of
Kaolinite
Kaolinite ( ) is a clay mineral, with the chemical composition Al2 Si2 O5( OH)4. It is an important industrial mineral. It is a layered silicate mineral, with one tetrahedral sheet of silica () linked through oxygen atoms to one octahedral ...
, the activation of the Factor XII occurs in both an earlier amount of time than it otherwise would, and at an increased, more rapid rate than it otherwise would.
This coating is widely considered amongst
combat medics
A combat medic, or healthcare specialist, is responsible for providing emergency medical treatment at a point of wounding in a combat or training environment, as well as primary care and health protection and evacuation from a point of injury ...
to be vastly superior to the older
QuikClot
QuikClot is a brand of hemostatic wound dressing, that contains an agent that promotes blood clotting. It is primarily used by militaries and law enforcement to treat hemorrhaging from trauma.
History
Using zeolite as a clotting agent was ...
powder formulation, which was poured into wounds, due to the fact that the older formulation used bead-form
Zeolite
Zeolites are microporous, crystalline aluminosilicate materials commonly used as commercial adsorbents and catalysts. They mainly consist of silicon, aluminium, oxygen, and have the general formula ・y where is either a metal ion or H+. These pos ...
, a mineral which promotes the coagulation cascade, due to the fact that the reaction between the Zeolite powder and the blood inside the wound site was an
Exothermic
In thermodynamics, an exothermic process () is a thermodynamic process or reaction that releases energy from the system to its surroundings, usually in the form of heat, but also in a form of light (e.g. a spark, flame, or flash), electricity (e ...
one, sometimes so intensely that it caused cases of
second degree burns on the inside surface of the wound. This, obviously, caused extreme pain to the patient, often more-so than the initial injury was causing them at the time (assuming the patient was still conscious at the time of the application of the powder).
This effect is often seen in movies and TV programs, with the QuikClot powder being poured into wounds, and the patient screaming out in pain as their wounds were violently burned on the inside surface of the wounds. This created a common misconception, which persists to this day, that commonly used QuikClot products still use this method of clot promotion (
Zeolite
Zeolites are microporous, crystalline aluminosilicate materials commonly used as commercial adsorbents and catalysts. They mainly consist of silicon, aluminium, oxygen, and have the general formula ・y where is either a metal ion or H+. These pos ...
powder) to this day. However, Zeolite-based clotting products are no longer widely used by militaries and police departments throughout the western world, as they have been widely supplanted by the Kaolinite-based bandage products, which do not cause any exothermic reaction whatsoever, nor do they have the absolute-requirement of the application of the product exclusively to the inside-surface of the wound.
References
Further reading
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External links
* The
MEROPS
MEROPS is an online database for peptidases (also known as proteases, proteinases and proteolytic enzymes) and their inhibitors. The classification scheme for peptidases was published by Rawlings & Barrett in 1993, and that for protein inhibitor ...
online database for peptidases and their inhibitors
S01.211*
*
{{DEFAULTSORT:Factor Xii
Coagulation system
EC 3.4.21
Zymogens