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Coagulation factor

Various protein components involved in blood coagulation

Coagulation factors are involved Blood coagulation Various processes protein Components. Its physiological function is to When bleeding Is activated, and platelet Stick together and plug the leak on the blood vessel. This process is called coagulation. whole Coagulation process Generally, it can be divided into Two stages , Coagulation activation of zymogen And gelatinous fibrin Formation of. They are partly generated by the liver. Can be coumarin Inhibited. For uniform naming, the World Health Organization uses Roman numerals The number includes coagulation factors I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, Xlll, etc. The coagulation factors discovered after factor XIII have been verified for many years Coagulation function , no decisive effect, no longer included in the number of coagulation factors. Factor VI is actually the fifth activated factor, and the name of factor VI has been canceled.

Chinese name: Coagulation factor
Foreign name: blood coagulation factor

Type: Protein composition
Named by: world health organization
Physiological function: Plug the leak on the blood vessel

catalog

five Fibrinogenesis
six Related diseases

Main coagulation factors

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Factor I, Fibrinogen

Factor II, prothrombin （ Coagulant ）

Factor III, tissue factor （ prothrombin Enzymes)

Factor IV, calcium factor (Ca2+)

Factor V, procoagulant, variable factor

Factor VII, Transition Acceleration factor Precursors, Prothrombin kinase Prothrombin, Assisted Prothrombin Kinase

Factor VIII, Anti hemophilia Globulin A (AHG A), Antihemophilic factor A（ AHF A) , Platelet Cofactor 1. Hemophilia factor VIII or A

Factor IX, antihemophilic globulin B (AHG B), antihemophilic factor B (AHF B), hemophilic factor IX or B

Factor X, STURT (- POWER) - F, self prothrombin C

Factor XI, ROSENTHAL factor, Antihemophilic globulin C

Factor XII, HAGEMAN factor, surface factor

Factor XIII, fibrin Stability factor

Coagulation factors

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Coagulopathy

FITZGERALD factor

FLETCHER factor（ Kallikrein Original)

Von Willebrand factor

Disqualified coagulation factor

Factor VI, procoagulant globulin: actually, it is the fifth factor after activation.

These factors work together to cause coagulation.

If one or more coagulation factors are missing, it will lead to hemophilia 。

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Synonyms Abbreviation symbols Plasma concentration storage stability in serum participates in coagulation pathway

Ⅰ Fibrinogen Fg 2000-4000 No stable common

Ⅱ prothrombin 10% - 12% of 200 are stable and common

Ⅲ Tissue coagulation kinase TF exogenous

Ⅴ Proaccelerator 5-10 without instability

Ⅶ Pretransformation 2 has stable exogenous

Ⅷ Antihemophilic factor AHG ＜ 10, no unstable endogenous

Ⅸ Plasma coagulation kinase PTC 3-4 has relatively stable endogenous

Ⅹ Stuart Prower factors 6-8 are stable and common

XI Plasma coagulation kinase precursor PTA 4 Stable endogenous

XII Stable endogenous receptor HF 2.9

PK prokallikrein PK 1.5-5.0 has stable endogenous

HMWK high molecular weight kininogen HMWK 7 has stable endogenous

XIII Fibrin stabilizing factor FSF 25 has no stable common

clinical application

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PT extension

It is generally believed that PT prolongation represents that the activity of coagulation factors II, V, VII and X is lower than normal or the presence of anticoagulant substances. liver function Slightly damaged, PT is still normal, it is only Hepatoparenchymal cells Only when it is seriously damaged can it be significantly prolonged. Only judged by PT hepatopathy patient Coagulation function Exceptions and Hepatocyte injury The degree is not enough. If the activity of coagulation factors is measured at the same time, it may be more valuable.

Liver Disease and Coagulation Factor II

Most studies believe that Acute hepatitis and chronic hepatitis In mild patients, the activity of coagulation factor II was normal or slightly decreased; Chronic hepatitis moderate, severe and cirrhosis In patients, the activity level of coagulation factor II decreased significantly, indicating that the degree of its reduction is similar to that of Hepatocyte The degree of damage is closely related. Some studies believe that it is abnormal prothrombin （ protein -Ⅱ induced by vitamin Kabscence, PIVKA - Ⅱ) Primary liver cancer Diagnosis of, partial AFP PIVKA - Ⅱ is positive in patients with negative primary liver cancer Small hepatocellular carcinoma The positive rate of PIVKA - Ⅱ in patients is higher than that in AFP, which is also helpful to the condition change and curative effect judgment of primary liver cancer Joint testing AFP and PIVKA - Ⅱ.

Coagulation factor V

Coagulation factor

Research shows that the activity of coagulation factor V decreases only when the liver function is decompensated or severe liver disease occurs, so it is considered as a judgment for patients with liver disease prognosis Good indicators. Izumi and other studies show that: Acetaminophen In patients with induced fulminant hepatic failure requiring liver transplantation, when the activity of coagulation factor V is less than 20% positive predictive value 0.49, 0.57 when<10%; However, those induced by other reasons need liver transplantation Fulminant hepatic failure For patients with coagulation factor V activity<20%, the positive predictive value for death is 0.85, and 1.00 for patients with coagulation factor V activity<10%. Therefore, it is considered that coagulation factor V activity is the best prognostic factor for patients with non acetaminophen induced fulminant hepatic failure Forecast indicators 。 Zou Zhengsheng and other researchers believe that the level of coagulation factor V is more specific than PTA Severe hepatitis The combination of the two may help to diagnose severe hepatitis earlier and more accurately. At the same time, it is pointed out that the detection of factor V of severe hepatitis should be strengthened and the role of factor V in hepatic failure Patient line Liver transplantation Study on the main screening indicators. The activity of coagulation factor V is not only used to judge the prognosis, but also closely related to the formation of thrombus Portal vein thrombosis Forecast indicators of.

Coagulation factor Ⅶ

Coagulation factor Ⅶ half life The shortest time (4~6h), low plasma content (0.5~2mg/L), so it can be used as a liver disease patient protein synthesis Early stage of hypofunction Diagnostic indicators 。 Rodriguez Inigo is waiting Chronic liver disease Patient passes Liver biopsy tissue in site hybridization The expression of coagulation factor Ⅶ and hepatic fibrosis The degree of fibrosis is negatively correlated, which can be used as an index to predict the degree of fibrosis. The activity of coagulation factor Ⅶ is also closely related to the prognosis. For example, Violi and other researchers believe that the activity of coagulation factor Ⅶ is less than 34% cirrhosis 93% of patients died within 10 months of follow-up, so it is considered to be an early predictor of the prognosis of patients with cirrhosis, which can better identify candidates for liver transplantation. The activity of coagulation factor Ⅶ in patients with cirrhosis can be significantly reduced, and the deficiency of coagulation factor Ⅶ can lead to the change of platelet activity platelet count Reduce Bleeding time Prolonged, so for patients with liver cirrhosis who have invasive diagnosis and treatment, the activity of coagulation factor Ⅶ should also be used for bleeding Risk And not just the platelet count. In addition to diagnosis, recombinant coagulation factor Ⅶ can effectively correct abnormal coagulation in patients with liver disease, which is conducive to the invasive examination.

Coagulation factor Ⅷ

Coagulation factor Ⅷ Not only by Hepatocyte It is produced by the sinus endothelial cells And Kupffer cell It can be produced by other tissues such as kidney. Sinus endothelial cells and Kupffer cells still maintain the synthesis of coagulation factor VIII when the synthesis function of hepatocytes declines; Decreased liver clearance function, endotoxin And immune factors stimulate its synthesis and release. Van Willebrand factor (vWF) is mainly synthesized outside the liver. Patients with liver cirrhosis may be due to Endotoxemia ， vascular endothelial cell Abnormal function increases its release; The vWF decomposition protease reduced its decomposition and also increased its plasma level. In most cases Viral hepatitis The activity of coagulation factor Ⅷ and vWF in patients were significantly increased. But liver disease is complicated DIC However, due to the large consumption of coagulation factors, the activity level of coagulation factor Ⅷ is reduced, so China takes the activity of coagulation factor Ⅷ less than 50% of normal as one of the necessary conditions for the diagnosis of liver disease with DIC.

participate in Blood coagulation Various components of the process; Most of them are sugary Serine protease 。 whole Coagulation process Generally, it can be divided into Two stages ， prothrombin Activation and gelatinous fibrin formation.

Prothrombin activation

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Activate the system

activation

There are endogenous and Exogenous Two activation systems. The former refers to cardiovascular Damaged intima or blood flowing out of the body through contact with abnormal surface Activation factor Ⅻ（Hageman factor）。 The latter is due to tissue damage Release factor III, thus activating factor VII. Both can initiate a series of chain reactions and converge at factor X, eventually leading to prothrombin Activation and fibrin formation.

Endogenous activation system

The activation pathway of the whole thrombin is shown in Figure 2. When blood and negatively charged collagen protein (outer wall of skin blood vessel) or allogeneic surface (such as kaolin , glass, etc.) Zymogen activation The latter not only activates factor XI, but also relaxes the plasma bradykinin Release enzyme activation. Activated Kallikrein At high molecular weight Kininogen Under the promotion of Proteolytic enzyme ）, make factor XII f. This is Yizheng Feedback effect Either XII a or XII f have the same vitality. The activated XIa then activated factor Ⅸ in the presence of Ca2+. Factor XII is composed of 596 Amino acid residue Factor XI is composed of two subunits, each of which contains 607 amino acid residues, and its structure is similar to that of plasma kallikrein.

Factor Ⅸ is composed of 416 amino acid residues. When activated, it releases a peptide segment, forming Disulfide bond Two links Peptide chain 。 And phospholipid The binding position is light chain , while enzyme catalysis Active site Then heavy chain 。 The activated factor Ⅸ a forms a complex with factor Ⅷ in the presence of Ca2+and phospholipids, which activates factor X to factor Xa. In normal Physiological conditions Lecithin consists of platelet Yes, factor Ⅸ a starts in this reaction Enzyme catalysis Factor Ⅷ only plays a regulatory role, because it can also combine with factor X, thus increasing the local substrate concentration. In fact, factor Ⅸ a alone can also activate factor X, but with the participation of factor VIII reaction rate It can be increased thousands of times. Factor VIII also needs the activation of factor Xa and thrombin to become factor VIII ', which is also a positive feedback effect. Factor VIII is a molecular weight of more than one million glycoprotein , dissociated into subunits with molecular weight of about 200000 at high salt concentration. If the body is due to Genetic defect , Factor VIII is deficient or inactive, which is clinically congenital hemophilia 。 Therefore, factor VIII is also called Antihemophilic factor 。

Factor X is composed of 448 amino acid residues. When activated, it releases a peptide segment to form two peptide chains linked by disulfide bonds. It is similar to factor Ⅸ, phospholipid and factor V Junction site stay light chain The catalytic active site of the enzyme is heavy chain 。

The activated factor X forms a complex with Ca2+, phospholipid and factor V, and the latter eventually makes prothrombin Activated as thrombin. The nature of factor V is similar to that of factor VIII, which is not enzymatic Catalysis It accelerates the activation of prothrombin. When factor V and phospholipid exist simultaneously, the activation process can be accelerated 20000 times. Similarly, factor V can also be activated into V 'by thrombin, becoming another Positive feedback effect 。 Factor V is also a glycoprotein with a large molecular weight, which is composed of subunits with a molecular weight of about 300000. It is extremely unstable in the body and easy to be Protein C (also a kind of Serine protease ）Therefore, it is called instability factor.

Prothrombin (i.e. factor II) consists of 581 amino acid When activated by factor Xa complex- Thr (Su 275) and Arg (Jing 322) - Ile (Yi Liang 323) are hydrolyzed, and a peptide segment (residue 1~274) with a molecular weight of about 30000 is released from the N-terminal, forming a thrombin connected by two peptide chains through disulfide bonds. Activated thrombin can catalyze degradation prothrombin The peptide bond at the residue Arg (156) - Ser (157) is hydrolyzed to release peptide A and form new prothrombin S, which is not easy to be activated by Xa. Some people think that segment A combines with factor Xa through Ca2+and phospholipids. If this peptide segment is hydrolyzed and removed, new prothrombin S will lose the ability to combine with factor Xa, even if it still contains a coverable factor Χ A The reaction of peptide bond specifically hydrolyzed is also very difficult. This is an important negative feedback regulation mechanism in the process of prothrombin activation, which avoids thrombus caused by excessive thrombin in the body.

The peptide released from the N-terminal when prothrombin is activated can be roughly divided into two regions, namely, A peptide (residues 1~156) and S-peptide (residues 157~274). The two peptides are very similar in amino acid composition, especially in the position of disulfide bond. Among them, 31 amino acid residues are identical and seem to be independent units in configuration, which is called "ring cake" structure. It is generally believed that these two Annular structure It can combine with factor Xa respectively, so it can be simultaneously hydrolyzed at two peptide bonds (residues 274-275322-323) to activate thrombin. If only the peptide bond at residue 274 is hydrolyzed by factor Xa prothrombin -T can no longer be activated as thrombin 。

Exogenous activation system

Coagulation factor

in vivo tissue damage Factor III, also known as tissue factor 。 In the presence of Ca2+, it can form a complex with the activated factor Ⅶ in the blood, which can activate factor Ⅹ. Since then, it has the same reaction steps as the endogenous activation pathway. adopt Exogenous Sexual pathway Blood coagulation It can be completed in more than 10 seconds, while it takes several minutes to go through the endogenous pathway. Factor III is a membrane glycoprotein, composed of 263 amino acid residues, and exists in vascular endothelial cell It is distributed in various tissues of the body and is more abundant in the lung, brain and placenta. If cell membrane It is released when it is lost. Factor III is similar to factors VIII and V Regulatory factor The difference is that because it exists on the membrane, it does not need the phospholipids of platelets to participate. The mechanism of factor Ⅶ activating factor X is similar to that of factor IX. Each coagulation factor XII, XI, IX, X, VII, thrombin and Coagulation system Related Kallikrein And protein C belong to serine proteases sequence of amino acid Both with Trypsin They are very similar, but they are all glycoproteins.

Factor Ⅶ is composed of 406 amino acid residues, which do not release peptide segments when activated, and its structure is very similar to factors Ⅸ and Ⅹ.

Coagulation factors and vitamin K stay prothrombin There is a special amino acid in the peptide segment near the N-terminal, namely γ- Carboxyglutamic acid 。 Because in the same glutamate Side chain Contains two carboxyl , and Ca2+ Affinity Especially strong. In this way, prothrombin can combine with phospholipid through Ca2+, which is necessary for factor X to activate prothrombin. If animals give vitamin K Antagonists such as dihydroxy coumarin , the original γ－ The carboxyl glutamic acid residue is replaced by normal glutamic acid, and the coagulation function is also damaged, so it is believed that vitamin K is used as a γ Carboxylase coenzyme In total, there are 10 prothrombin molecules γ- Carboxyglutamic acid, which is concentrated on the peptide segment of 32 amino acid residues at the N-terminal (Figure 3). It is easy to understand that once peptide A is degraded by thrombin itself and removed, the new thrombin S left behind is difficult to be activated by factor Xa again. except prothrombin Other coagulation factors related to vitamin K include factors Ⅸ, Ⅹ and Ⅶ, as well as factors Ⅴ and Ⅷ Inactivation Protein C. They all have a similar sequence near the N-terminal peptide segment, γ－ The position of carboxyl glutamic acid also remains unchanged, and two chains are formed after activation. The light chain is the N-terminal part, which contains γ- Carboxyglutamic acid, which can combine with Ca2+and phospholipid. The heavy chain is the C-terminal part, which contains the catalytic center of the enzyme.

Fibrinogenesis

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from Fibrinogen Change to fibrin It can be roughly divided into three stages:

Formation of fibrin monomer

Coagulation factor

Fibrinogen （ Factor I ）A molecular weight of about 340000 glycoprotein , is made up of two identical Subunit Each subunit contains three Peptide chain , i.e α、β、γ Chain, passing each other Disulfide bond Interconnection. These three peptide chains contain 610, 461 and 410 respectively Amino acid residue 。 Two subunits in the peptide chain N-end The symmetrical two subunits are connected by three disulfide bonds nearby (Fig. 4). Therefore, the whole fibrinogen molecule can be used (A α， B β，γ） 2, A and B respectively represent α、β The peptide segment released by hydrolysis of the N-terminal of the peptide chain is used to form fibrin（ α、β、γ） 2. In fibrin molecules, the disulfide bond positions are quite concentrated, and there is a so-called "disulfide bond" structure, whose position is also close to the N-end of the peptide chain (Figure 4). β And γ Peptide amino acid The order is very similar, especially close C-end Around 1/3 of them are the same. According to Fibrinogen Of Physical and chemical properties The model in Figure 5 is proposed, and the connecting part between spheres is the spiral area, which is composed of three peptide chains to form a rope like Helical structure 。 The size and shape of the C-terminal sphere of the peptide chain are similar Plasma albumin , the structure is relatively tight, and a loose α C-terminal peptide of chain, easy to be Fibrinolytic enzyme Or others protease Degraded.

When thrombin acts on fibrinogen α A 16 peptide peptide A is released from the N end of the chain, and after a lag period β The N end of the chain starts to accelerate the release of a 14 peptide peptide B, and the rest is the monomer of fibrin. The hydrolysis sites of fibrinogen A and B peptides of different species are all in Arg - Gly (Gan) Peptide bond On. Peptide A, B amino acid composition It may vary greatly due to different species, but there are 2~6 negative charge , and contains some special amino acids, such as the band in peptide A phosphoric acid Basal serine , peptide B contains bands sulphuric acid Basal Tyrosine 。 Because peptide segments A and B have net negative charges Fibrinogen Molecules cannot polymerize due to electrostatic repulsion before being degraded by thrombin.

Polymerization of fibrin monomer

In the polymerization process of fibrin monomer Mesopeptide The release of segment A plays a major role, first the first is the end to end polymerization, while the release of peptide B can accelerate the polymerization and start the lateral polymerization. Due to the release of A and B peptide segments, the fibrin monomer exposes two complementary regions embedded in each subunit, so that the monomer can Noncovalent bond Head tail or lateral polymerization, as the degree of lateral polymerization deepens, clot It looks viscous, turning from transparent Opaque 。

Cross-linking of fibrin

Coagulation factor

Activated thrombin degradation Fibrinogen In addition to releasing peptide segments A and B, factor XIII is rapidly activated in the presence of Ca2+, which enables polymerized fibrin to form between adjacent peptide chains Bridge key And become stable and cross-linked fibrin POLYMER , even at 5M urea The gel before crosslinking can be dissolved under this condition. Factor XIII is Transglutaminase , which makes the peptide chain Lysine Residue On ε amino And glutamine Residual γ amide The ligands form new peptide bonds. Each fibrin monomer can form up to 6 Covalent If there are 2-3 bridge bonds in each molecule, a very stable cross-linked fibrin can be formed.

Long term evolution Fibrinogen Be ideal Hemostatic agent For example, before activation, molecules cannot polymerize due to electrostatic repulsion Sol ； Peptides A and B at the N end of the peptide chain are easy to be removed by thrombin hydrolysis Electrostatic effect Disappearance and rapid formation of gel; A bridge bond can be formed near the end of peptide chain C to form a stable gel with enough mechanical strength ； High molecular weight, Hydrophilicity Strong and present Symmetry , conforming to gel characteristics; The molecule contains a section of rope like helical structure, which is easy to be degraded by protease, and will not form thrombus in the body; Fibrin gelatinous Degradation product It can inhibit the activity of thrombin and also prevent the polymerization of fibrin monomer, thus Self regulation Of Feedback 。

In the coagulation system, in addition to the positive and negative feedback and self regulation among various factors, the coagulation factors belonging to protease are also affected by the corresponding Protease inhibitor Constraints, such as those in plasma Antithrombin III （ AT Ⅲ, antihro mbi Ⅲ), in addition to specifically inhibiting thrombin, it can also inhibit factors Xa, Ⅸ a, and Ⅶ a, especially Xa. heparin Can greatly accelerate AT - Ⅲ inhibition Therefore, it is used clinically as an important Anticoagulant 。 In addition to AT - Ⅲ, there are other protease inhibitors in the plasma, such as α 1 Anti protease Antifibrinolytic enzyme and α 2 Megaglobulin They also have a certain degree of inhibition on each protease in coagulation factors.

Related diseases

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hemophilia (Hemophilia) is a group of patients who suffer from serious disease due to the lack of some coagulation factors in the blood Coagulation disorder Of genetic Hemorrhagic disease Both men and women can get sick, but most of the patients are men. include Hemophilia A (A) Hemophilia B (B) and factor XI deficiency (formerly known as hemophilia C). The first two are Sex linkage Recessive inheritance, the latter is autosomal imperfection Recessive inheritance 。 Hemophilia is the most common congenital hemorrhagic disease, and bleeding is the main disease clinical manifestation 。 Treatment methods include local hemostasis, substitution therapy, etc. The emerging therapies in the latter include recombinant human coagulation factor (recombinant human coagulation factor Ⅶ a for injection, NovoSeven ）The treatment will be popularized in the future due to its characteristics of no artificial pollution and high safety.

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