Factor XIII

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coagulation factor XIII,
A1 polypeptide
Human factor XIII 1EVU.png
Inactive A1 peptide homodimer with all of the domains and main catalytic residues shown with different colors.
Identifiers
Symbol F13A1
Alt. symbolsF13A
NCBI gene 2162
HGNC 3531
OMIM 134570
RefSeq NM_000129
UniProt P00488
Other data
EC number 2.3.2.13
Locus Chr. 6 p24.2-p23
Search for
Structures Swiss-model
Domains InterPro
coagulation factor XIII,
B polypeptide
Identifiers
Symbol F13B
NCBI gene 2165
HGNC 3534
OMIM 134580
RefSeq NM_001994
UniProt P05160
Other data
Locus Chr. 1 q31-q32.1
Search for
Structures Swiss-model
Domains InterPro

Factor XIII, or fibrin stabilizing factor, is a plasma protein and zymogen. It is activated by thrombin to factor XIIIa which crosslinks fibrin in coagulation. Deficiency of XIII worsens clot stability and increases bleeding tendency. [1]

Contents

Human XIII is a heterotetramer. It consists of 2 enzymatic A peptides and 2 non-enzymatic B peptides. XIIIa is a dimer of activated A peptides. [1]

Function

Within blood, thrombins cleave fibrinogens to fibrins during coagulation and a fibrin-based blood clot forms. Factor XIII is a transglutaminase that circulates in human blood as a heterotetramer of two A and two B subunits. Factor XIII binds to the clot via their B units. In the presence of fibrins, thrombin efficiently cleaves the R37–G38 peptide bond of each A unit within a XIII tetramer. A units release their N-terminal activation peptides. [1]

Both of the non-covalently bound B units are now able to dissociate from the tetramer with the help of calcium ions (Ca2+) in the blood; these ions also activate the remaining dimer of two A units via a conformational change. [1]

Factor XIIIa (dimer of two active A units) crosslinks fibrins within the clot by forming isopeptide bonds between various glutamines and lysines of the fibrins. These bonds make the clot physically more durable and protect it from premature enzymatic degradation (fibrinolysis). [1]

In humans, plasmin, antithrombin and TFPI are the most relevant proteolytic inhibitors of the active factor XIIIa. α2-macroglobulin is a significant non-proteolytic inhibitor. [1]

Genetics

Human factor XIII consist of A and B subunits. A subunit gene is F13A1 . It is on chromosome 6 at the position 6p24–25. It spans over 160 kbp, has 14 introns and 15 exons. Its mRNA is 3.9 kbp. It has a 5' UTR of 84 bp and a 3' UTR of 1.6 kbp. F13A1 exon(s) [1]

B subunit gene is F13B . It is on chromosome 1 at the position 1q31–32.1. It spans 28 kpb, has 11 introns and 12 exons. Its mRNA is 2.2 kbp. Exon 1 codes 5' UTR. Exons 2–12 code the 10 different sushi domains. [1]

Structure

Factor XIII of human blood is a heterotetramer of two A and two B linear polypeptides or "units". A units are potentially catalytic; B units are not. A units form a dimeric center. Non-covalently bound B units form a ring-like structure around the center. B units are removed when XIII is activated to XIIIa. Dimers containing only A units also occur within cells such as platelets. Large quantities of singular B units (monomers) also occur within blood. These dimers and monomers are not known to participate in coagulation, whereas the tetramers do. [1]

A units have a mass of about 83 kDa, 731 amino acid residues, 5 protein domains (listed from the N-terminal to C-terminal, residue numbers are in brackets): [1]

B units are glycoproteins. Each has a mass of about 80 kDa (8.5% of the mass is from carbohydrates), 641 residues and 10 sushi domains. Each domain has about 60 residues and 2 internal disulfide bonds. [1]

Physiology

A subunits of human factor XIII are made primarily by platelets and other cells of bone marrow origin. B subunits are secreted into blood by hepatocytes. A and B units combine within blood to form heterotetramers of two A units and two B units. Blood plasma concentration of the heterotetramers is 14–48 mg/L and half-life is 9–14 days. [1]

A clot that has not been stabilized by FXIIIa is soluble in 5 mol/L urea, while a stabilized clot is resistant to this phenomenon. [2]

Factor XIII deficiency

Factor XIII deficiency, while generally rare, does occur, with Iran having the highest global incidence of the disorder with 473 cases. The city of Khash, located in Sistan and Balochistan provinces, has the highest incidence in Iran, with a high rate of consanguineous marriage. [3]

Diagnostic use

Factor XIII levels are not measured routinely, but may be considered in patients with an unexplained bleeding tendency. As the enzyme is quite specific for monocytes and macrophages, determination of the presence of factor XIII may be used to identify and classify malignant diseases involving these cells. [4]

Discovery

Factor XIII Deficiency is also known as Laki–Lorand factor, after Kalman Laki and Laszlo Lorand, the scientists who first proposed its existence in 1948. [2] A 2005 conference recommended standardization of nomenclature. [4]

See also

Related Research Articles

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Factor XIII deficiency occurs exceedingly rarely, causing a severe bleeding tendency. The incidence is one in a million to one in five million people, with higher incidence in areas with consanguineous marriage such as Iran that has the highest global incidence of the disorder. Most are due to mutations in the A subunit gene. This mutation is inherited in an autosomal recessive fashion.

<span class="mw-page-title-main">Coagulation factor XIII A chain</span> Protein found in humans

Coagulation factor XIII A chain, (FXIIIa) is a protein that in humans is encoded by the F13A1 gene.

<span class="mw-page-title-main">Coagulation factor XIII B chain</span> Mammalian protein found in Homo sapiens

Coagulation factor XIII B chain is a protein that in humans is encoded by the F13B gene.

Clotting time is a general term for the time required for a sample of blood to form a clot, or, in medical terms, coagulate. The term "clotting time" is often used when referring to tests such as the prothrombin time (PT), activated partial thromboplastin time, activated clotting time (ACT), thrombin time (TT), or Reptilase time. These tests are coagulation studies performed to assess the natural clotting ability of a sample of blood. In a clinical setting, healthcare providers will order one of these tests to evaluate a patient's blood for any abnormalities in the time it takes for their blood to clot. Each test involves adding a specific substance to the blood and measuring the time until the blood forms fibrin which is one of the first signs of clotted blood. Each test points to a different component of the clotting sequence which is made up of coagulation factors that help form clots. Abnormal results could be due to a number of reasons including, but, not limited to, deficiency in clotting factors, dysfunction of clotting factors, blood-thinning medications, medication side-effects, platelet deficiency, inherited bleeding or clotting disorders, liver disease, or advanced illness resulting in a medical emergency known as disseminated intravascular coagulation (DIC).

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<span class="mw-page-title-main">Fibrinopeptide</span> Chemical compound

The fibrinopeptides, fibrinopeptide A (FpA) and fibrinopeptide B (FpB), are peptides which are located in the central region of the fibrous glycoprotein fibrinogen and are cleaved by the enzyme thrombin to convert fibrinogen into covalently-linked fibrin monomers. The N-terminal FpA is cleaved from the Aα chains of fibrinogen and FpB from the Bβ chains of fibrinogen, with FpA released before FpB. Subsequent to their formation, fibrin monomers are converted to cross-linked fibrin polymers by the action of thrombin-activated factor XIII, and these fibrin polymers form the backbone of a thrombus. Hence, the fibrinopeptides are sensitive markers of fibrinogenesis, thrombin activity, and coagulation.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 Muszbek L, Bereczky Z, Bagoly Z, Komáromi I, Katona É (July 2011). "Factor XIII: a coagulation factor with multiple plasmatic and cellular functions". Physiological Reviews. 91 (3): 931–72. doi:10.1152/physrev.00016.2010. PMID   21742792. S2CID   24703788.
  2. 1 2 Laki K, Lóránd L (September 1948). "On the Solubility of Fibrin Clots". Science. 108 (2802): 280. Bibcode:1948Sci...108..280L. doi:10.1126/science.108.2802.280. PMID   17842715.
  3. Dorgalaleh A, Naderi M, Hosseini MS, Alizadeh S, Hosseini S, Tabibian S, et al. (2015). "Factor XIII Deficiency in Iran: A Comprehensive Review of the Literature. Seminars in thrombosis and hemostasis". 41 (3): 323–29.{{cite journal}}: Cite journal requires |journal= (help)
  4. 1 2 Muszbek L, Ariëns RA, Ichinose A (January 2007). "Factor XIII: recommended terms and abbreviations". Journal of Thrombosis and Haemostasis. 5 (1): 181–83. doi: 10.1111/j.1538-7836.2006.02182.x . PMID   16938124. S2CID   20424049.