What is the structure, production, and half-life of factor XIII (FXIII)?

Updated: Aug 01, 2019
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Perumal Thiagarajan, MD  more...
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Plasma FXIII is a heterotetramer consisting of 2 identical proenzyme subunits (A2) and 2 identical carrier protein subunits (B2). Subunit A contains the catalytic site, the activation peptide, a calcium-binding site, and free sulfhydryl (SH) groups. Subunit B, a glycoprotein, acts as a carrier protein that stabilizes subunit A, binds the zymogen (subunit A) to fibrinogen, and acts as a brake on FXIII activation. [22, 23] Subunit B circulates in plasma as part of the tetramer A2 B2 and as a free B2 dimer; all of plasma subunit A is complexed with subunit B. The concentration of subunit A in plasma is 15 mg/mL, while that of subunit B is 21 mg/mL. Much of FXIII circulates in blood in association with fibrinogen. [24, 25]

Platelet FXIII (an A2 homodimer) constitutes approximately 50% of total FXIII activity in blood. Plasma FXIII has a long half-life of approximately 9-14 days. A similarity exists between a portion of the carboxy terminal (C terminal) domain of FXIII and the receptor-binding region of a2 -macroglobulin. The complex of a2 -macroglobulin and its substrate protease is removed from the circulation by binding to its receptor in the liver and other tissues; therefore, as has been suggested, FXIII also may be removed from the circulation by a similar mechanism. [26, 27] Some features of the A and B chains of FXIII are listed below. Monoclonal antibodies and naturally occurring inhibitors are used to elucidate structure-activity relationships.

Bone marrow cells, megakaryocytes, and monocytes/macrophages synthesize FXIII, with a possible role for hepatocytes in the synthesis of subunit A. Subunit B is synthesized by the liver. Tissue transglutaminase, the intracellular form of FXIII, consists of the A2 subunit (an A2 homodimer) and is present in a variety of cells including platelets, megakaryocytes, monocytes/macrophages, and in the liver, placenta, uterus, prostate, and dermal dendrocytes. [28] Red cells contain a transglutaminase that is activated by Ca2+ but is different from plasma transglutaminase in its cross-linking activity and can cross-link fibrinogen as well as fibrin. Trapped erythrocytes release FXIII when red cells lyse, providing additional cross-links to the aging thrombus. [22]

Table. Some Features of the A and B Chains of Factor XIII (Open Table in a new window)


A Chain

B Chain

Plasma FXIII

Has 2 A chains

Has 2 B chains

Plasma level

Approximately 15 mg/mL

Approximately 21 mg/mL

Chains are free in plasma

No. All bound to B chain and present as an A2 B2 tetramer

Yes. Excess B chain present in plasma as a B2 dimer

Chain contains the catalytic site



Chain is the carrier protein



Chain acts as a brake on FXIII activation



Cellular FXIII

Has 2 A chains (A2 dimer)

Has no B chains

Mutations can lead to decreased FXIII activity



Comparative biology shows that transglutaminases are distributed widely in nature and may represent the prototype for the evolution of clotting enzymes. [29] Partial homology of plasma FXIII exists with several proteins including tissue and keratinocyte transglutaminases, erythrocyte transglutaminase, and the hemocyte transglutaminase of the horseshoe crab and other zymogens of the same family.

A recent example is from the crystal structure of transglutaminase of the Red Sea bream, which shows that its active site and overall structure resemble that of human FXIII. [30] These homologies attest to conservation of the enzyme during evolution. Since the gene structures are similar, it is believed that they evolved from a common ancestor. Subunit B contains 10 repeating "sushi" units linked by disulfide bonds; the function of the sushi unit is unknown. Sushi structures are present in at least 26 proteins, including proteins in the horseshoe crab and in the vaccinia virus.

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