What is the pathophysiology of pediatric factor XIII (FXIII) deficiency?

Updated: Mar 15, 2019
  • Author: Helge Dirk Hartung, MD; Chief Editor: Cameron K Tebbi, MD  more...
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Answer

The factor XIII zymogen circulates in plasma as a tetramer composed of 2 catalytic A subunits and 2 carrier B subunits (A2 B2). The A subunits are synthesized in megakaryocytes and monocyte precursors in the bone marrow and placenta; A2 dimers are present in circulating platelets and monocytes. The B subunits are synthesized in hepatocytes. The A2 and B2 dimers assemble in the plasma to form a heterotetramer, which has a long plasma half-life of 7-12 days. Activation of the zymogen to factor XIIIa depends on limited thrombin cleavage of the A subunits followed by calcium-dependent dissociation of the B subunits, exposing the A subunit active site (as shown in the image below).

Activation of factor XIII (FXIII) by thrombin and Activation of factor XIII (FXIII) by thrombin and calcium is a 2-step process. Thrombin cleaves an arginine-lysine bond in the A subunit and calcium causes dissociation of the B subunit, exposing the active site on the A subunit (XIIIa).

Factor XIIIa catalyzes the formation of covalent bonds between glutamine and lysine residues on the fibrin a and g chains, enhancing the mechanical strength of the fibrinpolymer.

Investigators have demonstrated other substrates for factor XIIIa, including proteins such as osteopontin, factor V, thrombospondin, vinculin, and endothelial cell receptors αvβ3 integrin and VEGFR-2. These observations have suggested physiologic and pathologic roles for factor XIII in angiogenesis, atherosclerosis, and inflammation. By cross-linking bacterial surface proteins to fibrinogen, factor XIIIa causes bacteria to be immobilized and killed. Wound healing is promoted by factor XIIIa via cross-linking of the provisional matrix, a process that influences the extracellular matrix–leukocyte interaction. [1]

Inherited factor XIII deficiency is usually due to mutations in the gene encoding the catalytic A subunit, located on chromosome 6. More than 40 different mutations have been identified, half of which are missense mutations. [2] In patients homozygous for this defect, the A subunit is absent in plasma, platelets, and monocytes, resulting in a severe bleeding diathesis; the concentration of B subunits is relatively normal. The impaired cross-linking of extracellular matrix proteins at sites of wound healing or placental implantation can lead to abnormalities in these processes, resulting in abnormal or delayed healing and spontaneous abortion.

Mutations have also been found in the gene encoding the B subunit, located on chromosome 1; however, this has been reported in only 5 families to date. With the absence of the carrier B subunits, the plasma half-life of the A subunits is shorter (ie, 3 d), resulting in decreased plasma levels of both A and B. However, because of the presence of A subunits in platelets and monocytes, the phenotype is less severe.


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