eMedicine Specialties > Pediatrics: General Medicine > Hematology
Factor XIII Deficiency
Updated: Aug 20, 2007
Introduction
Background
Congenital factor XIII (FXIII) deficiency, originally recognized by Duckert in 1960, is a rare autosomal recessive disease usually associated with a severe bleeding diathesis. Although acquired FXIII deficiency has been described in association with hepatic failure, inflammatory bowel disease, and myeloid leukemia, the only significant association with bleeding in children is the inherited deficiency.
FXIII is a plasma transglutaminase that catalyzes the final step in the coagulation cascade, cross-linking the loose fibrin polymer into a highly organized structure. In addition, FXIII covalently binds fibronectin, a 2 -plasmin inhibitor, and collagen to the fibrin plug; this enhances adherence to the wound site, resistance to fibrinolysis, and wound healing by providing a scaffold for fibroblast migration and proliferation. Fibrin-fibronectin cross-linking is necessary to support the formation of the cytotrophoblastic shell at the site of placental implantation, which accounts for the role of FXIII in the maintenance of pregnancy.
Recent investigators have demonstrated other substrates for FXIIIa, including proteins such as osteopontin, factor V, thrombospondin, vinculin, and endothelial cell receptors avb3 and VEGFR-2. These observations have suggested physiological and pathological roles for FXIII in angiogenesis, atherosclerosis, and inflammation.
The FXIII 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 FXIIIa depends on limited thrombin cleavage of the A subunits followed by calcium-dependent dissociation of the B subunits, exposing the A subunit active site (see Image 1). FXIIIa 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.Pathophysiology
Inherited FXIII 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. 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.
Frequency
International
The incidence is about 1 case per 2-5 million population.
Mortality/Morbidity
The mortality and morbidity are primarily related to bleeding; intracranial hemorrhage can be life threatening. The spontaneous abortion rate in women with severe FXIII deficiency approaches 80%.
Sex
This is an autosomal recessive disease; the male-to-female ratio is 1:1.
Age
Because the clinical bleeding is severe in most patients with hereditary FXIII deficiency, the diagnosis is made at an early age, often during infancy.
Clinical
History
The bleeding diathesis in inherited factor XIII (FXIII) deficiency is severe in most patients. Bleeding from the stump of the umbilical cord within the first days to weeks of life is a characteristic sign that occurs in 80% of affected individuals; bleeding from this specific site is uncommon in other inherited hemostatic diseases except afibrinogenemia. Additional signs of bleeding include the following:
- CNS hemorrhage is frequent (25-30%) and may occur spontaneously or after minor trauma. Prevention of this complication is the major rationale for initiating prophylactic therapy.
- Infants are at risk of bleeding immediately after birth; the greatest risk is due to CNS hemorrhage.
- Soft tissue bleeding and bruising are very common, as is bleeding into the mouth and gums during teething.
- Hemarthroses occur in 20% of cases; however, incidence is less frequent than in severe hemophilia.
- Bleeding that is delayed (ie, 12-36 h) after trauma or surgery is pathognomonic of FXIII deficiency.
- Recurrent spontaneous abortions are very common in women with FXIII deficiency who do not receive FXIII replacement.
- Wound healing is abnormal in a subset of patients.
Physical
Physical manifestations related to bleeding may include the following:
- Persistent bleeding from the stump of the umbilical cord in newborns
- Soft tissue and subcutaneous bleeding
- Neurologic findings commensurate with CNS hemorrhage
- Bleeding in the oral cavity
- Hemarthroses or periarticular bleeding
- Poor wound healing
More on Factor XIII Deficiency |
 Overview: Factor XIII Deficiency |
| Differential Diagnoses & Workup: Factor XIII Deficiency |
| Treatment & Medication: Factor XIII Deficiency |
| Follow-up: Factor XIII Deficiency |
| Multimedia: Factor XIII Deficiency |
| References |
| Next Page » |
References
Anwar R, Miloszewski KJ. Factor XIII deficiency. Br J Haematol. Dec 1999;107(3):468-84. [Medline].
Anwar R, Minford A, Gallivan L, Trinh CH, Markham AF. Delayed umbilical bleeding--a presenting feature for factor XIII deficiency: clinical features, genetics, and management. Pediatrics. Feb 2002;109(2):E32. [Medline].
Ariëns RA, Lai TS, Weisel JW, Greenberg CS, Grant PJ. Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms. Blood. Aug 1 2002;100(3):743-54. [Medline].
Ichinose A. Physiopathology and regulation of factor XIII. Thromb Haemost. Jul 2001;86(1):57-65. [Medline].
Ichinose A, Asahina T, Kobayashi T. Congenital blood coagulation factor XIII deficiency and perinatal management. Curr Drug Targ. 2005;6:541-549.
Israels LG, Israels ED. Fibrinogen, factor XIII, and fibrinolysis. In: Mechanisms in Hematology. 3rd ed. Concord ON: Core Health Services, Inc; 2002:355-367.
Jennings I, Kitchen S, Woods TA, Preston FE,. Problems relating to the laboratory diagnosis of factor XIII deficiency: a UK NEQAS study. J Thromb Haemost. Dec 2003;1(12):2603-8. [Medline].
Lovejoy AE, Reynolds TC, Visich JE, Butine MD, Young G, Belvedere MA, et al. Safety and pharmacokinetics of recombinant factor XIII-A2 administration in patients with congenital factor XIII deficiency. Blood. Jul 1 2006;108(1):57-62. [Medline].
Nugent DJ. Prophylaxis in rare coagulation disorders -- factor XIII deficiency. Thromb Res. 2006;118 Suppl 1:S23-8. [Medline].
Further Reading
Keywords
FXIII deficiency, fibrin-stabilizing factor deficiency, fibrin-stabilizing factor, FSF, fibrinoligase, Laki-Lorand factor, L-L factor, LLF, fibrinase, congenital factor XIII deficiency, plasma transglutaminase, coagulation
