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Coagulation

Hereditary bleeding disorders

Factor XIII deficiency


Reviewers: Julie Gober-Wilcox, M.D., Resident, University of New Mexico; Kendall Crookston, M.D., Ph.D., University of New Mexico (see Reviewers page)
Revised: 24 July 2011, last major update July 2011
Copyright: (c) 2002-2011, PathologyOutlines.com, Inc.

General
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● Factor XIII deficiency is a congenital disorder that is inherited as an autosomal recessive trait and is associated with a variable bleeding tendency
● Acquired factor XIII deficiency is associated with liver failure, inflammatory bowel disease, leukemia, disseminated intravascular coagulation, Henoch-Schonlein purpura, systemic lupus erythematosus and exposure to certain drugs (phenytoin, isoniazid, valproate)

Terminology
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● Factor XIII is also known as fibrin stabilizing factor

Epidemiology
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● Estimated at 1 in 2 to 5 million births
● More frequent in regions where consanguineous marriages are more common

Sites
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● Skin and mucosa, joints, soft tissue, gastrointestinal tract, genitourinary tract, CNS (see clinical features below)

Pathophysiology
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● Factor XIII is a transglutaminase that circulates as a zymogen comprised of 2 catalytic A subunits and 2 carrier B subunits
● The A subunit is synthesized in platelets, monocytes and macrophages while the B subunit is synthesized in the liver; the A and B dimers then assemble in the plasma to form a heterotetramer
● Factor XIII is activated by thrombin and is responsible for catalyzing the final step in the coagulation cascade by cross-linking fibrin (in the presence of calcium)
● Deficiency is due to a defect in either the A gene (type 2) or B gene (type 1)


Diagram of factor XIII activation

Etiology
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● Inherited as an autosomal recessive trait
● Most cases are due to mutations in A subunit gene on chromosome 6
● More than 70 mutations have been identified, most of which are missense and nonsense mutations
● Only 5 mutations in FXIII B deficient patients have been identified; gene is on chromosome 1

Clinical features
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● Variable bleeding tendency, from mild to severe depending on factor levels
● Umbilical cord stump bleeding, intracranial hemorrhage, soft tissue hematoma, bleeding after circumcision, gastrointestinal bleeding, gingival bleeding, epistaxis, hematuria, surgical site bleeding, menorrhagia, joint bleeding, delayed healing, spontaneous abortion, recurrent miscarriage
● Plasma half –life is 9-12 days
● Factor XIII levels above 3-5% are usually sufficient to prevent spontaneous bleeding
● Severe bleeding typically occurs in individuals with <1% circulating levels
● Compound heterozygotes are usually asymptomatic

Laboratory
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● Normal PT, PTT, thrombin time, fibrinogen
● Screening test for factor XIII deficiency uses the clot solubility test in which patient plasma is incubated with thrombin and calcium; deficiency will cause the clot to dissolve in the presence of urea or acid
● A standard mixing test using patient plasma and normal pooled plasma is usually performed to rule out the presence of an inhibitor
● Confirmatory testing uses a quantitative factor XIII activity assay

Prognostic factors
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● Although there is a life-long risk of bleeding, prognosis is excellent due to good response to treatment; subsequent risk of development of inhibitors is low

Case reports
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● Spontaneous splenic rupture in a patient with factor XIII deficiency (Pediatr Blood Cancer 2008;50:113)

Treatment
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● Factor XIII concentrate, FFP or cryoprecipitate for replacement therapy or for treatment of acute bleeding episodes:
● Factor XIII concentrate: 10-20U/kg at 4-6 week intervals
● FFP: 10 mL/kg every 4-6 weeks
● Cryoprecipitate: 1 bag per 10-20 kg every 3-4 weeks
● To prevent miscarriage, maintain factor XIII levels >10% in early gestation and >30% at time of delivery to prevent significant bleeds

Differential diagnosis
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● Acquired factor XIII deficiency

Additional references
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J Thromb Haemost 2003;1:1852, Semin Thromb Hemost 2009;35:426, Haemophilia 2008;14:1190

End of Coagulation > Hereditary bleeding disorders > Factor XIII deficiency


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