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Pediatrics: General Medicine > Hematology
Factor XIII Deficiency
Article Last Updated: Aug 20, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Sara J Israels, MD, FRCPC, Professor of Pediatric Hematology/Oncology, Section Head of Pediatric Hematology/Oncology/BMT, Department of Pediatrics and Child Health, University of Manitoba
Sara J Israels is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, Canadian Medical Association, Children's Oncology Group, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada
Editors: Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center; Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada; Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, DC; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Author and Editor Disclosure
Synonyms and related 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
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, a2-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 (A2B2). 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.
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
Other Problems to be Considered
Acquired FXIII deficiency can be caused by liver disease, inflammatory bowel disease, and disseminated intravascular coagulation, although controversy exists as to whether the low plasma levels in these conditions actually contribute to clinical bleeding. The development of autoantibodies to FXIII has been reported. Consider other congenital coagulation factor deficiencies, most notably afibrinogenemia.
Lab Studies
- Screening tests
- Results from standard hemostatic screening tests such as activated partial thromboplastin time (aPTT) and international normalized ratio (INR) assessments are normal in factor XIII (FXIII) deficiency.
- Assessment of clot stability is the most common screening test for FXIII deficiency.
- The patient's plasma is incubated with thrombin with or without calcium for a sufficient period to allow formation of a stable clot; the formed clot is suspended in 5 mol/L urea, 2% acetic acid, or 1% monochloroacetic acid. Thrombin (without calcium) and acetic acid may provide the most sensitive combination.
- In the presence of FXIII, the clot is stable for more than 24 hours; in its absence, the clot dissolves in minutes to hours.
- The qualitative test findings are positive in the absence of FXIII; however, FXIII levels as low as 1-3% may be sufficient to crosslink the fibrin, stabilizing the clot. Therefore, in patients with milder deficiencies or in patients who have recently received a transfusion, results of the clot stability assay may be normal.
- A quantitative assay is required to confirm the diagnosis of FXIII deficiency.
- Functional assays
- The 2 methods used to measure the enzymatic activity of FXIII include measurement of synthetic amine incorporation into a fibrin clot, and measurement of ammonium ion release during the transglutaminase reaction.
- Both assays are available as commercial kits.
- Immunologic assays
- FXIIIA and FXIIIB antigen levels can be quantified by means of enzyme-linked immunosorbent assay (ELISA).
- Patients with subunit A mutations have less than 2% of the reference range levels of A antigen.
- The rare individuals with B subunit mutations have low B antigen levels, and, because of the shorter half-life of the A subunit in the absence of the B subunit, the A subunit antigen levels are also reduced.
- Genotyping
Imaging Studies
- Appropriate imaging studies are required in the evaluation of suspected bleeding.
- For instance, CT scanning or MRI of the brain is indicated in patients with a suspected CNS hemorrhage.
Medical Care
- Plasma, cryoprecipitate, and factor XIII (FXIII) concentrates have been used for replacement of FXIII and the treatment of bleeding. The treatment of choice is plasma-derived FXIII concentrate that is pasteurized to provide virologic safety and is less likely than plasma to cause systemic reactions. Recombinant FXIII-A2 concentrates are currently being evaluated in clinical trials.
- Because levels of FXIII above 3-5% are usually sufficient to prevent spontaneous bleeding and because the plasma half-life is long (7-12 d), prophylaxis is the management strategy of choice. Prophylactic therapy with FXIII concentrate 10-20 U/kg every 4-6 weeks provides adequate plasma levels in most patients. The dose and frequency should be tailored to plasma levels and clinical efficacy for each patient.
- The half-life of FXIII is shorter during pregnancy; therefore, treating pregnant patients requires more frequent dosing. In addition, a booster dose is recommended during labor to decrease the risk of bleeding in the mother.
- Neonates at risk for FXIII deficiency because of their family history should be screened at birth and treated promptly if FXIII deficiency is found.
Surgical Care
In preparation for surgical procedures, patients should receive FXIII concentrate immediately before surgery to ensure optimal hemostasis and wound healing.
Consultations
- Consult a hematologist and/or hemostasis specialist for patients who require FXIII replacement therapy.
- Genetic counseling and family studies should be part of a complete evaluation.
Scheduled factor XIII (FXIII) replacement every 4-6 weeks maintains FXIII levels above the critical threshold for spontaneous bleeding and allows patients to participate in regular activities.
Drug Category: Clotting factors
Hemostasis is the physiological response to bleeding. Injury to the blood vessel wall and factors released by platelets initiate the coagulation cascade. Formation of an insoluble fibrin clot, which reinforces the initial platelet plug, is mediated by blood clotting factors. Clotting factors function as cofactors in the blood-coagulation cascade.
| Drug Name | Factor XIII concentrate (Fibrogammin P) |
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| Description | A plasma-derived concentrate (Fibrogammin P, Aventis Behring) is available in the United States as an orphan drug. Fibrogammin is a purified pasteurized concentrate that is a lyophilized powder in 250- and 1250-U vials. Several recombinant products are also available as orphan drugs from Novo Nordisk and Zymogenetics. |
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| Adult Dose | Prophylaxis: 10-20 U/kg IV q4-6wk raises plasma levels to 15-30%
Severe bleeding episodes or preoperatively: 35-50 U/kg IV
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | None reported |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
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| Precautions | To determine appropriate dose and frequency of administration required to maintain levels >3%, monitoring of FXIII levels over 1 mo after initial prophylactic dose of concentrate recommended; allergic reactions can occur; caution in recent thrombosis |
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Further Outpatient Care
- Ideally, a comprehensive hemophilia care team with experience in the diagnosis and management of inherited bleeding disorders should monitor individuals with severe factor XIII (FXIII) deficiency.
Deterrence/Prevention
- For patients with homozygous FXIII deficiency, prophylaxis is the best approach.
- Individuals who require plasma-derived FXIII concentrate should be immunized with hepatitis A and hepatitis B vaccines.
- Aspirin and other drugs that impair platelet function should be avoided.
- Women at risk for spontaneous abortion should be evaluated for the need of enhanced prophylaxis starting in early pregnancy.
Patient Education
- Provide patients and families with individual instruction and educational materials so they can understand FXIII deficiency, recognize the symptoms and signs of bleeding, and identify emergency situations.
- Patients should know where to receive emergency care and how to contact their treatment center for immediate treatment.
- Patients should wear a MedicAlert bracelet or carry other identification stating their bleeding disorder and recommended therapy.
- For excellent patient education resources, visit eMedicine's Teeth and Mouth Center. Also, see eMedicine's patient education article Teething.
Medical/Legal Pitfalls
- Failure to make the specific diagnosis of congenital factor XIII (FXIII) deficiency
- Failure to investigate family members for FXIII deficiency
- Failure to treat bleeding episodes with appropriate FXIII replacement and to consider the appropriate use of prophylaxis
| Media file 1:
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). |
 |  View Full Size Image | |
Media type: Image
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Factor XIII Deficiency excerpt Article Last Updated: Aug 20, 2007
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