Pediatric Factor XIII Deficiency 

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

Overview

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 factor XIII deficiency has been described in association with chronic conditions such as hepatic failure, inflammatory bowel disease, and myeloid leukemia, the only significant cause for bleeding in children is an inherited deficiency.

Factor XIII 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, factor XIII 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 factor XIII in the maintenance of pregnancy.

 

Pathophysiology

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.

 

Epidemiology

Frequency

International

The prevalence of factor XIII deficiency is about 1 case per 2 million in the general population. Worldwide, the prevalence is highest in the Sistan and Baluchistan province of Iran.[3] In addition to Iran, population-specific mutations due to founder effects have been reported in Pakistan, India, Tunisia, and Finland.

A study by Gebhart et al of Austrian patients with mild to moderate bleeding disorders found that out of 418 individuals with these conditions, just one (0.2%) had factor XIII deficiency. Factor VIII, IX, and XI deficiencies occurred in 11 (2.6%), 3 (0.7%), and 3 (0.7%) patients, respectively.[4]

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 factor XIII 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 factor XIII deficiency, the diagnosis is made at an early age, often during infancy.

 

 

Presentation

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 concern relates 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, the incidence is less frequent than in severe hemophilia.

  • Bleeding that is delayed (ie, 12-36 h) after trauma or surgery is pathognomonic of factor XIII deficiency.

  • Recurrent spontaneous abortions are very common in women with factor XIII deficiency who do not receive factor XIII replacement.

  • Women with inherited disease often experience menorrhagia.

  • Wound healing is abnormal in a subset of patients.

While the majority of heterozygous individuals are completely asymptomatic, some persons who carry a single mutated copy of the F13A1 or F13B gene have 20-60% of the normal factor XIII level and may experience bleeding after major trauma, surgery, or dental work.

Physical

Physical manifestations related to bleeding may include the following:

  • Persistent bleeding from the stump of the umbilical cord in newborns[5]

  • Soft tissue and subcutaneous bleeding

  • Neurologic findings commensurate with CNS hemorrhage

  • Bleeding in the oral cavity

  • Hemarthroses or periarticular bleeding

  • Poor wound healing

 

DDx

Diagnostic Considerations

Acquired factor XIII (FXIII) deficiency can be caused by liver disease, inflammatory bowel disease, and disseminated intravascular coagulation, although controversy surrounds whether the low plasma levels in these conditions actually contribute to clinical bleeding. The development of autoantibodies to factor XIII has been reported. Consider other congenital coagulation factor deficiencies, most notably afibrinogenemia.

 

Workup

Laboratory 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 factor XIII deficiency, even though sensitivity and specificity are low.

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 factor XIII, 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 factor XIII; however, factor XIII 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 factor XIII deficiency.

Functional assays

The two methods used to measure the enzymatic activity of factor XIII include measurement of synthetic amine incorporation into a fibrin clot, and measurement of ammonium ion release during the transglutaminase reaction.[6] Both assays are available as commercial kits.

Immunologic assays

Factor XIIIa and factor XIIIb 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.

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.

 

Treatment

Medical Care

Fresh frozen plasma (FFP), cryoprecipitate, and factor XIII (FXIII) concentrates have been used for replacement of factor XIII and the treatment of acute bleeding. For years the treatment of choice has been plasma-derived factor XIII concentrate that is pasteurized to provide virologic safety and is less likely than plasma to cause systemic reactions. Recombinant factor XIII-A2 (Tretten) was approved by the FDA in December 2013 and presents an alternative in the treatment of congenital factor XIII A-subunit deficiency. Approval was based on results from a study that demonstrated the safety and efficacy of rFXIII A-subunit. The phase 3 trial included 41 patients and showed that when compared to an historic control group of individuals who did not receive routine FXIII infusions, preventive treatment with monthly 35 IU/kg rFXIII A-subunit injections significantly decreased the number of treatment-requiring bleeding episodes.[7]

Because levels of factor XIII 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 factor XIII concentrate 10-20 U/kg every 4-6 weeks or rFXIII A-subunit 35 IU/kg monthly provides adequate plasma levels in most patients. The dose and frequency should be tailored to plasma levels and clinical efficacy for each patient.[8]

The half-life of factor XIII 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 factor XIII deficiency because of their family history should be screened at birth and treated promptly if factor XIII deficiency is found.[9]

Surgical Care

In preparation for surgical procedures, patients should receive factor XIII concentrate immediately before surgery to ensure optimal hemostasis and wound healing.

A retrospective study of perioperative acquired factor XIII deficiency by Fahlbusch et al found that in pediatric patients undergoing cardiopulmonary bypass, neither preoperative nor postoperative factor XIII activity accurately predicted the need for postoperative transfusion. There was also no link seen between factor XIII activity and postoperative chest tube drainage loss.[10]

Consultations

Consult a hematologist and/or hemostasis specialist for patients who require factor XIII replacement therapy.

Genetic counseling and family studies should be part of a complete evaluation.

 

Medication

Medication Summary

Scheduled factor XIII (FXIII) replacement every 4-6 weeks maintains factor XIII levels above the critical threshold for spontaneous bleeding and allows patients to participate in regular activities.

For patients with congenital factor XIII A-subunit deficiency, which includes the majority of patients, treatment with recombinant factor XIII, as well as treatment with factor XIII concentrate, can be considered.

For patients with a B-subunit deficiency, the recombinant product cannot be used.

For all patients, treatment with cryoprecipitate and fresh frozen plasma (FFP) should be considered in the event of acute bleeding if concentrate and recombinant factor are not available.

Clotting factors

Class Summary

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.

Factor XIII A-subunit, recombinant (Tretten)

Recombinant human factor XIII-A2 homodimer composed of 2 FXIII A-subunits. FXIII is the terminal enzyme in the blood coagulation cascade; when activated by thrombin at the site of vessel wall injury, FXIII plays an important role in the maintenance of hemostasis through cross-linking of fibrin and other proteins in the fibrin clot.

Factor XIII concentrate (Corifact)

FXIII is a proenzyme that is activated, in the presence of calcium ion, by thrombin cleavage of the A-subunit to become activated FXIII (FXIIIa). Promotes cross-linking of fibrin during coagulation and is essential to the physiological protection of the clot against fibrinolysis.

Indicated for routine prophylactic treatment of congenital factor XIII (FXIII) deficiency.

 

Follow-up

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 factor XIII deficiency, prophylaxis is the best approach.[11]

  • Individuals who require plasma-derived factor XIII 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 factor XIII 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 eMedicineHealth's Oral Health Center. Also, see eMedicineHealth's patient education article Teething.

 

Questions & Answers

Overview

What is pediatric factor XIII (FXIII) deficiency?

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

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

What is the morbidity and mortality associated with pediatric factor XIII (FXIII) deficiency?

What are the sexual predilections of pediatric factor XIII (FXIII) deficiency?

At what age is the diagnosis of pediatric factor XIII (FXIII) deficiency typically made?

Presentation

Which clinical history findings are characteristic of pediatric factor XIII (FXIII) deficiency?

Which physical findings are characteristic of pediatric factor XIII (FXIII) deficiency?

DDX

Which conditions are included in the differential diagnoses of pediatric factor XIII (FXIII) deficiency?

Workup

Which tests are performed to screen for pediatric factor XIII (FXIII) deficiency?

What is the role of functional assays in the workup of pediatric factor XIII (FXIII) deficiency?

What is the role of immunologic assays in the workup of pediatric factor XIII (FXIII) deficiency?

What is the role of imaging studies in the workup of pediatric factor XIII (FXIII) deficiency?

Treatment

How is pediatric factor XIII (FXIII) deficiency treated?

How are patients with pediatric factor XIII (FXIII) deficiency undergoing surgical procedures managed?

Which specialist consultations are beneficial to patients with pediatric factor XIII (FXIII) deficiency?

Medications

What is the role of clotting factors in the treatment of pediatric factor XIII (FXIII) deficiency?

Which medications in the drug class Clotting factors are used in the treatment of Pediatric Factor XIII Deficiency?

Follow-up

Which specialists should provide long-term monitoring of pediatric factor XIII (FXIII) deficiency?

What is the role of prophylaxis in the treatment of pediatric factor XIII (FXIII) deficiency?

What is included in patient education about pediatric factor XIII (FXIII) deficiency?