History
The following symptoms should trigger an evaluation for factor XIII (FXIII) deficiency:
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Spontaneous miscarriages early in pregnancy
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Bleeding from the umbilical cord 1-19 days after birth
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Easy bruising and soft tissue bleeding, particularly in association with trauma, as the infant starts to ambulate; bleeding following trauma may be immediate, delayed, and/or recurrent
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CNS hemorrhage, which is common and recurs in approximately 30% of patients, and may be the initial manifestation in patients with severe FXIII deficiency.
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CNS bleeding may be preceded by head trauma in children, while adults may develop a CNS bleed in the absence of obvious trauma.
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Symptoms typical of any CNS event may be present, eg, headaches, seizures, vomiting, and focal neurologic defects. Symptoms may be acute at onset or may be superimposed on residual findings of a past bleed
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Menorrhagia and intra-abdominal bleeding during menses may be present
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Bleeding into joints may be precipitated by trauma. Although reports exist of recurrent target joint bleeds, destructive changes in the joints are uncommon. [5] Spontaneous joint and extensive muscle bleeding, characteristic of patients with severe hemophilia, are uncommon in patients with severe FXIII deficiency.
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The severity of bleeding is variable. An unusual example is the history of a very mild bleeding disorder in 2 sisters despite severely reduced levels of FXIII (< 1%). One of the sisters had 2 successful pregnancies without product replacement (see Causes for details). [76]
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Poor wound healing, although described, is less common.
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Heterozygous parents of a proband with severe bleeding usually are asymptomatic, although some cases of bleeding in heterozygotes have been reported.
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Development of alloantibodies is a serious complication that results in increased bleeding and a lack of response to usual therapy. This condition can have fatal consequences (see DDx: Diagnostic Considerations for more information).
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Autoantibodies to FXIII are an acquired cause of a bleeding diathesis. A detailed drug history is essential in assessing the possible contribution to inhibitor development. As the frequency of tuberculosis rises worldwide and the use of isoniazid increases, the number of patients with inhibitors may increase (see DDx: Diagnostic Considerations for more information).
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Patients may have acute and/or chronic viral illnesses transmitted by less-pure products, such as fresh frozen plasma or cryoprecipitate, that are used to treat bleeding. HIV-related illnesses, AIDS, chronic hepatitis, progressive hepatic failure, and parvovirus-related illnesses present in the usual manner.
Physical
Physical findings depend on the site at which bleeding develops and include the following:
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Bleeding from the umbilical cord in neonates usually manifests with persistent oozing, which may start a few days after birth.
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Findings associated with CNS bleeding depend on the location of the bleeding. Trauma may precede the event, with additional findings. A new CNS bleed may be superimposed on residual findings related to a prior bleed.
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Findings in patients with bruising and soft tissue bleeding are similar to those seen in other patients with coagulation disorders; it is uncommon to find the large hematomas or joint bleeds characteristic in patients with severe hemophilia.
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Patients may present with vaginal spotting or bleeding during early pregnancy, preceding a spontaneous miscarriage.
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Persistent, delayed, or recurrent bleeding may occur at sites of trauma or surgery.
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Poor wound healing may be noted.
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Acquired causes of FXIII deficiency, such as disseminated intravascular coagulation (DIC) and liver disease, present in a well-recognized manner.
Causes
To date, most identified mutations leading to severe FXIII deficiency and a bleeding disorder involve subunit A, with very few mutations reported involving subunit B. The gene for subunit A is located on chromosome 6 bands p24-25. The gene is 160 kilobases in length and has 15 exons and 14 introns with specific structural and functional domains. Catalytic activity is encoded in the second exon, and the active cysteine is encoded by the seventh exon. The 2 Ca2+ -binding sites and a thrombin-inactivation site have been identified at other locations. The gene for subunit B is located on chromosome 1 bands q31-32.1, is 28 kilobases in length, and has 12 exons and 11 introns. [12, 77] (See the image below.)
Gene, messenger RNA, and protein for subunit A of factor XIII. Adapted from Reitsma PH. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Lippincott Williams & Wilkins; 2001:59-87 and from Roberts HR, Monroe DM III, Hoffman M. In: Williams Hematology. McGraw-Hill Professional; 2001:1409-34.
Detailed characteristics of complementary ribonucleic acid (cRNA) and messenger ribonucleic acid (mRNA) of the placental subunit A are known. The presence of an acetylated amino terminal end and the absence of glycosylation and disulfide bonds apparently are features typical of secreted cytoplasmic proteins. The presence of these characteristics makes it conducive for subunit A expressed in yeast systems to make a recombinant product.
Substitutions in the core domain of the enzyme, affecting highly conserved residues, result in a serious defect in structure and function. Missense mutations in the A chain are a common cause, accounting for approximately 50% of cases of severe FXIII deficiency. The defects result in an absence of subunit A protein but also are accompanied by a reduction in subunit B carrier protein (type II defect).
Nonsense mutations are an equally common cause of A chain defects, resulting in a frameshift-type, splice-type, or termination-type mutation. The few defects that have been reported in the B chain lead to a deficiency of the carrier protein (subunit B), which then leads to instability and reduction of plasma subunit A levels despite the presence of functional intracellular subunit A (type I defect). [78] Therefore, patients who are homozygous for subunit B mutations have a bleeding disorder. Most recently, impaired intracellular transport from the endoplasmic reticulum to the Golgi apparatus, with failure of secretion of the truncated FXIII subunit B produced by a single-base deletion, was reported to be the cause of severe FXIII deficiency in 3 unrelated patients. [79]
Many kinds of mutations have been (and continue to be) identified, with some mutations unique to certain families. The finding of compound heterozygotes has eliminated the mandatory search for consanguinity in all parents of patients with severe FXIII deficiency. [80, 81, 47]
An unusual mutation has been described in 2 Finnish sisters with a very mild bleeding disorder. One sister had 2 successful pregnancies without regular replacement therapy. The sisters had no detectable subunit A activity (< 1%) using plasma screening tests; however, using the 3H-putrescine incorporation assay, subunit A showed 0.35% of normal activity, with partial g-g dimerization of fibrin in clotted plasma. A full-length subunit A was detected in the patients' platelets using Western blot analysis.
The sisters had an Arg661→stop mutation on one allele and a T→C transition on the other allele. These data showed that a mutation in the splice donor site of intron C can result in different variant mRNA transcripts and that small amounts of correctly processed mRNA can produce a type of FXIII that can produce, at least, dimerization of fibrin, thus minimizing the clinical consequences. [76]
Various reported mutations are spread throughout the gene coding for FXIII without specific hot spots. In many patients, low steady-state mRNA levels have been found, which result in inefficient production of the abnormal protein. [13]
Data in the literature conflict regarding the impact of the common FXIII subunit A Val34Leu mutation (associated with higher plasma transglutaminase activity) on thrombotic disease. Note the following:
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The Val34Leu mutation continues to be studied in different populations because current data provide conflicting evidence about its causal role in coronary artery disease. The Val34Leu mutation appears to protect whites but not Asian Indians from myocardial infarction. However, in the Asian Indian population in Britain, a strong link was found between FXIII subunit B levels and risk factors for cardiovascular disease and, possibly, insulin resistance. [82]
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In separate studies, a higher frequency of the Val34Leu mutation was found in whites with primary intracerebral hemorrhage; however, the mutation reportedly was associated with a reduction in brain infarcts.
A possible cooperative interaction between the Val34Leu mutation and other known thrombophilic mutations also has been explored. Note the following:
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In a study of patients from southern France, a higher than usual odds ratio was found for the association between carriers of an angiotensin receptor mutation and coronary artery disease, but no association was found between the disease and any of the FXIII polymorphisms that were studied. [83]
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A study of the contribution of the Val34Leu mutation to thrombotic risk in a large number of carriers of factor V Leiden (who were relatives of thrombotic probands with factor V Leiden) found a very modest contribution of the Val34Leu mutation to venous thrombotic disease. [84]
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This study contrasts with a report of a protective role of the mutation in venous thrombosis. [85]
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A review by Kohler discusses the possible role of FXIII in vascular diseases. [86] The FXIII Val34Leu mutation does not appear to influence the induction or modification of the course of inflammatory bowel disease.
Genetic polymorphisms affecting both the A and B subunits have been reported, but because they do not involve conserved amino acids or are not important for protein structure, they do not result in FXIII deficiency and bleeding. Based on an analysis of polymorphisms in the gene for FXIII subunit A and their products in a northern Portuguese population, it has been stated that the evolutionary order of appearance of the main protein alleles for FXIII is 1B-->2B-->1A-->2A and that intragenic combinations are likely to have played a role in the molecular diversity in the main FXIII subunit A alleles. [87]
Genetic polymorphisms and, particularly, intragenic polymorphisms are useful in genetic counseling of families with unknown mutations. For example, 80% of whites are heterozygous for a tetrameric repeat in intron 1 of subunit A, which can help differentiate defects in subunit A from defects in subunit B. [12, 13, 77, 7] Some polymorphisms are universal, while others appear to be restricted to particular ethnic groups. The latter situation will change as ethnic intermarriages increase in this global society. Families with severe FXIII deficiency associated with a serious disabling bleeding disorder have access to all of the genetic tools available to patients with hemophilia A and B. Next-generation sequencing technology allows a rapid and simultaneous analysis of all regions of all the genes involved in the disorder. [88]
Disorders of fibrin stabilization can affect the activity of FXIII or its substrates fibrin and fibrinogen. A proposed classification of disorders leading to a positive urea solubility test result is presented below.
Abnormalities of FXIII (enzyme) are as follows:
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Genetic mutation - (1) Subunit A, (2) subunit B, (3) subunit A and B
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Acquired - (1) Decreased production (ie, liver disease), (2) increased loss due to excessive activation (ie, DIC, exposure to snake venoms and caterpillar toxins), (3) secondary to inhibitors (ie, alloantibodies and autoantibodies)
Abnormalities of the substrate for FXIII (fibrin/fibrinogen) are as follows:
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Genetic mutation - (1) Afibrinogenemia, (2) dyshypofibrinogenemia
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Acquired - (1) Decreased production (ie, acute massive hepatic necrosis or severe chronic liver disease), (2) increased loss resulting from defibrination syndromes (ie, DIC, exposure to snake venoms and caterpillar toxins, and systemic hyperfibrinolysis [drug induced or disease induced])
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Coagulation reactions leading to thrombin generation and activation of factor XIII.
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Final steps in clot formation (from article: Factor XIII).
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Activation of factor XIII and generation of insoluble cross-linked fibrin. Adapted from Lorand L. Ann N Y Acad Sci. 2001;936:291-311.
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Postulated interaction between factor XIII and thrombin-activatable fibrinolytic inhibitor.
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Cell surfaced–directed hemostasis. Initially, a small amount of thrombin is generated on the surface of the tissue factor–bearing (TF-bearing) cell. Following amplification, the second burst generates a larger amount of thrombin, leading to fibrin (clot) formation (from article: Factor XIII). Adapted from Hoffman and Monroe. Thromb Haemost. 2001;85(6):958-65.
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Gene, messenger RNA, and protein for subunit A of factor XIII. Adapted from Reitsma PH. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Lippincott Williams & Wilkins; 2001:59-87 and from Roberts HR, Monroe DM III, Hoffman M. In: Williams Hematology. McGraw-Hill Professional; 2001:1409-34.
Tables
Properties |
A Chain |
B Chain |
Plasma FXIII |
Has 2 A chains |
Has 2 B chains |
Plasma level |
Approximately 15 mg/mL |
Approximately 21 mg/mL |
Chains are free in plasma |
No. All bound to B chain and present as an A2 B2 tetramer |
Yes. Excess B chain present in plasma as a B2 dimer |
Chain contains the catalytic site |
Yes |
No |
Chain is the carrier protein |
No |
Yes |
Chain acts as a brake on FXIII activation |
No |
Yes |
Cellular FXIII |
Has 2 A chains (A2 dimer) |
Has no B chains |
Mutations can lead to decreased FXIII activity |
Yes |
Yes |
