Factor XIII Deficiency

Etiology

Congenital FXIII Deficiency

FXIII-A is primarily produced in hematopoietic cells, whereas FXIII-B production occurs in hepatocytes. Assembly of the proteins occurs in the plasma. Once fully formed, FXIII consists of a dimer of catalytic A subunits (FXIII-A₂) and a dimer of carrier or inhibitory B subunits (FXIII-B₂), forming a heterotetrameric complex, FXIII-A₂B₂. Acquired forms of FXIII deficiency are more prevalent than congenital forms. Congenital FXIII deficiency has an autosomal recessive pattern of inheritance. Most patients with the congenital form carry variants in the F13A1 gene on chromosome arm 6p24-25, which encodes the FXIII-A subunit.[1]

To date, 153 genetic variations associated with FXIII deficiency have been identified, with missense mutations occurring in more than 50% of cases.[2] In addition, the F13B gene, located on chromosome arm 1q31-32.1 and encoding the FXIII-B subunit, can be affected, with missense mutations being the most prevalent.[3] Currently, nearly 16 mutations are known in the B subunit.[3] The B subunit acts as a carrier for subunit A, preventing spontaneous activation. Therefore, a deficiency or defect in subunit B destabilizes the FXIII-A₂B₂ complex, leading to a relative deficiency of subunit A. Patients with a B subunit deficiency have a less severe bleeding phenotype.[4]

Acquired FXIII Deficiency 

Acquired FXIII deficiency can arise secondary to autoimmune conditions such as systemic lupus erythematosus, rheumatoid arthritis, and idiopathic retroperitoneal fibrosis.[5] Immunoglobulin G1 and G4 autoantibodies were believed to inhibit FXIII. Studies found that acquired acute myeloid leukemia was associated with FXIII deficiency, possibly via RUNX1 and TP53 mutations.[6] In addition, medications such as isoniazid and conditions such as monoclonal gammopathy of undetermined significance have been implicated in causing FXIII deficiency.[7][8][9]

Hyperconsumption of FXIII can result from various factors, including surgical procedures, disseminated intravascular coagulation, inflammatory bowel disease, immunoglobulin A vasculitis, sepsis, leukemia, and thrombosis. Furthermore, hyposynthesis resulting from liver disease and certain medications, including valproic acid, chemotherapeutic agents, and tocilizumab (an anti–interleukin 6 receptor antibody), can also lead to FXIII deficiency.[10] The use of extracorporeal membrane oxygenation is associated with an exceedingly high rate of acquired FXIII deficiency, with figures reported in the 80th to 90th percentiles.[11] The pathophysiological origin of FXIII deficiency is considered consumptive.

Epidemiology

FXIII deficiency, a rare condition, is estimated to have a frequency of 1 in 2 to 3 million live births. The prevalence of FXIII deficiency tends to be higher in regions such as Iran, where consanguinity rates are elevated. However, global prevalence does not vary by race or ethnicity.[12][13][14]

Pathophysiology

FXIII deficiency results in defective fibrin cross-linking, rendering individuals susceptible to delayed bleeding once the initial hemostatic plug is overwhelmed. FXIII is a zymogen, or inactive precursor, that becomes an enzyme upon activation by another enzyme. FXIII-A is the protransglutaminase that undergoes catalysis to become the active transglutaminase. FXIII-B acts as a carrier and regulatory protein for the A subunit, which is inherently unstable in plasma. Half of FXIII-B circulates in plasma bound to FXIII-A, whereas the remainder circulates as FXIII-B₂. Cellular FXIII-A exists primarily as FXIII-A₂ and is present in macrophages, monocytes, megakaryocytes, and platelets.

FXIII-A introduces covalent bonds between fibrin monomers, resulting in a stiff and compact fibrin clot protected from degradation by α2-antiplasmin and thrombin-activatable fibrinolysis inhibitor. Platelet-bound FXIII, present on activated platelet surfaces, aids in clot stabilization and retraction, which are essential processes for wound healing. Furthermore, FXIII plays a pivotal role in wound healing by cross-linking extracellular matrix proteins, including fibronectin, vitronectin, thrombospondin, and collagen, and by promoting cellular signaling in leukocytes and endothelial cells.[12] FXIII activates vascular endothelial growth factor receptor 2 by binding to αVβ3 integrin, promoting endothelial cell proliferation, survival, and angiogenesis.[12] FXIII-A notably promotes angiogenesis.[12]

The function of FXIII extends beyond hemostasis to encompass critical roles in wound healing, tissue repair, extracellular matrix deposition, osteoblastic differentiation, and regulation of the immune response at the cellular and humoral levels. The fibrin clot, aided by FXIII, is a crucial component of innate immunity, with FXIII-A enhancing monocyte proliferation and migration. Furthermore, FXIII-A regulates preadipocyte differentiation and modulates insulin signaling by facilitating the assembly of plasma fibronectin into the extracellular matrix, potentially influencing adipogenesis.

History and Physical

Individuals who are homozygous may have delayed detachment and bleeding of the umbilical cord, hemarthrosis, intracranial hemorrhage, heavy menstrual bleeding, recurrent early pregnancy loss, delayed postoperative bleeding, and prolonged bleeding after trauma or a surgical procedure.[15] Caregivers may notice easy bruising and soft tissue bleeding when a child begins to ambulate or during episodes of emotional distress. In contrast, patients who are heterozygous typically remain asymptomatic.

Umbilical cord bleeding is reported in up to 80% of neonates, often occurring within the first 3 weeks after birth.[12][16] The extent of bleeding usually correlates with plasma FXIII levels; symptoms are often observed in patients with FXIII levels less than 5%. The risk of significant spontaneous bleeding increases markedly when FXIII activity falls less than 15%. Individuals with undetectable FXIII levels typically present with symptoms in the neonatal period.

Thirty percent of neonates with severe FXIII deficiency, defined as FXIII levels less than 1%, experience spontaneous, life-threatening intracranial hemorrhage, a significantly higher incidence compared with hemophilia A and B.[17][18] Posttraumatic intracranial hemorrhage is frequently recognized as the initial indicator of FXIII deficiency in older children, with one-third experiencing recurrence. Recurrent intracranial hemorrhage is associated with higher mortality in patients with FXIII deficiency.[19] Factor XIII deficiency in infancy is associated with supratentorial hemorrhage, often leading to mass effect with subsequent hydrocephalus.[20]

Acquired FXIII deficiency is rare, and its presentation varies based on the underlying cause.[21] Immune-mediated acquired FXIII deficiency often presents with spontaneous bleeding in the subcutaneous or intramuscular compartments.[7] Immune-mediated acquired FXIII deficiency predominantly affects individuals aged 70 or older who have underlying conditions such as systemic lupus erythematosus, rheumatoid arthritis, and leukemia. For further information regarding underlying conditions, please refer to the Etiology section of this article.[7] 

Evaluation

The evaluation for potential bleeding disorders typically begins with a comprehensive assessment of personal and family medical histories. When a family history of a bleeding disorder is present, clinicians should examine the family pedigree to determine the inheritance pattern. Subsequently, factor activity levels should be tested in the neonate, preferably in cord blood.

Pregnant individuals may choose to undergo chorionic villous sampling between 10 and 12 weeks of gestation or amniocentesis between 16 and 20 weeks of gestation to obtain fetal cells for DNA analysis in linkage studies. If fetal DNA is unobtainable, clinicians may use fetoscopy to collect fetal blood at 20 weeks of gestation. Given the 0.5% risk of maternal-fetal complications and the 1% to 6% risk of fetal death associated with fetoscopy, thorough genetic and obstetric counseling is essential before these procedures.

Although routine clotting tests, such as prothrombin time, activated partial thromboplastin time (aPTT), and international normalized ratio, help diagnose many other factor deficiencies, they do not detect FXIII deficiency because FXIII acts after fibrin generation. Consequently, results from these tests are typically normal in individuals with FXIII deficiency.[22] Evaluating FXIII deficiency requires specialized laboratory tests, including the clot solubility test, FXIII activity assay, FXIII antigen assay, inhibitor assay, and genetic analysis. Thromboelastography lacks standardization across institutions and is not considered a reliable diagnostic tool for this condition. Although growing evidence suggests that Thromboelastography is more sensitive than solubility tests,[23] further prospective studies are required to validate this observation.

Other coagulation factor deficiencies may have associated abnormal aPTT and prothrombin time results if the following conditions exist:

• Isolated elevation of prothrombin time levels: Test FVII activity
• Isolated elevation of aPTT levels: Test FVIII, FIX, and FXI activities
• Elevated prothrombin time and aPTT levels: Test FII, FV, FX, or thrombin, and fibrinogen activities
• Prothrombin time and aPTT in reference range: Test FXIII activity

Clot Solubility Test

The benefits of the clot solubility test include its simplicity, cost-effectiveness, and the absence of specialized equipment. This test evaluates clot solubility in either 5 mol/L urea or 1% monochloroacetic acid. If clot lysis occurs within a few hours, severe FXIII deficiency is likely, provided that fibrinogen levels are qualitatively and quantitatively within the reference range. However, the test's clinical reliability is limited by its false-positive rate. The acetic acid assay is faster and more sensitive than the urea solubility test, but lacks specificity.[24] 

Various scenarios may influence the results of the clot solubility test, including: 

• Hypofibrinogenemia or dysfibrinogenemia can lead to false-positive results on the 5 mol/L urea test. Therefore, clinicians should assess patients for hypofibrinogenemia using tests such as thrombin time, reptilase time, fibrinogen assay, and fibrinogen activity before diagnosing FXIII deficiency.[25]
• Elevated pepsinogen levels, which can occur in certain gastric disorders, can yield false-positive results on the acetic acid test.[26]

The clot solubility test has additional limitations. The clot sensitivity test lacks adequate sensitivity and specificity and may underestimate the degree of FXIII deficiency. Furthermore, the test cannot reliably identify patients with mild or moderate FXIII deficiency, and heterozygous carriers may go undetected.

Standardization of the clot solubility test across various laboratories is lacking, and its use is uncommon in resource-limited countries. However, this test remains widely used in resource-limited countries where alternative assays may be unavailable due to its low cost. No standard guidelines exist for using the clot solubility test. An alternative diagnostic approach involves using 2 different assays, each using distinct clotting and solubilizing agents, and conducting both tests concurrently. If 1 test result is positive, further investigations are warranted to assess for FXIII deficiency.[27] 

Quantitative Assays

Quantitative or functional assays, if available, are the preferred initial tests to diagnose FXIII deficiency. 

Ammonia release assay: A quick and efficient method for assessing FXIII activity. This assay relies on the release of ammonia during the transglutaminase reaction and quantifies FXIII activity by measuring photometric absorbance at 340 nm. FXIII activity leads to the release of ammonia, which in turn converts nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) or nicotinamide adenine dinucleotide hydrogen (NADH) to nicotinamide adenine dinucleotide (NAD+) or nicotinamide adenine dinucleotide phosphate (NADP+).

The assay determines FXIII activity by measuring NADPH consumption. However, because FXIII independently releases ammonia, this test may overestimate FXIII activity and report falsely elevated levels. To address this issue, manufacturers include a plasma blank in the kit, which corrects for this phenomenon and ensures accurate FXIII activity readings.[13]

Amine incorporation assay: These tests use fluorescent, radiolabeled, or biotinylated amines covalently bound to a glutamine residue of the substrate, and the amount of unbound amines is measured after the protein fraction is released. Although more sensitive than the ammonia release assay, this assay is not standardized, lacks validity, and is time-consuming.[13] 

Isopeptide assay: The amine incorporation assay uses fluorescent, radiolabeled, or biotinylated amines that are covalently bound to a glutamine residue on the substrate. The unbound amines are measured after the protein fraction releases them. Although this assay is more sensitive than the ammonia release assay, it is time-consuming and lacks standardization and validity.

Immunological Assays

Immunological assays can distinguish between FXIII-A, FXIII-B, and the FXIII-A₂B₂ complex, thereby identifying the type of deficiency present. However, these assays cannot detect rare forms of FXIII deficiency, such as type 2 defects, where the FXIII-A subunit is present but functionally inactive. An example of a widely used immunoassay is the enzyme-linked immunosorbent assay (ELISA).

The Reanal-ker enzyme-linked immunosorbent assay (R-ELISA; Reanal-ker, Budapest, Hungary) is a single-step sandwich ELISA using an anti–FXIII-A primary antibody and an anti–FXIII-B secondary antibody. This assay effectively eliminates interference from free FXIII-B subunits and fibrinogen, allowing determination of FXIII concentrations as low as 0.001 IU/mL. Electroimmunoassays and radioimmunoassays, although available, are less commonly used due to their lack of standardization and cumbersome procedures.

FXIII Inhibitor Assays

Inhibitor assays are necessary for patients suspected of developing anti-FXIII antibodies. Patients can develop the following 2 types of antibodies:

• Neutralizing autoantibodies against FXIII-A, which are typically not detected by mixing studies.
• Nonneutralizing inhibitors, generally IgG or IgM antibodies, can be detected by ELISA.[28][29]

These assays are conducted only in select countries and institutions where the necessary tests are available. With more than 1000 polymorphisms present in both FXIII subunits, mapping the entire gene in all patients is impractical. Evidence suggests that these polymorphisms vary based on ethnicity.[2] Consequently, many countries and institutions prioritize testing for the most prevalent polymorphisms in their respective populations.[30][31] 

Treatment / Management

All neonatal invasive procedures, such as circumcision, should be postponed until the diagnosis of FXIII deficiency can be confirmed or excluded. Treatment options should be tailored to each patient's specific needs. Clinicians use FXIII replacement products to treat and prevent acute bleeding in patients with FXIII deficiency.

Two such products are catridecagog, a recombinant FXIII-A subunit (marketed as Tretten by Novo Nordisk), and FXIII purified from human plasma (known as Fibrogammin and Fibrogammin-P in Europe, South America, and Asia, and Corifact in the United States).[32][33][34] The plasma-derived product contains both A and B subunits, making it universally acceptable and effective for controlling bleeding in patients, regardless of whether the mutation affects either subunit.[34] 

Recombinant FXIII-A (rFXIII-A₂) contains only FXIII-A, making it specific to most patients with FXIII deficiency. In results from a multinational, open-label, single-arm phase 3 trial, prophylactic administration of rFXIII-A₂ to 41 patients with congenital FXIII-A deficiency reduced the annual bleeding rate from 0.138 to 2.91 bleeds per patient, compared with 2.91 bleeds per patient treated on demand.[17] In addition, findings from the MENTOR-2 trial indicate that patients undergoing surgical procedures who received prophylactic doses of 35 IU/kg of rFXIII-A₂ had an annual bleeding rate of 0.043 per patient and a mean annual spontaneous bleeding rate of 0.011 per patient. All study participants remained in the trial and tolerated the drug well.[35] The efficacy of rFXIII-A₂ was further confirmed in results from a real-world study conducted in Italy, which demonstrated effective control over a broad range of dosing schedules.[36]

When FXIII replacement products are unavailable, cryoprecipitate and fresh frozen plasma (FFP) are suitable alternatives. Solvent-detergent-treated FFP is ideal if available. Cryoprecipitate contains approximately 20% to 30% of the plasma's original FXIII content.[37] Although many European countries have withdrawn cryoprecipitate due to safety concerns such as pathogen transfer, it remains available in the United States, Canada, and many other countries.[38] 

The average FXIII content in FFP ranges from 0.5 to 1.5 U/mL.[39] Compared with FFP, cryoprecipitate has a higher FXIII enrichment.[39][40] However, 1 bag of cryoprecipitate yields less than 1 bag of FFP.[39] FFP may be preferred when infusion volume is not a significant consideration.

Acute Bleeding

The treatment goal is to attain FXIII activity levels greater than 5%. Higher targets may be required for severe, life-threatening bleeding episodes. A single dose of replacement product is typically sufficient to achieve therapeutic objectives. The dosing for patients experiencing acute bleeding is outlined as follows:

• Recombinant FXIII-A subunit: 35 IU/kg
• Plasma-derived FXIII concentrate: Corifact 40 IU/kg; Fibrogammin and Fibrogammin-P 10 to 20 IU/kg
• Fresh frozen plasma: 15 to 20 mL/kg
• Cryoprecipitate: 1 bag per 10 kg

Perioperative Treatment

Dosing remains consistent for patients with acute bleeding. The usual therapeutic aim is to achieve FXIII activity levels greater than 5%. Nonetheless, bleeding may still arise during surgical procedures or trauma in affected patients, necessitating higher activity levels.[41] If the patient has received a routine prophylactic dose within 7 days before a surgical procedure, additional treatment may not be required. However, if the patient has not received prophylactic treatment, administration of FXIII concentrate is warranted. Given the long half-life of FXIII, ranging from 11 to 14 days, a single dose is typically adequate.(B3)

Pregnant patients with FXIII deficiency: Pregnant individuals with severe FXIII deficiency face significant risks, necessitating FXIII replacement therapy for successful pregnancy outcomes. Initiation of replacement therapy should ideally occur by 5 weeks of gestation to mitigate the risk of miscarriage.[42] FXIII activity should be maintained at 2% to 3%, with optimal levels exceeding 10%.(B3)

Dosing typically involves a regimen of 250 IU/wk for the first 22 weeks of gestation, followed by an increase to 500 IU/wk from 23 weeks of gestation until the onset of labor. In addition, pregnant patients are administered 1000 IU at the onset of labor to attain factor activity levels greater than 30% for delivery. An alternative dosing schedule involves 10 IU/kg every 2 weeks throughout pregnancy.[43][44](B2)

Prophylaxis: Prophylactic therapy is warranted for patients with FXIII activity levels less than 5% or a history of recurrent bleeding episodes. The dosing regimen mirrors that used to treat acute bleeding. Patients diagnosed with FXIII-B deficiency should be treated with plasma-derived factor concentrate. Alternatively, FFP and cryoprecipitate are viable options. Prophylactic dosing intervals are typically every 20 to 30 days to maintain FXIII trough levels above 5%.

Patients with acquired FXIII deficiency: Treatment strategies include FXIII replacement therapy, antifibrinolytic therapy, and inhibitor eradication. Mild inhibitors may respond to corticosteroid therapy alone, whereas more potent inhibitors may require B-cell–directed therapy, typically with rituximab. In addition, plasma exchange has demonstrated efficacy in the short-term removal of FXIII inhibitors.[45]

Differential Diagnosis

All bleeding disorders, including factor deficiencies and platelet dysfunction syndromes, can mimic FXIII deficiency. The following list outlines potential differential diagnoses:

• Inherited afibrinogenemia or dyshypofibrinogenemias, α2-plasmin inhibitor deficiency, plasminogen activator inhibitor 1 deficiency, hemophilia A or B, and type 3 von Willebrand disease.
• Platelet dysfunction disorders, such as Glanzmann thrombasthenia, Bernard-Soulier syndrome, and von Willebrand disease types 1 and 2.
• Additional coagulation factor deficiencies include FII, FV, FVII, FX, and FXI.
• Acquired causes of FXIII deficiency include malignant neoplasms, autoimmune disorders, medications, hyperconsumption, disseminated intravascular coagulation, and liver disease.

Prognosis

Congenital FXIII deficiency is extremely rare, and acquired FXIII deficiency is even rarer. Patients receiving replacement therapy can typically expect a life expectancy comparable to that of the general population, although few large-scale studies have evaluated mortality rates. In untreated individuals, intracranial hemorrhage is the primary cause of death.[29] 

Approximately 30% of central nervous system bleeding cases recur, with approximately 50% of recurrent cases resulting in death. However, the severity of FXIII deficiency can vary among families. The development of FXIII inhibitors, whether alloantibodies or autoantibodies, is associated with significant morbidity and mortality.

Complications

Complications associated with FXIII deficiency are most common in untreated patients. The following is a list of potential complications related to FXIII deficiency:

• Umbilical bleeding, intracranial hemorrhage, recurrent fetal loss, hemarthrosis, delayed postoperative or posttraumatic bleeding, pathogen transmission from plasma-derived products, development of FXIII inhibitors, and transfusion reactions.
• Central venous catheter-related complications include pneumothorax, arrhythmia, venous air embolism, arterial injury, catheter-site infection, catheter vein stenosis, and catheter-related venous thrombosis.
• The development of inhibitors or antibodies to the foreign protein or factor most frequently occurs in patients with undetectable factor activity.