Factor XIII Deficiency

Etiology

Congenital FXIII Deficiency

FXIII-A is primarily produced in the hematopoietic cells, whereas FXIII-B production occurs in hepatocytes. Assembly 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 FXIIIA₂B₂. Acquired forms of FXIII deficiency are more prevalent than the congenital forms. Congenital FXIII deficiency has an autosomal recessive pattern of transmission. Ninety-five percent of patients with the congenital form carry variations in the F13a1 gene located on chromosome arm 6p24-25 encoding the FXIII-A subunit.[1]

To date, researchers are aware of 153 genetic variations associated with FXIII deficiency, with missense mutations occurring in over 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. Hence, a deficiency or defect of the subunit B makes the FXIIIA₂B₂ complex unstable, 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 (SLE) and rheumatoid arthritis. In these cases, affected patients produce autoantibodies targeting FXIII. In addition, medications such as isoniazid and conditions such as monoclonal gammopathy of undetermined significance have been implicated in causing FXIII deficiency.[5][6][7]

Hyperconsumption of FXIII can occur due to various factors such as surgery, disseminated intravascular coagulation, inflammatory bowel disease, Henoch-Schönlein purpura, 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.[8] 

Epidemiology

FXIII deficiency, a rare condition, is estimated to have a frequency of 1 in 2 to 3 million live births. The prevalence of this condition tends to be higher in regions such as Iran, where consanguinity rates are elevated. However, there is no discernible variation in prevalence based on ethnicity or race globally.[9][10][11] Notably, prevalence rates may change with increased awareness, improved laboratory testing, and the increased global use of isoniazid worldwide for tuberculosis treatment.

Pathophysiology

FXIII deficiency results in defective cross-linking of fibrin, rendering individuals susceptible to delayed bleeding once the initial hemostatic plug becomes overwhelmed. FXIII is a zymogen, or inactive precursor, which transforms into an enzyme upon activation by another enzyme. FXIII-A is the pro-transglutaminase 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, while 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, which is protected from degradation by α-2 antiplasmin and thrombin-activatable fibrinolysis inhibitor. Platelet-bound FXIII, present on activated platelet surfaces, aids in clot stabilization and retraction, essential processes for wound healing. Furthermore, FXIII plays a pivotal role in wound healing by cross-linking proteins within the extracellular matrix, including fibronectin, vitronectin, thrombospondin, and collagen, and by promoting cellular signaling in leukocytes and endothelial cells.[9] FXIII causes vascular endothelial growth factor receptor 2 (VEGFR-2) activation by binding to αVβ3-integrin, leading to endothelial cell proliferation, survival, and angiogenesis.[9] FXIII-A notably exhibits a positive effect on angiogenesis.[9]

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

History and Physical

Homozygous individuals may exhibit 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 surgery.[12] Caregivers may notice easy bruising and soft tissue bleeding when a child begins to ambulate or during episodes of emotional distress. In contrast, heterozygous patients typically remain asymptomatic. Umbilical cord bleeding is reported in up to 80% of neonates, often occurring within the first 3 weeks after birth.[9][13] The extent of bleeding usually correlates with plasma FXIII levels; symptoms are often observed in patients with FXIII levels below 5%. The risk of experiencing significant spontaneous bleeding increases notably when FXIII factor activity falls below 15%. Individuals with undetectable FXIII levels typically present symptoms during the neonatal period.

Thirty percent of neonates with severe FXIII deficiency, or FXIII level less than 1%, experience spontaneous, life-threatening intracranial hemorrhage, a significantly higher incidence compared to hemophilia A and B.[14][15] 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.[16]

Acquired FXIII deficiency is rare, and its presentation varies based on the underlying cause.[17] In cases where it is immune-mediated, acquired FXIII deficiency often presents with spontaneous bleeding in the subcutaneous or intramuscular compartments.[5] This condition predominantly affects individuals aged 70 or older who have underlying conditions such as SLE, rheumatoid arthritis, and leukemia. For further information regarding underlying conditions, please refer to the Etiology section of this article.[5] 

Evaluation

The evaluation for potential bleeding disorders typically begins with a comprehensive assessment of personal and family medical histories. In instances of a family history of a bleeding disorder, clinicians should examine the family pedigree to ascertain the inheritance pattern. Subsequently, factor activity levels of the neonate should be tested, preferably utilizing cord blood. Pregnant patients 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 opt for a 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 the prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR), help diagnose many other factor deficiencies, they do not detect FXIII deficiency, as FXIII plays a role after fibrin generation. Consequently, these tests typically yield normal results in individuals with FXIII deficiency.[18] Evaluating FXIII deficiency necessitates specialized laboratory tests, including the clot solubility test, FXIII activity assay, FXIII antigen assay, inhibitor assay, and genetic analysis.

As thromboelastography (TEG) lacks standardization across different institutions, it is, therefore, not considered a reliable diagnostic tool for this condition. Although growing evidence suggests that TEG is more sensitive than the solubility tests,[19] further prospective studies are required to validate this observation.

All other FXIII deficiencies will have associated abnormal aPTT and PT if the following conditions exist: 

• Isolated elevation of PT and test FVII activity.
• Isolated elevation of aPTT, test FVIII, FIX, and FXI activities.
• Elevated PT and aPTT, test FV, FX, FII or thrombin, and fibrinogen.
• Normal PT and aPTT test FXIII.

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 5M 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.[20] 

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

• Hypofibrinogenemia or dysfibrinogenemia can lead to false-positive outcomes on the 5M 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.[21]

• High levels of pepsinogen, which can be present in certain gastric disorders, can potentially generate false-positive outcomes on the acetic acid test.[22]

The clot solubility test is fraught with 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 usage is uncommon in developed countries. However, this test is still widely popular in developing countries where alternative assays may be unavailable due to its low cost. No standard guidelines exist for the utilization of the clot solubility test. An alternative diagnostic approach involves using 2 different assays, each utilizing distinct clotting and solubilizing agents, and conducting both tests concurrently. If 1 test yields a positive result, further investigations are warranted to assess for FXIII deficiency.[23] 

Quantitative Assays

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

Ammonia release assay: The ammonia release assay is a quick and efficient method for assessing FXIII activity. This assay operates based on the release of ammonia during the transglutaminase reaction and quantifies FXIII activity by measuring the photometric absorbance at a wavelength of 340 nm. FXIII activity leads to the release of ammonia, which in turn converts nicotinamide adenine dinucleotide phosphate plus hydrogen (NADPH) or nicotinamide adenine dinucleotide plus hydrogen (NADH) to NAD+ or NADP+. The assay determines FXIII activity by measuring the consumption of NADPH. 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 this phenomenon and ensures an accurate reading of FXIII activity.[10]

Amine incorporation assay: These tests use fluorescent, radiolabeled, or biotinylated amines covalently bound to a glutamine residue of the substrate measured after the protein fraction releases unbound amines. Although a more sensitive test than the ammonia release assay, this assay is not standardized, lacks validity, and is time-consuming.[10] 

Isopeptide assay: The amine incorporation assay utilizes fluorescent, radiolabeled, or biotinylated amines that are covalently bound to a glutamine residue of 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 FXIIIA2B2 complex, thereby identifying the type of deficiency present. However, these assays cannot detect rare forms of FXIII deficiency, such as type II defects, where the FXIII-A subunit is present but functionally inactive. An example of a widely utilized immunoassay is the enzyme-linked immunoassay (ELISA). The 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 for determining 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 antibodies to FXIII. Patients can develop the following 2 types of antibodies:

• Neutralizing autoantibodies against FXIII-A, which are typically not detected by mixing studies.

• Non-neutralizing inhibitors, generally immunoglobulins IgG or IgM antibodies, which can be detected through ELISA assays.[24][25]

These assays are conducted only in select countries and institutions where the necessary tests are available. With over 1000 polymorphisms present in both FXIII subunits, it is impractical to map the entire gene in all patients. 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.[26][27] 

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 the specific needs of each patient. 

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).[28][29][30] The plasma-derived product has both subunits A and B, making it a universally acceptable product that can control bleeding in patients regardless of a mutation in subunit A or B.[30] 

Recombinant FXIII-A (rFXIII-A₂) contains only FXIII-A, making it specific to most patients with FXIII deficiency. In a multinational, open-label, single-arm phase 3 trial, prophylactic administration of rFXIII-A2 to 41 patients with congenital FXIII-A deficiency resulted in a decline in the annual rate of bleeding from 0.138 compared to 2.91 annual bleeds per patient historically treated on demand.[14] In addition, findings from the MENTOR-2 trial indicate that surgical patients receiving prophylactic doses of 35 IU/kg of rFXIII-A2 experienced annual bleeding rates of 0.043 per patient, with a mean yearly spontaneous bleeding rate of 0.011 per patient. All study participants remained in the trial and tolerated the drug well.[31] The efficacy of rFXIII-A2 was further confirmed in a real-world study conducted in Italy, demonstrating effective control over a broad range of dosing schedules.[32]

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 original quantity of FXIII as plasma.[33] 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.[34] 

The average content of FXIII in FFP varies between 0.5 and 1.5 U/mL.[35] Compared to FFP, cryoprecipitate has a higher enrichment of FXIII.[35][36] However, 1 bag of cryoprecipitate yields lower than that of a bag of FFP.[35] 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 Management

The dosing remains consistent for patients experiencing acute bleeding. The usual therapeutic aim is to achieve FXIII activity levels exceeding 5%. Nonetheless, bleeding may still arise during surgical procedures or trauma in affected patients, necessitating higher activity levels.[37] If the patient has received a routine prophylactic dose within 7 days before a surgical procedure, additional treatment may not be required. However, if not, 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 patients 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.[38] FXIII activity levels should be maintained above 2% to 3%, with levels greater than 10% being optimal. Dosing typically involves a regimen of 250 IU/week up to 22 weeks of gestation, followed by an increase to 500 IU/week from 23 weeks gestation until the onset of labor. In addition, pregnant patients are administered 1000 IU at the onset of labor to attain factor activity levels exceeding 30% for delivery. An alternative dosing schedule involves 10 IU/kg every 2 weeks throughout pregnancy.[39][40](B2)

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

Patients with acquired FXIII deficiency: For patients diagnosed with acquired FXIII deficiency, treatment strategies may involve FXIII replacement therapy, antifibrinolytics administration, and inhibitor eradication. Mild inhibitors may respond to steroid therapy alone, while more potent inhibitors may necessitate B-cell-directed therapy, frequently using rituximab. In addition, plasma exchange has demonstrated efficacy in the short-term removal of FXIII inhibitors.[41]

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 III von Willebrand disease.

• Platelet dysfunction disorders such as Glanzmann thrombasthenia, Bernard Souilier syndrome, and von Willebrand disease types I and II.

• Additional coagulation factor deficiencies, including FII, FV, FVII, FX, and FXI.

• Acquired causes of FXIII deficiency, including malignancy, autoimmune disorders, medications, hyperconsumption, disseminated intravascular coagulation (DIC), and liver disease.

Prognosis

Congenital FXIII deficiency is extremely rare, and acquired FXIII deficiency is even rarer. Patients receiving replacement therapy can typically expect an average life expectancy, although there is a lack of large-scale studies on mortality rates. In untreated individuals, intracranial hemorrhage stands as the primary cause of death.[25] 

Approximately 30% of cases of central nervous system bleeding experience recurrence, with approximately 50% of these instances resulting in fatality. 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.