Factor XIII Deficiency
Factor XIII (FXIII) is one of several clotting factors that are components of the coagulation cascade (Figure 1). This complex sequence of step-wise interactions is initiated in response to injury to a blood vessel wall. Several pathways lead to the activation of thrombin, which then acts on the protein fibrinogen to form fibrin at the site of injury. Single strands of fibrin join together to form a mesh-like structure – the basis of a blood clot. Thrombin and calcium ions together activate FXIII to form FXIIIa, which catalyses the formation of cross-links between the strands of the fibrin mesh [Schmaier, 2012; Schroeder and Kohler, 2013]. This makes the clot more stable and stronger; the actions of FXIII also prolong the duration of the clot by protecting fibrin from breakdown by the anticoagulation system.
- Subunit A (FXIII-A2) is the component that actively contributes to coagulation; it is produced in the bone marrow and is present in plasma and platelets, monocytes/macrophages
- Subunit B (FXIII-B2) acts as a carrier and regulatory protein. It is is produced by hepatocytes in the liver?
FXIII occurs in plasma as a complex of two pairs of subunits (FXIII-A2-B2). The complex is broken up when activated by thrombin.
- FXIII-A2 occurs in cells as the unbound subunit
- FXIII-B2 occurs in plasma at levels 50% higher than those of Subunit A, so that all Subunit A in plasma is bound in the complex FXIII-A2-B2.
FXIII has many physiological functions in addition to its role in the coagulation system, including the formation of new blood vessels, endothelial cell proliferation and barrier function, modulation of the activity of cells involved in inflammation and promotion of atherosclerosis, and the development of bone [Schroeder and Kohler, 2013].
Types of FXIII deficiency
FXIII deficiency may be inherited or acquired.
Inherited factor XIII deficiency is caused by mutations in genes encoding for the two subunits. F13A1is most frequently affected, F13B less so. An inherited deficiency may affect Subunit A or B although subunit A deficiency accounts for almost all cases of FXIII deficiency. There are two types:
- Type I A deficiency is caused by decreased synthesis of FXIII
- In Type II A deficiency, levels of Subunit A are normal but the protein is functionally defective
In Subunit B deficiency, plasma levels of Subunit A are reduced by about 90% but intracellular levels are normal.
An acquired deficiency is due to:
- reduced synthesis or increased consumption of FXIII (for example, due to major surgery, stroke, inflammatory bowel disease, haematological cancer or liver cirrhosis)
- the development of antibodies against either of the subunits; this may occur in a person with an autoimmune disorder such as systemic lupus erythematosus.
The various types of deficiency differ in the extent to which the activity and levels of FXIII subunits in plasma and platelets are reduced (Table 1) and this is one determinant of the severity of the bleeding tendency [Kohler et al, 2011]. Subunit B deficiency is associated with less severe bleeding because levels of circulating Subunit A are still high enough to contribute to coagulation [Ivaskevicius et al, 2007].
Table 1. Types of FXIII deficiency and activity and levels (antigen) in plasma and platelets [Kohler et al, 2011]
| Plasma | Platelets | |||||
| FXIII activity | FXIII-A2B2antigen | FXIII-A antigen | FXIII-B antigen | FXIII activity | FXIII-A antigen | |
| Inherited | ||||||
| FXIII-A | ||||||
| – Type I | ↓↓↓ | ↓↓↓ | ↓↓↓ | >30% | ↓↓↓ | ↓↓↓ |
| – Type II | ↓↓↓ | ↓ – N | ↓-N | >30% | ↓↓↓ | ↓ – N |
| FXIII-B | ↓↓ | ↓↓↓ | ↓↓ | ↓↓↓ | N | N |
| Acquired | ||||||
| Anti-FXIII-A | ||||||
| – neutralising | ↓↓↓ | ↓ – N | ↓-N | >30% | N | N |
| – non-neutr | ↓↓↓ | ↓↓↓ | ↓↓↓ | >30% | N | N |
| Anti-FXIII-B | ↓↓↓ | ↓↓↓ | ↓↓↓ | ↓↓↓ | N | N |
| Other | ↓ | ↓ | ↓ | ↓ – N | na | na |
↓↓↓ highly decreased activity/level, usually below 3%
↓↓ considerably decreased activity/concentration, usually 5% – 10%
↓ slightly decreased activity, usually 20% – 70%
N normal
Na not applicable
Inherited FXIII deficiency
A registry of patients with FXIII deficiency was established in 1993 [Ivaskevicius et al, 2007], since when more than 100 mutations of the FXIII gene have been reported [de Moerloose et al, 2016]. The pattern of inheritance is autosomal recessive, meaning a child must inherit an abnormal gene from both parents to develop the disorder.
As is the case with some other inherited coagulation disorders, the prevalence of FXIII deficiency is higher in countries where consanguineous marriage is more common [Peyvandi et al, 2002].
Circulating Subunit A is absent in individuals who are homozygous for the abnormal gene; they also have reduced levels of Subunit B. Levels of Subunit A are reduced by about half in heterozygous individuals (identified as relatives of homozygous individuals through genetic testing) [Schroeder and Kohler, 2013].
Acquired FXIII deficiency
A review of 48 cases of FXIII deficiency associated with autoantibodies in published reports found that 15% – 25% were associated with an underlying autoimmune disorder overall, though the proportion in a small series of children was 75% [Muszbek at al, 2018]. Almost one-third were associated with drug treatment and no underlying disorder was identified in a further third; four cases were associated with malignancy. Compared with the inherited disorder, FXIII activity was higher in acquired deficiency. About three-quarters of the 48 cases were due exclusively to neutralising antibodies, two cases were not associated with neutralising antibodies and the remainder appeared to be caused by both accelerated clearance of FXIII and neutralising antibodies.
There is a lack of published information on acquired FXIII deficiency in underlying disorders associated with inflammation or bleeding. It is likely that other coagulation factors are also deficient when FXIII deficiency is due to activation of the coagulation system [Schroeder and Kohler, 2013].
Epidemiology
FXIII deficiency affects men and women equally. The estimated prevalence is 1 – 3 per million [Schroeder and Kohler, 2013; de Moerlose et al, 2016; Peyvandi et al, 2002] but there is marked variation between countries. The proportion of undiagnosed cases, in particular bleeding disorders due to Subunit B deficiency and heterozygous individuals and others with non-severe bleeding disorder, is not known. It has been suggested that up to 1 per 1000 of the German population may be heterozygous, though many would not be clinically affected [Biswas et al, 2011].
- The overall prevalence in Iran may be as high as 1 per 160,000, or 12 times higher than the global estimate, but in one region it is 1 in 7,700 with most cases occurring in one ethnic group [Dorgalaleh et al, 2015].
- In India, FXIII deficiency is the most frequent rare coagulation disorder other than haemophilia or von Willebrand disease, accounting for 30% of cases; of these, parental consanguinity was present in 73% of cases and 3% had a positive family history [Shetty et al, 2014].
- The UK Haemophilia Centres Doctors’ Organisation registry included 69 people with FXIII deficiency in 2016/17, giving a crude prevalence of 1.06 per million in the UK [Shetty et al, 2014; UKHCDO, 2017].
Symptoms
FXIII deficiency causes bleeding, abnormal wound healing and spontaneous abortion. The diagnosis may be suspected in less severely affected individuals only when bleeding complications develop after trauma or surgery. This may become apparent as ‘delayed bleeding’ due to premature lysis of clots following normal primary haemostasis [Biswas et al, 2014]. Bleeding severity correlates strongly with the plasma level of FXIII (Table 3) [Peyvandi et al, 2012]. Bleeding symptoms and their prevalence among people with mutations for FXIII deficiency in a German registry are illustrated in Figure 3 [Biswas et al, 2014].
Table 3. Relationship between plasma FXIII and bleeding severity (at least one episode) in 33 registry patients with FXIII deficiency [Peyvandi et al, 2012]
| Bleeding severity | Prevalence | FXIII level (U/dl) |
| Asymptomatic | 39% | 31.07 |
| Grade 1 Bleeding that occurred after trauma or drug ingestion (antiplatelet or anticoagulant therapy) |
6% | 16.85 |
| Grade 2 Spontaneous minor bleeding: bruising, ecchymosis, minor wounds, oral cavity bleeding, epistaxis and menorrhagia |
6% | 2.63 |
| Grade 3 Spontaneous major bleeding: intramuscular hematomas requiring admission, hemarthrosis, CNS, GI and umbilical cord bleeding |
49% | 0 |
Bleeding symptoms and their prevalence among people with mutations for FXIII deficiency in a German registry are illustrated in Figure 3 [Biswas et al, 2014].
According to reviews of published literature, intracranial bleeding is common and is associated with 80% of deaths due to FXIII deficiency in adults. It occurs spontaneously or, more frequently in children, after trauma. Misdiagnosis occurs because FXIII deficiency is so rare that it is seldom considered as a possible cause. Reportedly 40% – 60% of people with Factor XIII deficiency experience intracranial bleeding, with 80% of cases occurring in the first 6 years of life. About one fifth of people experience recurrent intracranial bleeding if they do not receive prophylaxis with replacement FXIII. Evidence from Iran suggests that 50% – 75% of survivors experience neurological complications, most frequently locomotor impairment [Dorgalaleh et al, 2015; Alavi et al, 2018].
A systematic review of publications describing 121 women with FXIII deficiency found differences in the pattern of bleeding associated with deficiencies of Subunit A and Subunit B (Table 4) [Sharief et al, 2013].Overall, umbilical bleeding was the most frequent symptom (27%); others included bruising after trauma (20%), intracranial haemorrhage (17%), post-surgical bleeding (12%), intramuscular bleeding (9%), joint bleeding (7%), bleeding after tooth extraction (7%), epistaxis (7%) and haematuria (8%).
Table 4. Bleeding and pregnancy outcome in women with FXIII deficiency affecting Subunit A and Subunit B [Sharief et al, 2013]
| Subunit A deficiency
(n=104, 179 pregnancies) |
Subunit B deficiency
(n=17, 13 pregnancies) |
|
| Menorrhagia | 26% | 13% |
| Ovulation bleeding | 10% | 0 |
| Miscarriage | 70% | 15% |
| Antepartum haemorrhage | 4% | 27% |
| Postpartum haemorrhage | 13% | 82% |
Of the total of 192 pregnancies reported in this review:
- 66% ended in miscarriage
- 25% of women reported a history of at least three miscarriages (median 5, range 1 – 13)
- of the 136 pregnancies not covered by prophylaxis, 91% ended in miscarriage.
- of the 65 pregnancies reaching full term, 62 delivered live babies.
A retrospective review involving 28 people who were heterozygous for FXIII deficiency [Mahmoodi et al, 2011] found that bleeding symptoms were uncommon:
- three reported subcutaneous bleeding
- purpurae, mucosal and gingival bleeding were each reported by two people
- one experienced bleeding after delivery
- two reported bleeding after minor trauma.
However, heterozygosity was significantly associated with ‘prolonged or massive bleeding’ after minor trauma (p=0.018).
Diagnosis
Guidance on the diagnosis of FXIII deficiency was published in 2011 by the FXIII and Fibrinogen SSC Subcommittee of the International Society on Thrombosis and Haemostasis [Kohler et al, 2011]. This states that when clinical symptoms suggest the possibility of a coagulation disorder, a full evaluation of blood clotting should include a laboratory test to screen for FXIII deficiency and further tests to identify the type of deficiency, ascertain the presence of antibodies and identify the genetic mutation. Testing for FXIII subunits is, however, expensive.
In the past, the solubility of a fibrin clot was used as a screening tool but this non-standardised test is sensitive only for very severe FXIII deficiency and its use has resulted in substantial underdiagnosis [Dorgalelah et al, 2015]. However, it is inexpensive and still widely used in many countries, including the UK [Jennings et al, 2017]. An algorithm more suitable for use in less economically developed countries has been proposed that includes the determination of genetic mutations specific to a country in place of FXIII assays [Karimi et al, 2018]. A 2013 case report describes the presentation, diagnosis and treatment of a 13-year-old girl with FXIII deficiency [Sawlani et al, 2013].
Treatment of inherited FXIII deficiency
The primary treatment for FXIII deficiency is lifelong prophylaxis with FXIII replacement therapy [Mumford et al, 2014]. Prophylaxis is recommended for neonates and children from the point of diagnosis.
Compared with other clotting factors, FXIII has a relatively long plasma half-life (6 – 9 days for plasma-derived FXIII and 12 – 14 days for recombinant FXIII). This means that target plasma levels can be maintained with relatively infrequent doses.
In 2014, UKHCDO published guidance on the management of FXIII deficiency, including recommendations for replacement therapy [Mumford et al, 2014]. These express a preference for the recombinant product over plasma-derived alternatives (Table 5).
Table 5. UKHCDO 2014 recommendations for factor replacement therapy in the treatment of FXIII deficiency [Mumford et al, 2014]
| Diagnosis and monitoring of FXIII requires a FXIII activity assay that enables accurate measurement of FXIII activity <0.1 IU/ml |
| Long-term prophylaxis with FXIII concentrate is recommended in all cases with FXIII deficiency and a personal or family history of bleeding and those with plasma FXIII activity <0.1 IU/ml.
Prophylaxis should start with FXIII concentrate 20–40 IU/kg every 28 d, adjusted to maintain trough FXIII activity 0.1–0.2 IU/ml |
| Consider prophylaxis with recombinant FXIII concentrate rather than plasma-derived FXIII in people with FXIII A-subunit deficiency that have not previously been exposed to plasma products |
| For mild bleeding or minor surgery in FXIII deficiency, consider tranexamic acid 15–20 mg/kg or 1 g four times daily alone |
| For severe bleeding or major surgery in FXIII deficiency, consider additional FXIII concentrate 10–40 IU/kg depending on the interval since last prophylaxis and severity of bleeding |
| Women with FXIII deficiency who are having prophylaxis with FXIII concentrate should be monitored closely throughout pregnancy; the dose frequency should be increased to every 14–21 days to maintain FXIII activity >0.2 IU/ml.
For delivery, consider additional FXIII concentrate 10–40 IU/kg once in established labour or before caesarean section, depending on the interval since last prophylaxis |
Menorrhagia can be managed with hormonal contraceptives, intra-uterine devices or antifibrinolytic drugs.
There are two main sources of FXIII:
- plasma-derived concentrate (virus-depleted)
- recombinant FXIII
Standard and pathogen-reduced fresh frozen plasma, cryoprecipitate and platelet concentrates are also sources of FXIII; they may be suitable emergency replacement therapy if a FXIII concentrate is unavailable [Mumford et al, 2014].
Plasma-derived concentrate
FXIII derived from human plasma greatly reduces bleeding risk in people with inherited FXIII deficiency. In one trial involving 41 people who required FXIII prophylaxis, a dose of 40 IU/kg every 4 weeks maintained plasma FXIII levels over a year [Ashley et al, 2015]. Trough levels were maintained above 5% in 97% of patients and above 10% in 85%.
There were 14 bleeding episodes in nine patients; all were mild or moderate in severity, five were spontaneous, eight followed a traumatic event and one was secondary to surgery despite additional cover with FXIII. No spontaneous bleeding events required factor replacement compared with an historical incidence of 2.5 per patient-year. Hypersensitivity reactions possibly related to treatment were reported in three people. A laboratory test suggested the presence of inhibitors in one asymptomatic participant after 48 weeks but no antibodies were confirmed.
Plasma-derived FXIII concentrate is available in the UK as Fibrogammin (CSL Behring). If contains both subunits of FXIII and is therefore effective in the treatment of deficiencies of Subunit A or Subunit B. It is also specifically licensed for prophylaxis to cover surgery. The dose is administered as a slow intravenous injection.
Recombinant FXIII-A
Catridecacog (Novothirteen, NovoNordisk), the recombinant form of FXIII-A, was approved by the European regulatory authority in 2012 for ‘Long term prophylactic treatment of bleeding in patients with congenital factor XIII A -subunit deficiency’ in people of all ages. It is not effective in Subunit B deficiency. Full details are available in the European Public Assessment Report (EMEA, 2012]. The recommended dose is 35 IU/kg, given once monthly as a slow intravenous injection, adjusted in adults to achieve target FXIII levels. Dose adjustment is recommended for small children only (<24 kg).
In the pivotal clinical trial (designated mentor 1), 41 patients (mean age 26, range 6 – 70) received prophylaxis with catridecacog for an average of 322 days [Inbal et al, 2012]. All had previously been treated with regular FXIII replacement therapy. Thirty-three completed the trial; of those who did not, 3 were withdrawn after developing non-neutralising antibodies and one after worsening leukopenia and neutropenia. Mean trough plasma FXIII level was 19%.
The age-adjusted rate of bleeds requiring treatment was 0.048 per patient-year, lower than an historical rate associated with regular treatment (0.33/PY) and on-demand treatment (2.91/PY). The annualised bleeding rate (ABR) was 0.138/PY. Five bleeding episodes requiring treatment occurred in 4 participants, all associated with trauma. There were 48 bleeding episodes that did not require treatment.
An 52-week extension trial (mentor 2) was designed to assess safety and included people who did not participate in mentor 1 (Carcao et al, 2018]. Mean trough plasma FXIII level was 17%; 2.9% of 2,245 FXIII measurements made were <10%. Seven of 60 participants experienced 8 bleeding episodes (ABR 0.043). Two of the bleeds were spontaneous (epistaxis, muscle bleed) (ABR 0.011) and the remainder were traumatic (ABR 0.032). Twelve minor surgical procedures were carried out in 9 patients without additional FXIII doses (but antifibrinolytic drugs in 4 procedures); there were no bleeding complications.
A small study suggests catridecacog is probably safe and effective in children aged <6 years [Kerlin et al, 2014]. Three boys and three girls (mean age 3, range 1 – 4) received monthly prophylaxis for 1.8 – 3.5 years. Mean trough FXIII-A was again 19%. There were no bleeding episodes requiring treatment; 5 participants experienced 14 minor bleeding episodes (eight minor trauma, five epistaxis, one bruising). No antibodies were detected. Two adverse events were considered by investigators to be possibly treatment-related: gastroenteritis and lymphocytopenia, both of which resolved.
Inhibitors of FXIII products
FXIII replacement therapy is rarely associated with the development of inhibitors but the true risk is not known. A 2018 review identified only 6 published cases of antiFXIII-A antibodies and one of anti-FXIII-B antibodies [Francini et al, 2018]. One report of >4 years’ prophylaxis with plasma-derived concentrate in 50 people with severe FXIII deficiency (mean age 14) identified no cases with inhibitors [Naderi et al, 2017]. In clinical trials of catridecacog, non-neutralising antibodies were considered of no clinical significance; no cases of neutralising antibodies were recorded but inhibitors were observed in preclinical studies and therefore remain a possibility [Inbal et al, 2012].
Treatment of acquired FXIII deficiency
Published reports of treating acquired FXIII deficiency focus on the management of patients who have developed antibodies to FXIII. In one series of 93 patients, treatment comprised high-dose FXIII concentrate to overcome the antibodies (or, if this was not available, fresh frozen plasma or cryoprecipitate) and haemostatic therapy with antifibrinolytic drugs (tranexamic acid, epsilon aminocaproic acid). Immediate immunosuppression is considered essential but the optimal strategy is not known. Prednisolone as monotherapy or with cyclophosphamide or rituximab, and high-dose immunoglobulin have been used [Ichinose. 2017]. A treatment guideline based on experience in Japan has been published [Ichinose, 2014].
Sources of information
There appear to be no organisations specifically representing the interests of people with FXIII deficiency but national associations for bleeding disorders include subsections for rarer disorders that include FXIII deficiency. UK haemophilia nurse Shaun Emmitt has produced a booklet for young patients with Factor VIII deficiency available here.
There are also relevant sections in the US National Organization for Rare Disorders, Orphanet and the US National Library of Medicine section on genetic conditions.