Factor (F) XIII congenital deficiency (FXIII CD; 2017 ICD-10-CM: 68.2) is a rare autosomal recessive bleeding disorder that affects all races and both sexes equally.1,2 Its prevalence is estimated to be 1 in approximately 2 million people worldwide, although it is more prevalent in regions such as the Middle East, in which consanguineous marriages are common.1
FXIII CD is the result of an impaired production of clotting factor XIII (FXIII), the terminal enzyme in the blood coagulation cascade. The FXIII transglutaminase covalently cross-links and stabilises fibrin strands that form the blood clot during the haemostatic process.2-4 The lack of functional FXIII therefore often presents as “delayed bleeding” following trauma due to premature lysis of the haemostatic clot.3 FXIII further plays an important role in wound healing and tissue repair, affects cell adhesion, cell proliferation and angiogenic activity and is necessary for pregnancy maintenance.2
FXIII circulates in plasma and is a hetero-tetramer composed of two A-subunits (FXIII-A), containing the active catalytic domain of the transglutaminase, and two B-subunits (FXIII-B), which serve as carrier proteins that also extend the half-life of circulating FXIII-A.1-3 The majority of FXIII CD patients (>95%) are FXIII-A-deficient, and often present with more severe bleeding symptoms, whereas only very few cases of FXIII-B CD (<5%) have been reported worldwide.1,2
Most people with FXIII CD experience symptoms form birth, often bleeding from the umbilical cord stump. Symptoms tend to continue throughout life. As a general rule, the less FXIII a patient has in their blood, the more frequent and/or severe their symptoms.
Clinical symptoms can range from mild to severe, with homozygous or compound heterozygous FXIII-A CD patients usually presenting with a more severe phenotype.1,2 The first and most characteristic manifestation of FXIII CD is bleeding from the umbilical cord after birth, which occurs in almost two-thirds of patients.2,3 Other frequent bleeding symptoms include subcutaneous bleeding, muscle haematomas, bleeding after surgery or tooth extraction and joint haemorrhages.1-4 Importantly, FXIII CD is associated with a high risk of intracranial haemorrhage, which occurs in approximately 30% of untreated FXIII CD patients and is the main cause of death in FXIII CD.1-3 Due to the diverse biological functions of FXIII, symptoms in FXIII CD are not restricted to bleeding, but also include impaired wound healing, abnormal scar formation and repeated spontaneous abortions in pregnant women.1-3
Early diagnosis of FXIII CD in patients with a bleeding tendency is essential to avoid any fatal or severely disabling bleeding complications.2 FXIII CD is likely to be underdiagnosed due to lack of awareness and challenges with diagnostic procedures.2 Once the diagnosis is confirmed, prophylactic replacement therapy is recommended to prevent the occurrence of potentially life-threatening bleeds.2 The long in vivo half-life of FXIII (9–14 days)2,3 and the observation that FXIII levels of only 3–10% of normal in plasma are sufficient to control bleeding allow for a monthly treatment regimen that makes prophylaxis manageable.3 Bleeding episodes can also be managed on demand using FXIII replacement therapy.
An acquired form of FXIII deficiency also exists and is usually the result of increased consumption or decreased synthesis of FXIII associated with several medical conditions, including major surgery, trauma, pulmonary embolism, stroke, Crohn’s disease, ulcerative colitis, leukaemia, sepsis, liver cirrhosis and disseminated intravascular coagulation.2,3 The development of autoantibodies, usually against FXIII-A, and very rarely against FXIII-B, is also a rare cause of acquired FXIII deficiency.2,3
1. Odame JE, Chan AK, Wu JK, Breakey VR. Factor XIII deficiency management: a review of the literature. Blood Coagul Fibrinolysis 2014;25:199-205.
2. Schroeder V, Kohler HP. Factor XIII deficiency: an update. Semin Thromb Hemost 2013;39:632-41.
3. Biswas A, Ivaskevicius V, Thomas A, Oldenburg J. Coagulation factor XIII deficiency. Diagnosis, prevalence and management of inherited and acquired forms. Hamostaseologie 2014;34:160-6.
4. de Jager T, Pericleous L, Kokot-Kierepa M, Naderi M, Karimi M. The burden and management of FXIII deficiency. Haemophilia 2014;20:733-40.