Factor XIII deficiency

Factor XIII deficiency is a multisystem bleeding disorder affecting haemostasis and tissue repair across the lifespan. The clinical picture is dominated by haemorrhagic manifestations, with first presentation most often in the neonatal period as delayed bleeding from the umbilical cord stump within days of birth. Intracranial haemorrhage is the most serious complication and may occur spontaneously in infancy or after minor trauma at any age. Additional clinical features include soft-tissue and intramuscular haematomas, prolonged bleeding after surgery or dental procedures, delayed and abnormal wound healing, mucocutaneous bleeding such as recurrent epistaxis and gingival haemorrhage, and menorrhagia in affected women. Recurrent first-trimester pregnancy loss is a characteristic obstetric complication in women with severe disease. The bleeding phenotype shows considerable inter-individual and intra-individual variability; women heterozygous for F13A1 variants may experience haemorrhagic complications during haemostatic challenges such as childbirth or major surgery.

The estimated prevalence of severe congenital factor XIII deficiency is 1:2,000,000.

Two genes underlie congenital factor XIII deficiency: F13A1 and F13B. Biallelic germline pathogenic variants in either gene produce the disorder. F13A1 encodes the catalytic A-subunit, and loss-of-function variants account for the majority of severe cases and the high-morbidity bleeding phenotype. F13B encodes the carrier B-subunit; biallelic variants in this gene are less common and
generally produce a milder bleeding phenotype. The reported molecular spectrum is heterogeneous and includes nonsense, frameshift, splice-site, missense, and large-deletion variants.

It is important to note that the majority of cases of factor XIII deficiency are not genetic in origin. Causes of acquired deficiency include, among others, impaired hepatic synthesis, chronic inflammatory bowel disease, disseminated intravascular coagulation, and haematologic malignancies. An autoimmune aetiology with the detection of antibodies directed against factor XIII has also been
described in rare cases. Finally, factor XIII deficiency can also be acquired perioperatively as a result of blood loss, haemodilution, and increased consumption. In particular, extracorporeal circulation appears to be associated with the development of factor XIII deficiency.