Diagnosis and management of severe congenital factor XIII deficiency in the Emergency Department: lessons from a "model" family.

Abstract

Plasma factor XIII (FXIII) is a pro-enzyme (composed of 2α2β subunits), activated to XIIIa by calcium and thrombin in the final step of the coagulation cascade. FXIII stabilises the clot during the process of haemostasis by catalysing the cross-linking of fibrin, platelet membrane and matrix proteins. Moreover, FXIII prevents premature clot degradation by the fibrinolytic system. FXIII also plays an important role in wound healing and tissue repair1. Congenital FXIII deficiency is a rare genetic bleeding disorder that is inherited in an autosomal recessive manner with a frequency of one case per 2–3 million individuals in the human population. The genes involved in FXIII production are located on different chromosomes, namely subunit A on 6p25-p24 and subunit B on 1q31-q32.1. Genetic analyses have revealed that in most cases congenital FXIII deficiency is associated with deficiency of subunit A located on chromosome 6, while in a minority of cases it is found associated with deficiency of subunit B located on chromosome 12. Affected subjects often have a positive history for consanguinity. Although rare, congenital FXIII deficiency is an important disorder because of the severity of its bleeding manifestations. In particular, the incidence of intracranial haemorrhage is 20–30%, which is significantly higher than that in any other bleeding disorder3. The clinical manifestations of congenital FXIII deficiency include a lifelong bleeding diathesis, in particular subcutaneous bleeding (57%), delayed umbilical cord bleeding (56%), muscle haematoma (49%), haemorrhage after surgery (40%), intracerebral bleeding (34%), and a high risk of miscarriage. Delayed bleeding (i.e., 12–36 hours) after trauma or surgery is pathognomonic of factor XIII deficiency2,4. Differently from all other congenital haemostatic protein deficiencies, in congenital FXIII deficiency typical coagulation screening tests and platelet function tests are absolutely normal; specific FXIII assays must, therefore, be performed2. Indeed, factor XIII deficiency should be considered in patients with recurrent delayed bleeds and a normal coagulation profile.