Most patients suffer a severe bleeding diathesis that includes postnatal umbilical cord bleeding, cutaneous bruising and haematomas, intramuscular and joint haemorrhage, postoperative haemorrhage, impaired wound healing, spontaneous abortions in early pregnancy and intracranial haemorrhage, which is the major cause

of death [40]. Typically, bleeding Wnt inhibitor symptoms occur hours or days after trauma as the initially formed uncrosslinked fibrin clot is not stable. The possible diagnosis of congenital FXIII deficiency should not be delayed in any child with an unidentified bleeding disorder. Prolonged umbilical bleeding with a normal coagulation profile mandates FXIII analysis. Congenital FXIII deficiency can be caused by mutations in both FXIII genes. More than 70 causative mutations in the FXIII-A gene have been published, but only five mutations in the FXIII-B gene (see online databases www.f13-database.de, and those held by the ISTH at www.isth.org/and www.hgmd.cf.ac.uk). Most mutations code for a single amino acid exchange resulting in defective folding and instability of the mutant protein [40]. Acquired FXIII deficiency has been

reported in several conditions. FXIII A-subunit levels fall to 20–70% from decreased synthesis or consumption. Over 30 cases of severe FXIII deficiency caused by autoantibodies against FXIII-A have also been reported (∼30% in association with systemic lupus erythematosus [SLE]). These may inhibit FXIII activation or FXIIIa activity [41]. Clinical symptoms in congenital selleck chemical medchemexpress FXIII deficiency may be suggestive, but the diagnosis must be based on appropriate laboratory tests. Unless there is another concomitant coagulation disorder, typical coagulation screening tests are normal. Traditionally, solubility of fibrin clots in urea, acetic acid or monochloroacetic acid solution (clot solubility test)

has been used for screening. This qualitative method detects only very severe FXIII deficiency, is not standardized, and its sensitivity depends on the fibrinogen level, the clotting reagent (thrombin and/or Ca2+) and the solubilizing agent and its concentration. The detection limit varies between <0.5% and 5% FXIII activity. The high number of undiagnosed or late-diagnosed FXIII deficiencies is partly attributable to the use of this test and it is therefore no longer recommended. Diagnosis and classification of FXIII deficiencies require a quantitative functional FXIII activity assay that detects all forms of FXIII deficiency as a first-line screening test. Quantitative FXIII activity assays are based on two assay principles: (i) Measurement of ammonia released during the transglutaminase reaction and (ii) measurement of labelled amine incorporated into a protein substrate.