FACTOR XIII DEFICIENCY

Factor XIII (FXIII) is the last enzyme in the clotting cascade. Its main function is to convert the loose ®brin polymer into a ®rm, highly organized, cross-linked structure with increased tensile strength, ®rmly anchored to the site of the wound and possessing an in-built resistance to ®brinolysis. In FXIII de®ciency, standard clotting tests are normal, as the clotting end point is not affected by the absence of FXIII. It is the quality of the clot which is abnormal. Unless this is assessed, the diagnosis may be missed. Soon after its discovery by Robbins (1944), FXIII was aptly named: the `®brin stabilizing factor' or `FSF'. Fibrin formed in the absence of FSF was `unstable': it dissolved in weak acids, weak bases and 5 M urea. Addition of a small amount of plasma to the system `stabilized' the ®brin, it was no longer soluble in these reagents and it was also more resistant to ®brinolysis. Solubility of clots in 1% monochloroacetic acid or in 5 M urea still forms the basis of the standard laboratory screening test for inherited FXIII de®ciency. Initially it was believed that FSF combined with ®brin stoichiometrically, acting as a kind of glue, sticking molecules of ®brin together (Laki & Lorand, 1948; Lorand, 1950). Later it became obvious that FSF was an enzyme (Buluk et al, 1961; Loewy et al, 1961; reviewed in detail by Board et al, 1993) and the cross-link introduced into ®brin by FSF was found to be the «(g-glutamyl)lysine link (reviewed by Miloszewski & Losowsky, 1988), identifying FXIII as a member of the transglutaminase family of enzymes (see reviews by Greenberg et al, 1991; Aeschlimann & Paulsson, 1994). FXIII is the only transglutaminase found both intraand extracellularly and the only one requiring thrombin as well as calcium for activation. Thus, in common with other clotting factors, it exists as a pro-enzyme (Lorand, 1977). In plasma, FXIII circulates in the form of a tetramer composed of two catalytic A subunits bound to two carrier protein B subunits (A2B2) (Schwartz et al, 1973). FXIII is found in plasma, platelets and monocytes (Muszbek et al, 1985, 1996). Intracellular FXIII is a dimer of two catalytic A subunits (A2). In inherited FXIII de®ciency the A subunit is absent from plasma, platelets and monocytes. The plasma level of the B subunit is usually reduced, and very rarely both A and B subunits are absent (Girolami et al, 1985). The clinical relevance of FXIII became apparent 16 years after its discovery, when Duckert et al (1960) described the case of a boy with a severe bleeding diathesis in whom the only abnormality in the clotting tests was the solubility of his clots in 5 M urea. His clots became insoluble when some normal plasma was mixed with his plasma in vitro. He formed insoluble clots, after blood or plasma transfusion which also controlled his bleeding temporarily. Since that original description, over 200 cases have been reported from all parts of the world. Most patients with inherited FXIII de®ciency suffer from a severe, lifelong, crippling bleeding diathesis with a very high risk of death in early life from intracranial haemorrhage. In a minority of patients defective wound healing has been reported. Women with the de®ciency are unable to carry a pregnancy to term and habitual abortion is usual (Fisher et al, 1966). Inherited FXIII de®ciency affects all races and both sexes equally. Inheritance is autosomal recessive. The genes for both the A and B subunits were cloned about 10 years ago (detailed in Board et al, 1993). Five years ago only ®ve mutations were tentatively identi®ed as probably being responsible for the de®ciency (Board et al, 1993). In recent years developments in DNA technology have facilitated detailed studies of the FXIII gene in families with inherited de®ciency as well as in normal individuals. Thirty-six different mutations resulting in FXIII de®ciency have now been identi®ed. Studies on the structural and functional consequences of the various mutations and the normal polymorphisms in the gene have resulted in a much better understanding of FXIII function. Discussion of these exciting developments in the ®eld will form the major part of this review.