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Factor XIII Deficiency Haemophilia (2008), 14, 1190–1200 DOI: 10.1111/j.1365-2516.2008.01857.x ORIGINAL ARTICLE Factor XIII deficiency L. HSIEH and D. NUGENT Division of Hematology, ChildrenÕs Hospital of Orange County, Orange, CA, USA Summary. Inherited factor XIII (FXIII) deficiency is been more than 60 FXIII mutations identified in the a rare bleeding disorder that can present with current literature. In addition, single nucleotide umbilical bleeding during the neonatal period, polymorphisms have been described, some of which delayed soft tissue bruising, mucosal bleeding and have been shown to affect FXIII activity, contribut- life-threatening intracranial haemorrhage. FXIII defi- ing further to the heterogeneity in patient presenta- ciency has also been associated with poor wound tion and severity of clinical symptoms. Although healing and recurrent miscarriages. FXIII plays an there is a lifelong risk of bleeding, the prognosis is integral role in haemostasis by catalysing the cross- excellent when current prophylactic treatment is linking of fibrin, platelet membrane and matrix available using cryoprecipitate or plasma-derived proteins throughout thrombus formation, thus sta- FXIII concentrate. bilizing the blood clot. The molecular basis of FXIII deficiency is characterized by a high degree of Keywords: bleeding disorders, coagulation, factor heterogeneity, which contributes to the different XIII, factor XIII deficiency, fibrin stabilizing factor, clinical manifestations of the disease. There have protransglutaminase clear that intracellular FXIII, especially in platelet Introduction and vascular bed may play an equally important role Prior to delving into the clinical and biochemical in haemostasis. details which characterize this fascinating clotting In plasma, FXIII circulates as a pro-transglutamin- factor, it is worth taking a moment to consider this ase (FXIII-A2B2) composed of two catalytic A important fact: factor XIII (FXIII) is not just another subunits (FXIII-A2) and two non-catalytic B subunits plasma protein in the clotting cascade. Like so many (FXIII-B2) held together by non-covalent bonds. The other discoveries, FXIII is defined by the function B subunits are found primarily in plasma, either free through which we first became aware of its existence, or in association with A subunits as part of the namely as a Ôfibrin stabilizing factorÕ (FSF) in the heterotetrameric form of FXIII. However, intracel- earliest papers [1,2]. However, it is now apparent lular FXIII exists only as a homodimer of FXIII-A that FXIII is capable of cross-linking an ever-growing subunits (FXIII-A2). A quick reference for the defi- list of proteins, not only within plasma, but also nitions of the various forms of FXIII discussed in this proteins within the vascular matrix, platelets, endo- article is listed below in Table 1. thelial cells and monocytes. Clearly intracellular Substrates for intracellular FXIII-A2 include myo- FXIII plays an important role in the platelet and sin, actin, vinculin and filamin suggesting a major vascular bed in achieving haemostasis, thrombosis role for FXIII in cytoskeletal remodelling in platelet and healing. Although we focus this review article on adhesion, aggregation and contraction. In the mono- the interaction of plasma proteins with FXIII, it is cyte/macrophage cytosol, FXIII-A2 facilitates Fcc and complement receptor mediated phagocytosis and deficient patients have been shown to have Correspondence: Loan Hsieh, Division of Hematology, ChildrenÕs Hospital of Orange County, 455 S. Main St, Orange, CA 92868, impaired function in these activities [3]. Murine USA. models of wound healing also support the important Tel.: +1 714 532 8744; fax: +1 714 532 8771; role of intracellular FXIII-A2 in leucocyte and tissue e-mail: [email protected] (or) [email protected] remodelling and repair. Recent research on myocar- Accepted after revision 21 July 2008 dial repair following infarction induced in FXIII)/) Ó 2008 The Authors 1190 Journal compilation Ó 2008 Blackwell Publishing Ltd FXIII DEFICIENCY 1191 Table 1. Factor XIII nomenclature. Plasma FXIII FXIII-A2B2 Cellular FXIII FXIII-A2 FXIII subunit A monomer FXIII-A FXIII subunit A dimer FXIII-A2 FXIII subunit B monomer FXIII-B FXIII subunit B dimer FXIII-B2 Inactive intermediate after thrombin cleavage FXIIIa¢ Ca2+ activated FXIII FXIIIa* knockout mice demonstrates significant reduction in leucocyte recruitment, phagocytosis and protease activity in the area of injury [4]. Finally, the production of FXIII-A2 in the placenta, particularly Fig. 1. Thromboelastogram (TEG) tracing of a severe FXIII-defi- the labyrinthine layer, confirms its important role in cient patient is shown in white, with decreased clot size and maintaining the integrity of placental attachment in strength in addition to increased lysis at 30 and 60 min. The green the uterus [5–7]. This along with prevention of tracing is from the same patient following infusion of Fibrogam- massive bleeding associated with microvascular min P (FXIII concentrate) resulting in restoration of a normal TEG bleeds is no doubt one of the major causes of pattern. miscarriage and foetal loss in deficient women. This article focus on the haemorrhagic disorder maximal amplitude and a rapid decrease in clot size resulting from deficiency of plasma FXIII because of and strength, whereas the clot solubility assay absent A or B subunits, but there is still much to be revealed increased breakdown of clots in 5 m urea. learned regarding the relationship of intracellular A2 After transfusing the patient with fresh frozen subunits and the integrity of the vascular bed, plasma, the clot solubility test normalized and his connective tissue and inflammation, all of which bleeding symptoms improved [9]. Subsequently, play a major role in thrombosis and healing. there have been numerous reports of patients with FXIII deficiency documenting their coagulopathy using the TEG and clot solubility assay [10]. History In 1944, Robbins [1] observed that the formation of Structure and function insoluble fibrin occurred with calcium and an unknown Ôserum factorÕ. Laki and Lorand confirmed Plasma FXIII, the heterotetramer (FXIII-A2B2), plays RobbinsÕ findings and concluded that the factor was an integral role in haemostasis by catalysing the a plasma protein and called it the FSF [2]. There have cross-linking of fibrin, a variety of integrins within been several names for FSF, including Laki–Lorand the platelet membrane and matrix proteins through- or L–L factor, fibrinase, protransglutaminase and out thrombus formation, thus strengthening and fibrin polymerase. In 1963, the International Com- stabilizing the blood clot. mittee of Blood Clotting Factors formally chose the Plasma FXIII is converted from a pro-transgluta- designation of factor XIII. Muszbek et al. [8] minase to activated FXIII (FXIIIa*) by thrombin in recently published the recommended nomenclature the presence of calcium ions and fibrin as seen in for the various forms of FXIII so that unified Fig. 2 FXIII-A contains both the thrombin cleavage abbreviations can be used for research publications. site and the calcium-binding site required for cata- Sixteen years after the discovery of FSF, Duckert lytic activation [11]. The gene coding for the FXIII-A et al. described the first clinical example of FXIII subunit (F13A) is located on chromosome 6p24–25, deficiency. In 1960, he evaluated a young boy in spanning 160 kb and consists of 15 exons inter- Switzerland with a severe bleeding diathesis. The rupted by 14 introns encoding a mature protein of only abnormal clotting test results were the throm- 731 amino acids (Fig. 3) [12]. boelastography (TEG) and the clot solubility screen. FXIII-A is divided into the activation peptide, These assays are still in use today and can provide a b-sandwich, catalytic core, b-barrel 1 and b-barrel 2 valuable clinical tool to determine when the patient [13] (Fig. 3). Crystal structure of the A subunit is at risk for bleeding or his response to therapy. An revealed a catalytic triad in the central core domain example of the TEG in a FXIIII deficient patient is formed through hydrogen bond interactions between seen in Fig. 1 The former study showed reduced Cys314, His373 and Asp396 [14]. Ó 2008 The Authors Journal compilation Ó 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 1190–1200 1192 L. HSIEH andD. NUGENT Fig. 2. Activation of plasma factor XIII heterotetramer. Fig. 3. Factor XIII A: gene (F13A) and protein structure. In the first step of FXIII activation, thrombin Gln328, Gln366 and Lys508 in multiple fibrin cleaves off the FXIII N-terminal activation peptide molecules (see Figs 4 and 5) [15]. The active site (AP-FXIII) of 37 amino acid residues at position contains cysteine residue (Cys311) which is found Arg37, forming the plasma FXIIIa¢. In the presence within the sequence Tyr-Gly-Gln-Cys-Trp. FXIII also 2+ of Ca and fibrin, the B subunits then dissociate forms a covalent bond with a2-antiplasmin [16,17] from the A subunits resulting in a conformational and thrombin activatable fibrinolysis inhibitor, fur- change thus leaving the active site cysteine accessible ther stabilizing the thrombus, making it more resis- for the substrate [11] (Fig. 2). Activated FXIII-A2 tant to proteolytic degradation by plasmin [16]. (FXIII-A2*) then catalyses the cross-linking of fibrin Additionally, FXIII also cross-links several other or other target proteins which contain appropriate protein substrates in the plasma and subendothelium, glutamine and lysine residues. Activated FXIII cova- including fibronectin, von Willebrand factor, vitro- lently cross-links fibrin through an (c-glutam- nectin, collagen, coagulation factor V, thrombospon- yl)lysine link. FXIII can cross-link fibrin polymers din and plasminogen activator inhibitor type 1 [11]. by c-dimerization, Gln 398 in one fibrin molecule In contrast to plasma FXIII, thrombin does not and Lys406 of the next fibrin molecule. Polymeriza- play a role in activation of intracellular FXIII. When tion can also occur through the alpha chains of intracellular calcium level rises in the presence of Ó 2008 The Authors Haemophilia (2008), 14, 1190–1200 Journal compilation Ó 2008 Blackwell Publishing Ltd FXIII DEFICIENCY 1193 Fig.
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