Factor XIII and fibrinogen are unusual among clotting factors in that neither is a serine protease. Fibrin is the main protein constituent of the blood clot, which is stabilized by factor XIIIa through an amide or isopeptide bond that ligates adjacent fibrin monomers. Many of the structural and functional features of factor XIII and fibrin(ogen) have been elucidated by protein and gene analysis, site-directed mutagenesis, and x-ray crystallography. However, some of the molecular aspects involved in the complex processes of insoluble fibrin formation in vivo and in vitro remain unresolved. The findings of a relationship between fibrinogen, factor XIII, and cardiovascular or other thrombotic disorders have focused much attention on these 2 proteins. Of particular interest are associations between common variations in the genes of factor XIII and altered risk profiles for thrombosis. Although there is much debate regarding these observations, the implications for our understanding of clot formation and therapeutic intervention may be of major importance. In this review, we have summarized recent findings on the structure and function of factor XIII. This is followed by a review of the effects of genetic polymorphisms on protein structure/function and their relationship to disease.

Overall structure of factor XIII

Plasma factor XIII is a tetrameric molecule composed of 2 A-subunits of 83.2 kd and 2 B-subunits of 79.7 kd that are held together noncovalently in a heterologous tetramer of 325.8 kd.1-3 In addition, 50% of the total fibrin-stabilizing activity in blood is found in the platelet where factor XIII exists as a dimeric molecule composed of only A-subunits.4 The A-subunit contains the active site of the enzyme and is synthesized by hepatocytes, monocytes, and megakaryocytes.5-8 Analysis of the protein phenotype after liver and bone marrow transplantation showed that the A-subunit circulating in plasma is derived from both liver and bone marrow.9 The B-subunit serves as a carrier for the catalytic A-subunit in plasma, is synthesized by the liver, and is secreted as a monomer that binds free A in plasma.8 

The A-subunit is divided into 4 domains, designated the β-sandwich, the catalytic core, barrel 1, and barrel 2 (Figure1).10,11 It contains an activation peptide of 37 amino acids that limits the access of the substrate to the active-site cysteine. The activation peptide from one subunit of the molecule crosses the opening of the active site on the other. This structure is stabilized by several hydrogen bonds and salt bridges between the activation peptide, the β-sandwich, and the catalytic core of one subunit and the catalytic core and β-barrel of the second subunit.11 

Fig. 1.

Factor XIII A-subunit structure and location of common coding polymorphisms.

The structure shown is that of recombinant factor A-subunit dimer, modeled with the use of x-ray crystallography coordinates from Weiss et al.11 The catalytic core region is colored orange; the beta-sandwich, yellow; the 2 beta-barrels, green; and the activation peptide, cyan. Highlighted are the active-site cysteine residue and 5 residues (Val34, Tyr204, Pro564, Val650, and Glu651) that show common variation in the general population (Table2).

Fig. 1.

Factor XIII A-subunit structure and location of common coding polymorphisms.

The structure shown is that of recombinant factor A-subunit dimer, modeled with the use of x-ray crystallography coordinates from Weiss et al.11 The catalytic core region is colored orange; the beta-sandwich, yellow; the 2 beta-barrels, green; and the activation peptide, cyan. Highlighted are the active-site cysteine residue and 5 residues (Val34, Tyr204, Pro564, Val650, and Glu651) that show common variation in the general population (Table2).

Close modal

Recent x-ray crystallography studies of thrombin-treated factor XIII A-subunit have suggested that the activation peptides do not dissociate upon cleavage.12 Earlier studies described the kinetics of the release of the activation peptide by thrombin13 and proposed that this reaction was enhanced by fibrin. However, in these studies, the samples were acidified prior to the high-pressure liquid chromatography analysis, and the activation peptide release may have been a consequence of this acidification. Further studies are required to determine whether the activation peptide is actually released during activation and whether substrates can modulate this reaction.

Whereas the A-subunit contains 6 potential asparagine-linked glycosylation sites, none of these have carbohydrate attachments, as judged by staining with periodic acid Schiff base reagent14 or by mass spectrometry.3 In contrast, carbohydrate contributes to approximately 8.5% of the total molecular weight of the factor XIII B-subunit.15 The B-subunit is a modular protein composed of 10 repeated Sushi or glycoprotein-1 domains.16 17 Each Sushi domain contains 2 disulfide bridges that sustain its tertiary structure, amounting to a total of 40 cysteine residues and 20 disulfide bridges in the mature B-subunit protein. The main function of the B-subunit is the stabilization and transport of the hydrophobic A-subunit in the aqueous environment of human plasma.

Factor XIII activation

Thrombin cleavage of the A-subunits is necessary to activate the plasma tetramer (Figure 2) and dimeric platelet factor XIII.18 In addition to thrombin, activation by cleavage of the Arg37-Gly38 peptide bond may occur by other serine proteases; both endogenous platelet acid protease19 and calpain20 have been reported to activate factor XIII. Fibrin polymers are an important cofactor to generate factor XIIIa.13 21-25 A complex between thrombin, fibrin polymers, and plasma factor XIII accelerates cleavage of the A-subunit, which has important implications for hemostasis. Factor XIII is not activated until a critical mass of fibrin polymerizes, a delay that ensures the hemostatic plug has a supply of factor XIII as it forms. Plasma concentrations of factor XIII and fibrinogen are approximately 0.07 μM and 9 μM, respectively. Thus, the molar ratio of factor XIII to fibrinogen in plasma is in the order of 1:100. The generation of factor XIIIa in plasma can be triggered when as little as 1% to 2% of fibrinogen is converted to fibrin polymers. This indicates that factor XIIIa begins stabilizing fibrin polymers before a visible thrombus appears, as the latter requires the conversion of at least 20% of fibrinogen into fibrin.

Fig. 2.

Factor XIII tetrameric structure and activation.

Plasma factor XIII is a heterologous tetramer consisting of 2 A- and 2 B-subunits. The A-subunits contain the enzyme's active site, and the B-subunits serve a carrier function of the hydrophobic A-subunit in the aqueous environment of human plasma. Activation of factor XIII involves cleavage of the activation peptides from the A-subunit, which then may or may not dissociate from the complex. In a second step, calcium and fibrin induce the dissociation of the B-subunits from A to expose the active site's thiol group.

Fig. 2.

Factor XIII tetrameric structure and activation.

Plasma factor XIII is a heterologous tetramer consisting of 2 A- and 2 B-subunits. The A-subunits contain the enzyme's active site, and the B-subunits serve a carrier function of the hydrophobic A-subunit in the aqueous environment of human plasma. Activation of factor XIII involves cleavage of the activation peptides from the A-subunit, which then may or may not dissociate from the complex. In a second step, calcium and fibrin induce the dissociation of the B-subunits from A to expose the active site's thiol group.

Close modal

Activation of platelet factor XIII by thrombin is very rapid.26 In contrast; there is a significant lag phase between thrombin cleavage and expression of the active site of plasma factor XIII. This lag phase in activation represents the time it takes for the B-subunits to dissociate from plasma factor XIIIa.25,27,28 Dissociation of the B- from the A-subunits is necessary to expose the active-site cysteine in plasma factor XIII A-subunit (Figure 2). There are no B-subunits bound to the fibrin clot, suggesting that B dissociates as fibrin gels.29 By contrast, more than 90% of the A-subunit remains bound to fibrin.

Localization of factor XIII to fibrin

Thrombin-activated factor XIII (FXIIIa) binds fibrin through an interaction with the αC-domains. The αC-domain consists of residues Aα220 through Aα610, which protrude from the distal region (D-region) of fibrin and end in a globular domain (Figure3).30,31 In total, both αC domains contribute to around 25% of the mass of the protein. In fibrinogen, the αC-domain connecting polypeptides contribute a fourth strand to the coiled coil while the globular end structures are positioned near the central region (E-region). During fibrin formation, this conformation of the αC-domains changes drastically: the globular portions dissociate from the central region so that they are available for intermolecular interactions.31 The binding site for FXIIIa in the αC-domain has been localized to residues 241 through 476 with the use of a fragment produced by cyanogen bromide cleavage.32 Binding of FXIIIa to this region has been confirmed by inhibition of the interaction with an antibody directed against residues 389 through 402.32 In an earlier study, a similar fragment of the α-chain produced by plasmin digestion (residues 242-424) was found to regulate dissociation of the B-subunit from thrombin-cleaved plasma factor XIII.33 Combined, these studies suggest that FXIIIa binds to fibrin in the αC-domain–connecting polypeptide and that this interaction enhances dissociation of the factor XIII subunits.

Fig. 3.

Schematic representation of the fibrinogen molecule.

Fibrinogen consists of 6 polypeptide chains held together by disulfide bonds in a molecule with bilateral symmetry. Illustrated in the Figure are the central region (E), which contains the fibrinopeptides; the distal region (D); α-helical coiled-coil segments parts of which are included in both the D and E regions; αC-domain; and the γ′ segment, which contains a thrombin and factor XIII binding site.

Fig. 3.

Schematic representation of the fibrinogen molecule.

Fibrinogen consists of 6 polypeptide chains held together by disulfide bonds in a molecule with bilateral symmetry. Illustrated in the Figure are the central region (E), which contains the fibrinopeptides; the distal region (D); α-helical coiled-coil segments parts of which are included in both the D and E regions; αC-domain; and the γ′ segment, which contains a thrombin and factor XIII binding site.

Close modal

Zymogen factor XIII binds fibrinogen in a different site than the active enzyme. This binding occurs through an interaction between the B-subunit and fibrinogen γ′ (Figure 3).34 Fibinogen γ′ is a product of alternative processing of the γ-chain transcript leading to a readthrough of the exon IX/intron I splice junction.35 The result of this alternative processing is a replacement of the last 4 amino acids at the carboxy terminus of the γ polypeptide with 20 different residues.35,36The γ′ extension is negatively charged and is found in about 10% of the fibrinogen in plasma. In addition to a binding site for factor XIII B-subunit, fibrinogen γ′ also contains a binding site for thrombin.37 Binding of factor XIII to γ′ may have important physiological consequences since an increase in γ′-chain concentration will increase the amount of factor XIII that is brought into the clot, and it has been postulated that alterations in the concentrations of the γ′-chain could be a potential risk factor for thrombosis.

Thrombin binding site

The reciprocal binding domains on factor XIII and thrombin are not well established. Serine proteases often use an exosite to orient the substrate and facilitate proteolysis. Recent studies provide evidence to suggest that exosites exist on both thrombin and factor XIII A-subunit that play a role in the binding and activation of factor XIII by thrombin.38 The B-subunits may sterically interfere with the cleavage of the A-subunit by thrombin since they can inhibit proteolysis of the activation peptide.25 28 It is possible that dissociation of the B-subunits by either soluble fibrinogen or fibrin complexes is involved in the exposure of the thrombin cleavage site on the A-subunits. One could hypothesize that as fibrin polymerizes, factor XIII attached to the γ′-chain extension on the D-region aligns with thrombin on the E-region to promote thrombin cleavage of factor XIII. Further studies are needed to define the structural domain(s) responsible for this well-controlled reaction.

Catalytic mechanism

The enzymatic reaction catalyzed by factor XIIIa is classified as a transglutaminase reaction, and the enzyme is designated an R-glutaminyl-peptide: amine γ-glutamyltransferase (EC 2.3.2.13). A catalytic triad is formed by residues Cys314, His373, and Asp396 and participates in the formation of the isopeptide bond.10The first step in catalysis is the recognition of a select group of protein-bound glutamine residues,39 which is followed by formation of a thioester bond that releases ammonia from the glutamine (Figure 4).40 The second step of the reaction involves binding of the enzyme-glutamine substrate complex to a primary amine, which is either a protein-bound lysine, a polyamine, or another primary amine. The thioester intermediate is highly reactive, and there is rapid formation of the isopeptide bond (Figure 4).41 42 If there are no primary amines available in the active-site pocket, the enzyme-substrate complex will react with water, releasing the enzyme and converting glutamine to glutamic acid.

Fig. 4.

Cross-linking reaction catalyzed by activated factor XIII.

Activated factor XIII first forms a thioester bond with a select protein-bound glutamine residue, releasing ammonia. The thioester intermediate then reacts with a primary amine from a protein-bound lysine residue, a polyamine, or other primary amines, resulting in an amide or isopeptide bond.

Fig. 4.

Cross-linking reaction catalyzed by activated factor XIII.

Activated factor XIII first forms a thioester bond with a select protein-bound glutamine residue, releasing ammonia. The thioester intermediate then reacts with a primary amine from a protein-bound lysine residue, a polyamine, or other primary amines, resulting in an amide or isopeptide bond.

Close modal

It has been shown that there are nonproline cis-bonds present in the molecule at residues Arg310-Tyr311 and Gln425-Phe426.11 On the basis of these findings, Weiss et al11 proposed that factor XIII can exist in 2 conformational states and that the conversion of these nonprolinecis-peptide bonds into the trans-configuration might provide the necessary conformational change to expose the active site for catalysis. Site-directed mutagenesis of either Arg310 or Tyr311 to Ala results in a mutant factor XIII molecule that is inactive,43 suggesting that productive catalysis cannot occur when this nonproline cis-peptide bond is disrupted. The importance of these bonds in the activation of factor XIII is a subject for future investigation.

The orientation of specific residues in the active site is beginning to be appreciated as more mutant forms of factor XIII are expressed and analyzed. Mutagenesis of residues on either side of the active-site cysteine results in substantial loss of the enzyme activity without altering the ability of factor XIII to recognize and bind fibrin.43 This suggests that the sites used for substrate binding are different or are less susceptible to disruption by the point mutations around the active-site cysteine (amino acid residues 310-317) than those required for catalytic activity.

Calcium and catalysis

Calcium ions are required for the activation of plasma factor XIII after thrombin cleavage.44,45 There is a calcium-dependent conformational change that causes the B-subunits to dissociate from thrombin-cleaved factor XIII. Calcium ions are also required for the first step in catalysis. The close proximity of the catalytic triad to the calcium-binding site suggests that calcium ions regulate conformational changes that accelerate catalysis.46 The catalytic mechanism uses calcium ions as a cofactor to hold the active site in proper conformation to trigger formation of the thioester intermediate with glutamine.

Platelet factor XIII A-subunit is rapidly activated at plasma calcium concentrations (2.5 mM). In contrast, calcium concentrations exceeding 10 mM are required for full expression of plasma factor XIII activity.44 45 This concentration is significantly higher than the one that exists in plasma and suggests that another cofactor regulates activation of plasma factor XIII. Indeed, fibrinogen reduces the calcium concentration required for dissociation of the B-subunits and facilitates factor XIII activation.

Nitric oxide regulation of factor XIII activity

A recent report by Catani et al47 demonstrates that nitric oxide donors can inhibit factor XIII activity by S-nitrosylation of the active-site cysteine. Regulation of factor XIII activity by nitric oxide at sites of vascular injury could influence clot formation and may provide a regulatory mechanism for inhibiting fibrin stabilization and enhancing fibrin degradation.

Factors regulating substrate specificity

The mechanism by which transglutaminases recognize their protein substrates remains unknown. Using recombinant chimeras of factor XIII and tissue transglutaminase, Hettasch et al48 reported that some of the properties required for the transglutaminases to recognize macromolecular substrates reside in the residues within the exon defining the active site of the molecule. This conclusion was based on the finding that exchanging the exon coding for the active site of factor XIII with the exon coding for the active site of tissue transglutaminase produced a recombinant transglutaminase that cross-linked fibrin in a pattern more characteristic of the tissue transglutaminase than of factor XIII. However, the efficiency of the cross-linking reaction was lower than that of either wild- type enzyme, indicating that regions outside the residues defined by exon 7 must also be important for macromolecular substrate recognition.

It is generally accepted that the second half of the cross-linking reaction with primary amines is not very specific. However, if one examines the enzyme's overall structure, there is some steric hindrance and constraints are placed on protein-bound lysine residues. The residue that precedes the donor lysine modulates the recognition of this lysine as a cross-linking site.49Even though studies with small peptide-bound glutamines, small peptide-bound lysines, and point mutations in recombinant factor XIII have provided information about the influence of single residues in modulating the cross-linking reaction, the macromolecular interactions that allow 3 large proteins to associate to produce intermolecular ε–(γ-glutamyl)lysine bonds remain to be defined.

The process of fibrin polymerization enhances cross-linking by aligning the molecules. In the presence of the tetrapeptide Gly-Pro-Arg-Pro, which inhibits fibrin polymerization, the glutamine sites in the carboxy terminal tail of the γ-chain are no longer aligned for rapid cross-linking by factor XIIIa.50 Further evidence that end-to-end alignment of the D-domains of fibrin plays an important role in the cross-linking reaction was provided by experiments performed by Lorand et al.51 The authors found that a double-headed ligand, produced from 2 Gly-Pro-Arg-Pro peptides linked to each end of a long polyethylene glycol molecule, could mimic the E-region in joining 2 D-regions and allow for γ-chain cross-linking to occur.51 In the absence of the double-headed ligand (or the E-region), no cross-linking takes place between 2 D-regions.

Fibrin γ-chain

Activated FXIII introduces a number of cross-links in the fibrin clot, of which the first are formed between γ-chains of 2 neighboring fibrin molecules in the longitudinal orientation of the (proto)fibril.52,53 Cross-linking occurs within 5 to 10 minutes between Gln398 or 399 on the γ-chain of one fibrin molecule and Lys406 on the γ-chain of another,52 54 resulting in the formation of 2 antiparallel isopeptide bonds that connect the D-regions of 2 fibrinogen molecules longitudinally.

There has been some controversy regarding the spatial orientation of γ-chain cross-links. Some studies suggested that the isopeptide bond was formed between 2 fibrin molecules aligned end to end in the same strand of the protofibril,53,55 while others suggested that the γ-γ cross-link was oriented between 2 fibrin molecules aligned across the fibrin protofibril in atrans-orientation.56,57 Recent crystallography data of the cross-linked D-fragment indicate that the predominant orientation is the cis-configuration.52 

Fibrin α-chain

Cross-linking of the fibrin α-chains occurs more slowly than cross-linking of the γ-chains. A number of residues have been reported to be involved in fibrin α-chain cross-linking. Studies of the incorporation of primary amines such as fluorescent dansylcadaverine have shown that glutamine residues involved in the cross-linking reaction of the α-chain include Gln221, Gln237, Gln328, and Gln366.58-60 Many lysine residues that potentially function as acceptor sites for the transglutaminase reaction have been reported, including Lys208, Lys219, Lys224, Lys418, Lys427, Lys429, Lys446, Lys448, Lys508, Lys539, Lys556, Lys580, Lys583, Lys601, and Lys606.61 62 The identification of lysine acceptor sites has been based mainly on incorporation studies of different glutamine-containing peptides such as dansyl-ε-aminocaproyl-Ala-Gln-Gln-Ile-Val, and the sites that are involved in α-chain cross-linking in vivo are not clear. The multiplicity of potential cross-linking sites provides the possibility for a highly complex and intricate cross-linking network to be formed between neighboring αC-domains in the fibrin clot.

The extent of α-chain cross-linking plays an important role in the regulation of fibrinolysis63,64 and viscoelastic properties of fibrin. Most investigators agree that α-chain cross-links appear to stabilize and promote the association of fibrin protofibrils into thick bundles of opaque fibers with higher tensile strength. The exact orientation of the α-chain cross-links in relationship to the fibrin network is, however, not thoroughly established. The α-chain cross-linked network appears to form a protective barrier that impedes the ability of plasmin to degrade the coiled-coil regions of the fibrin molecule maintaining clot structure. Plasmin must degrade fibrin in the coiled coil between the D- and E-regions to allow fibrin to release soluble fragments and lose its structure, and the extensive α-chain cross-linking interferes with this reaction.65 66 

α2-Antiplasmin

A plasma glycoprotein that is the major physiological inhibitor of plasmin in vivo is α2-antiplasmin. Factor XIIIa rapidly cross-links α2-antiplasmin to the α-chain of fibrin.67,68 This cross-linking reaction occurs between Gln2 in the amino terminus of α2-antiplasmin69 and Lys303 in the fibrin α-chain.68 The α2-antiplasmin remains an efficient plasmin inhibitor when covalently cross-linked to fibrin, and incorporation of the inhibitor into the clot by factor XIII plays a major role in the regulation of the breakdown of fibrin.70 71 

Fibronectin

Both the cellular and plasma forms of fibronectin are factor XIII substrates. Fibronectin can be cross-linked to both itself and collagen through Gln3 at the amino-terminal end of the molecule.72However, when fibrin is present, fibronectin-fibrin complexes are the preferred cross-linking products.73 Fibronectin is cross-linked to the α-chain of the fibrin molecule. Fibronectin can inhibit fibrin cross-linking and lead to the formation of soluble fibrin.74-76 Cross-linking of fibronectin to fibrin can alter the mechanical properties76-78 of the clot and promote cellular adherence as well as migration of cells into the clot.79 This may be important to facilitate the wound healing process.

Collagen

During vascular injury, fibrin clots may be covalently attached to collagen in the vessel wall by factor XIIIa, a reaction that may prevent the clot from being dislodged from the vessel wall. Collagen types I, II, III, and V can be cross-linked to fibronectin by factor XIIIa.80 Collagen provides the lysine residues necessary to form an isopeptide bond with Gln3 in fibronectin. The cross-linking of both fibronectin and collagen to fibrin suggests that these reactions could stabilize the extracellular matrix that forms at sites of tissue injury.

Other factor XIIIa substrates

Many other proteins are cross-linked by factor XIIIa. These substrates, which include inhibitors of fibrinolysis, von Willebrand factor, factor V, and platelet (glyco)proteins, are summarized in Table1, together with the potential physiological significance of their cross-linking.

Table 1.

Factor XIII substrates

SubstrateCross-linking siteSubstances with which it is cross-linkedKnown or potential function
Fibrin(ogen) γ-chain52-54  Gln398, Gln399, and Lys406 Itself and α-chain Clot stabilization 
Fibrin(ogen) α-chain58-62  Gln221, Gln237, Gln328, Gln366, and 15 potential lysines from Lys208 to Lys606 Itself and γ-chain Clot stabilization 
α2-Antiplasmin67-69  Gln2 Lys303 fibrin α-chain Resistance to fibrinolysis 
TAFI150 Gln2, Gln5, Gln292 Fibrin, itself Resistance to fibrinolysis 
PAI-2151 152  — Lys148, Lys230, Lys413 fibrin α-chain Resistance to fibrinolysis 
Fibronectin72 73  Gln3 Itself, fibrin, collagen Migration of cells into the clot; wound healing 
Collagen72 80  — Fibronectin, fibrin Stabilization of extracellular matrix  
Von Willebrand factor153 154  — Fibrin, collagen Platelet adhesion to the clot 
Vitronectin155 156  Gln93 — — 
Thrombospondin157 — Fibrin —  
Factor V158 159  — Fibrin, platelets Increased thrombin generation at the clot surface 
Actin160 161  — Fibrin Clot retraction, stabilization of the platelet cytoskeleton 
Myosin162 — Itself Clot retraction, stabilization of the platelet cytoskeleton 
Vinculin163 — Fibrin Clot retraction, stabilization of the platelet cytoskeleton 
αIIbβ3164 — Fibrin Stabilization of the platelet—fibrin clot 
SubstrateCross-linking siteSubstances with which it is cross-linkedKnown or potential function
Fibrin(ogen) γ-chain52-54  Gln398, Gln399, and Lys406 Itself and α-chain Clot stabilization 
Fibrin(ogen) α-chain58-62  Gln221, Gln237, Gln328, Gln366, and 15 potential lysines from Lys208 to Lys606 Itself and γ-chain Clot stabilization 
α2-Antiplasmin67-69  Gln2 Lys303 fibrin α-chain Resistance to fibrinolysis 
TAFI150 Gln2, Gln5, Gln292 Fibrin, itself Resistance to fibrinolysis 
PAI-2151 152  — Lys148, Lys230, Lys413 fibrin α-chain Resistance to fibrinolysis 
Fibronectin72 73  Gln3 Itself, fibrin, collagen Migration of cells into the clot; wound healing 
Collagen72 80  — Fibronectin, fibrin Stabilization of extracellular matrix  
Von Willebrand factor153 154  — Fibrin, collagen Platelet adhesion to the clot 
Vitronectin155 156  Gln93 — — 
Thrombospondin157 — Fibrin —  
Factor V158 159  — Fibrin, platelets Increased thrombin generation at the clot surface 
Actin160 161  — Fibrin Clot retraction, stabilization of the platelet cytoskeleton 
Myosin162 — Itself Clot retraction, stabilization of the platelet cytoskeleton 
Vinculin163 — Fibrin Clot retraction, stabilization of the platelet cytoskeleton 
αIIbβ3164 — Fibrin Stabilization of the platelet—fibrin clot 

TAFI indicates thrombin-activatable fibrinolysis inhibitor; PAI-2, plasminogen activator inhibitor 2.

Platelet factor XIII

Platelet factor XIII is localized in the cytoplasm and is composed of 2 A-subunits.1 The function of cytosolic platelet factor XIII is not well established. Plasma factor XIII can bind to glycoprotein IIb/IIIa on platelets, and this binding site can be cleaved by plasmin.81 Studies have indicated that normal platelets resuspended in factor XIII–free plasma catalyze the cross-linking of fibrin itself as well as the cross-linking of α2-antiplasmin to fibrin.82 Thus, factor XIII may further increase clot stabilization when released from platelets entrapped in fibrin clots.83 In addition, activated platelets may provide a surface for accelerating the cross-linking of fibrin polymers. Immunological studies have demonstrated that platelet-associated factor XIII is a marker of activation.84 Recently, Dale et al85 have shown that platelet factor XIII increases the procoagulant potential of activated platelets by cross-linking the primary amine serotonin to von Willebrand factor, factor V, and fibrinogen, which then localize to the platelet membrane via a serotonin receptor. The importance of platelet factor XIII in clot stabilization is illustrated by the fact that patients with A-subunit deficiency usually suffer a more severe bleeding diathesis than patients with B-subunit deficiency. In the latter case, factor XIII A-subunit is absent from plasma but normally present in platelets.

Structure of the factor XIII genes

The factor XIII A-subunit gene belongs to the transglutaminase family. The best-characterized members of this family are factor XIII, keratinocyte, tissue, and epidermal transglutaminases.86Erythrocyte protein band 4.2 has significant sequence homology to the transglutaminases and is also a member of the family.87The factor XIII A-subunit gene has been localized to chromosome 6p24-p25 and shows linkage with the major histocompatibilty complex.88,89 The gene codes for a mature protein of 731 amino acids, has 15 exons, and is more than 160 kilobases (kb) in size.90 

The factor XIII B-subunit gene codes for a mature protein of 641 amino acids, is 28 kb in size, and is composed of 12 exons.17 It is located on chromosome 1q32-q32.1.91 The B-subunit contains a structural feature of 10 short consensus repeat units also known as Sushi domains.16 Sushi domains are a common structural feature of proteins associated with the regulation of the complement system.92,93 This family of proteins includes 5 complement control proteins: factor H, C4 binding protein, CR1, decay accelerating factor, and the membrane cofactor proteins. The genes for other Sushi domain proteins are located in the same chromosome 1q32 locus.94-98 

Polymorphisms of the factor XIII A-subunit gene

Five common coding polymorphisms have been identified in the A-subunit (Figure 1; Table 2). A common G>T transition in codon 34 of the factor XIII A-subunit leading to a replacement of valine with leucine was found by investigators studying the molecular basis of factor XIII deficiency.99,100 This transition is not associated with factor XIII deficiency, but has been shown to change the function of factor XIII (see below). A tyrosine-to-phenylalanine polymorphism has been identified at residue 204 in the central domain of the factor XIII A-subunit.101Tyr204Phe has a frequency of 0.01 to 0.03, the lowest frequency in the general population of the 5 coding polymorphisms, and has been associated with an increased risk for recurrent miscarriage in women.102 A replacement of Pro564 with leucine in barrel 1 of the factor XIII A-subunit is responsible for the phenotypic discrimination on isoelectric focusing of factor XIII A*1A and 1B.103 Two further base changes, leading to a replacement of Val650 with isoleucine and Glu651 with glutamine in barrel 2, are responsible for the differences between the A*1A and 2A and A*1B and 2B phenotypes, respectively.103 Two polymorphisms have been identified in the noncoding regions of the gene, both occurring in the promoter region. One is a −246G>A transition,104,105 which is located close to SP-1 and MZF-1 protein-binding sites.106 Potential effects of this polymorphism on protein expression and factor XIII levels have not been investigated. The second polymorphism in the promoter is a short tandem repeat (AAAG)n approximately 800 to 900 base pairs upstream of the transcription start site.107 This tetranucleotide repeat occurs close to a GATA-1 binding site,106 but again, its potential functional effects are unknown.

Table 2.

Factor XIII polymorphisms

PolymorphimsApproximate allele frequencyLocationAssociation with diseaseBiochemical/molecular phenotype
A-subunit     
 Val34Leu 0.25 Activation peptide CAD, stroke, DVT (see Table 3Increases activation rate—affects fibrin structure 
 Tyr204Phe 0.01-0.03 Catalytic core Miscarriage,102stroke?146 Specific activity? 
 Pro564Leu 0.21 Catalytic core Stroke?146 Specific activity? 
 Val650Ile 0.06 Beta-barrel None None 
 Glu651Gln 0.27 Beta-barrel None None  
 − 246G > A — Promoter Unknown Unknown 
 (AAAG)n — Promoter, around 800 to 900 bp upstream of transcription site Unknown Unknown 
B-subunit     
 His95Arg 0.1 2ndSushi VTE? Increases subunit dissociation?124 
 B∗1 Varies in populations Unknown Unknown/unlikely? Unknown 
 B∗2 Varies in populations Unknown Unknown/unlikely? Unknown 
 B∗3 Varies in populations Unknown Unknown/unlikely? Unknown  
 HS-1 Alu insertion —  —  Unknown/unlikely? Unknown 
PolymorphimsApproximate allele frequencyLocationAssociation with diseaseBiochemical/molecular phenotype
A-subunit     
 Val34Leu 0.25 Activation peptide CAD, stroke, DVT (see Table 3Increases activation rate—affects fibrin structure 
 Tyr204Phe 0.01-0.03 Catalytic core Miscarriage,102stroke?146 Specific activity? 
 Pro564Leu 0.21 Catalytic core Stroke?146 Specific activity? 
 Val650Ile 0.06 Beta-barrel None None 
 Glu651Gln 0.27 Beta-barrel None None  
 − 246G > A — Promoter Unknown Unknown 
 (AAAG)n — Promoter, around 800 to 900 bp upstream of transcription site Unknown Unknown 
B-subunit     
 His95Arg 0.1 2ndSushi VTE? Increases subunit dissociation?124 
 B∗1 Varies in populations Unknown Unknown/unlikely? Unknown 
 B∗2 Varies in populations Unknown Unknown/unlikely? Unknown 
 B∗3 Varies in populations Unknown Unknown/unlikely? Unknown  
 HS-1 Alu insertion —  —  Unknown/unlikely? Unknown 

HS-1 indicates human specific-1; CAD, coronary artery disease; DVT, deep vein thrombosis; and VTE, venous thromboembolism.

Factor XIII Val34Leu

Factor XIII Val34Leu occurs in the activation peptide, 3 amino acids from the thrombin-cleavage site between Arg37 and Gly38 (Figure1). Val34Leu is relatively common, with an allele frequency of around 0.25 to 0.30 in the white population.108-110 The Leu allele frequency varies among different populations, being highest in whites (0.25-0.30) and American Indians (0.29), with a maximum of 0.40 among Pima Indians.109,110 In South Asians and in African populations, however, frequency of the Leu34 allele is lower, at around 0.13 and 0.17, respectively,109,110 and it reaches its lowest point in the Japanese at 0.01.110 

Despite the fact that the transition of valine to leucine is a relatively conservative change—the only difference between the 2 amino acids being an additional CH2 group present in the leucine side-chain—the Val34Leu polymorphism has a significant effect on factor XIII function.111-115 Activation of Leu34 factor XIII by thrombin proceeds more rapidly than that of the Val34 variant.112-115 This effect is independent of the interaction between the A- and B-subunits, as both plasma and platelet Leu34 factor XIII are activated more rapidly than their Val34 counterparts.113 The catalytic efficiency of cleavage by thrombin is increased approximately 2.5-fold, from 0.2 μM−1sec−1 for the Val34 activation peptide to 0.5 μM−1sec−1 for Leu34.112Trumbo and Maurer115 found that the catalytic efficiency of thrombin cleavage of a synthetic peptide spanning factor XIII residues 28 through 41 is increased 5-fold when leucine rather than valine is at position 34 (0.068 versus 0.013 μM−1sec−1). Overall, the catalytic efficiency of this segment is approximately 10 times less than that of the entire factor XIII polypeptide, and it appears that the difference between the Leu34 and Val34 variants is accentuated by the absence of the remainder of the A-subunit.

The mechanism by which replacement of Val34 with leucine accelerates thrombin cleavage is not clear, but 2 studies have suggested that sterical/structural effects may play a role. Balogh et al114 reported that the Leu34 variant of a factor XIII segment from residues 32 to 42 showed greater interaction energy than the Val34 variant in a computer model of the molecular interaction with thrombin. Sadasivan and Yee116 analyzed the interaction between thrombin and a factor XIII peptide from residues 28 to 37 by x-ray crystallography. The study confirmed the critical role that residue 34 plays in the interaction between factor XIII and thrombin, and it was found that residues Val34 and Val29 are closer in the 3-dimensional structure than expected from their position in the secondary structure.116 The authors surmised that a bulkier side-chain at either residue 34 or residue 29 would alter the substrate peptide conformation.116 A recent study by Trumbo and Maurer117 on peptide (FXIII A-subunit 28-41) hydrolysis and conformation confirmed this; in this study, replacement of Val34 with Leu increased both kcat andKm of thrombin cleavage, and replacement of Val29 with Phe increased the Km. However, analysis of a double 34/29 mutant peptide showed that residue 34 of the factor XIII activation peptide plays a more influential role in thrombin interaction than residue 29, indicating that the main interaction between thrombin and factor XIII resides in the P4-P1 (Val/Leu34-Arg37) segment of the activation peptide.117 

In the presence of polymerizing fibrin, the catalytic efficiencies of thrombin cleavage of the activation peptide are increased approximately 10-fold, but activation of factor XIII Leu34 remains faster than that of Val34, with a catalytic efficiency of 4.8 compared with 2.2 μM−1sec−1.112 An interesting observation is that release of the Leu34 activation peptide proceeds at a similar rate to that of fibrinopeptide A, whereas the rate of Val34 peptide cleavage is in tandem with that of fibrinopeptide B.112 These data suggest that factor XIII Leu34 is activated at the time of des-A fibrin formation, whereas the Val34 variant is activated when des-AB fibrin is formed.

The molecular structure of fibrin is dynamic in the sense that it changes from thin protofibrils immediately after fibrinopeptide A cleavage to thicker fibers induced by lateral aggregation upon slower release of fibrinopeptide B.118-120 The alteration in factor XIII activation kinetics induced by the Val34Leu polymorphism could change this fibrin formation process, whereby cross-linking by factor XIII Leu34 acts as a fixative of the early, thinner des-A fibrin structure, inhibiting molecular rearrangement and lateral aggregation of the fibers. In agreement with this hypothesis, fibrin clots formed in the presence of Leu34 factor XIII have thinner fibers, smaller pores, and altered permeation characteristics when compared with fibrin clots formed in the presence of the Val34 variant (Figure5).112 In addition, Schroeder et al121 recently reported that clot formation time as measured by thromboelastography was significantly shortened in factor XIII Leu34 samples.

Fig. 5.

Effect of the factor XIII Val34Leu polymorphism on cross-linked fibrin structure.

Scanning electron micrographs of fibrin clots cross-linked by factor XIII Val34 (A) and factor XIII Leu34 (B). The clots were made from plasma samples homozygous for each Val34Leu allele. Fibrin cross-linked by the Leu34 variant of factor XIII, which is associated with a protective effect on thrombotic disorders, consists of thinner fibers and has altered permeation characteristics.112 

Fig. 5.

Effect of the factor XIII Val34Leu polymorphism on cross-linked fibrin structure.

Scanning electron micrographs of fibrin clots cross-linked by factor XIII Val34 (A) and factor XIII Leu34 (B). The clots were made from plasma samples homozygous for each Val34Leu allele. Fibrin cross-linked by the Leu34 variant of factor XIII, which is associated with a protective effect on thrombotic disorders, consists of thinner fibers and has altered permeation characteristics.112 

Close modal

Polymorphisms of the factor XIII B-subunit gene

Factor XIII B-subunit shows 3 distinct alleles, B*1, B*2, and B*3 (Table 2).122 The noncoding region of the B-subunit gene contains a polymorphic human specific–1 Alu insertion.123In contrast to the factor XIII A-subunit polymorphisms, the molecular basis of the 3 most common B-subunit alleles has not been elucidated. Komanasin et al124 identified an A>G transition in codon 95 of the factor XIII B-subunit gene, which causes a replacement of histidine with arginine in the second Sushi domain. This polymorphism is relatively common, with an allele frequency of 0.10 in white subjects. It is unlikely that His95Arg would explain the phenotypic differentiation on isoelectric focusing, as both histidine and arginine have basic side-chains; however, this may need further investigation.

Pathophysiology of thrombotic disorders

Clinical conditions associated with the development of thrombosis are a major cause of morbidity and mortality in the developed world. Among these are the atherothrombotic disorders (myocardial infarction, ischemic cerebrovascular disease, and peripheral vascular disease) and the venous thrombotic disorders, (deep vein thrombosis and pulmonary embolus). The development of atherothrombotic vascular disorders occurs over many decades and involves the interaction of classic atherogenic risk factors (diabetes, dyslipidemia, hypertension, etc) with abnormalities of the hemostatic system. Arterial disease develops in what is a high-pressure, high-flow system, and lipid deposition and smooth muscle hyperplasia occur in the arteries of subjects at risk, which ultimately leads to coronary atheroma formation. Later in life, plaques become unstable and rupture, exposing the highly prothrombotic lipid core, which activates the extrinsic coagulation cascade (factor VII, tissue factor), thereby initiating a series of proteolytic events culminating in thrombotic occlusion of coronary arteries. Ultimately myocardial infarction (MI) arises from the development of a cross-linked, fibrinolysis-resistant, platelet-rich fibrin clot. By contrast, venous thrombosis occurs in the context of a low-pressure, low-flow system in which damage to the vessel wall and atheroma formation are not etiological factors. Classically, venous thrombosis occurs in individuals who are genetically predisposed to thrombosis (protein C, protein S, antithrombin III deficiency); in the general population, it usually occurs secondary to environmental risk (surgery, pregnancy, malignancy) in which genetic influences play a role (factor V Leiden, prothrombin variants). A thrombotic occlusion in the venous system is low in platelets as compared with arterial disease and is composed mainly of cross-linked fibrin.

Factor XIII Val34Leu and coronary artery disease

Several studies have investigated the relationship between factor XIII Val34Leu and the risk of MI (Table3). The first was carried out in a cohort of consecutive individuals undergoing coronary angiography and reported a highly significant underrepresentation of the Leu34 allele in subjects with a history of MI as compared with angiographic subjects who had no history of MI and as compared with controls.108 These results suggested that possession of the Leu allele was protective against MI, an impression reinforced by the observation that, in carriers of the Leu allele, cardioprotection was lost in the presence of increasing degrees of insulin resistance as estimated by the homeostasis model assessment method125 and in the presence of high levels of the fibrinolytic inhibitor plasminogen activator inhibitor–1 (PAI-1).126 These findings indicated a major gene (factor XIII Leu34)–environment (insulin resistance) interaction that modulated vascular risk. A study from Finland confirmed the protective association of factor XIII Leu34 in a combined postmortem and coronary angiography study but failed to demonstrate an interaction with the PAI-1 4G/5G promoter genotype.127 Interestingly, the prevalence of the Leu allele was reported as being lowest in the Eastern Kainuu area, in which the highest risk of MI is found in Finland. These findings are similar to those described for Asians living in Britain, who both are at high vascular risk and have a low prevalence of the Leu34 allele.109 Two further studies have reported a protective effect of Leu34 against MI, with similar odds ratios of around 0.6 (Table 3).128,129 A third study, which investigated acute MI risk in young women, showed a relative risk of 0.8 for the Leu34 allele in this group of patients.130 

Table 3.

Relationship between the factor XIIIA Val34Leu polymorphism and thrombotic disease

DiseaseAssociation with diseaseNo. subjects (controls)Origin of subjectsOdds ratioAuthor
MI 398 (196) Northern UK 0.67 (0.54-0.85) Kohler et al108 
MI 470 Finland 0.59 (0.38-0.93) Wartiovaara et al127 
MI 150 (150) Brazil 0.6 (0.4-0.9) Franco et al128 
MI − 201 (244) Southern France NA Canavy et al131 
MI − 423 (479) US NA Aleksic et al132 
MI − 191 UK Asians NA Warner et al134 
MI 120 (120) Northern Italy 0.59 Gemmati et al129 
ICH 130 (130) Northern Italy 1.74 Gemmati et al129 
BI 120 Northern Italy 0.60 Gemmati et al129 
MI3-150 68 US 0.8 Reiner et al130 
BI3-150 − 41 (345) US NA Reiner et al130 
MI − 101 Southern Spain NA Corral et al133 
DVT − 97 Southern Spain NA Corral et al133 
CVD − 104 Southern Spain NA Corral et al133 
DVT 226 (254) Northern UK 0.63 (0.38-0.82) Catto et al136 
DVT 189 (189) Brazil 0.16 (0.05-0.5) for homozygous Leu Franco et al137 
DVT 154 (308) Austria 0.7 (0.5-1.0) Renner et al138 
DVT − 273 (288) Hungary NA Balogh et al114 
DVT − 427 (1045) Southern Italy NA Margaglione et al139 
ICH 612 (436) Northern UK — Catto et al143 
BI 456 (456) France 0.58 (0.44-0.75) Elbaz et al145 
ICH − 201 (201) Southern Spain NA Corral et al144 
RAO 108 (313) Austria 0.22 for homozygous Leu Weger et al147 
DiseaseAssociation with diseaseNo. subjects (controls)Origin of subjectsOdds ratioAuthor
MI 398 (196) Northern UK 0.67 (0.54-0.85) Kohler et al108 
MI 470 Finland 0.59 (0.38-0.93) Wartiovaara et al127 
MI 150 (150) Brazil 0.6 (0.4-0.9) Franco et al128 
MI − 201 (244) Southern France NA Canavy et al131 
MI − 423 (479) US NA Aleksic et al132 
MI − 191 UK Asians NA Warner et al134 
MI 120 (120) Northern Italy 0.59 Gemmati et al129 
ICH 130 (130) Northern Italy 1.74 Gemmati et al129 
BI 120 Northern Italy 0.60 Gemmati et al129 
MI3-150 68 US 0.8 Reiner et al130 
BI3-150 − 41 (345) US NA Reiner et al130 
MI − 101 Southern Spain NA Corral et al133 
DVT − 97 Southern Spain NA Corral et al133 
CVD − 104 Southern Spain NA Corral et al133 
DVT 226 (254) Northern UK 0.63 (0.38-0.82) Catto et al136 
DVT 189 (189) Brazil 0.16 (0.05-0.5) for homozygous Leu Franco et al137 
DVT 154 (308) Austria 0.7 (0.5-1.0) Renner et al138 
DVT − 273 (288) Hungary NA Balogh et al114 
DVT − 427 (1045) Southern Italy NA Margaglione et al139 
ICH 612 (436) Northern UK — Catto et al143 
BI 456 (456) France 0.58 (0.44-0.75) Elbaz et al145 
ICH − 201 (201) Southern Spain NA Corral et al144 
RAO 108 (313) Austria 0.22 for homozygous Leu Weger et al147 

MI indicates myocardial infarction; ICH, intracranial hemorrhage; BI, brain infarction; TIA, transient ischemic attack, DVT, deep vein thrombosis; CVD, cerebrovascular disease; RAO, retinal artery occlusion; and NA, not applicable.

F3-150

Subjects were all young women.

Four publications have reported no association between possession of Leu34 and risk of MI. These include patients recruited from southern France,131 the United States,132 and southern Spain,133 and Asian Indian patients recruited from the United Kingdom (Table 3).134 One explanation for the discrepancies in the studies could have been linkage disequilibrium between Val34Leu and other polymorphisms in the factor XIII A-subunit gene. However, a study from Kohler et al135failed to show any association between 3 other coding polymorphisms (Pro564Leu, Val650Ile, and Glu651Gln; Table 2) and MI.

Factor XIII Val34Leu and venous thrombotic disorders

Six studies have investigated the relationship between factor XIII Val34Leu and venous thrombosis (Table 3). Three have shown significant protective associations similar to that described for MI,136-138 while 3 demonstrated no association.114,133,139 Two studies have addressed the question as to whether interactions occur between factor XIII Val34Leu and factor V Leiden.137,140 Neither study was positive although the study by Franco et al137 hinted at a weak interaction with increasing age. A study by Carter et al141 reported an interaction between a common polymorphism in the fibrinogen Aα gene (Thr312Ala) and factor XIII Val34Leu that negates the protective effect afforded by Val34Leu. Additionally, studies of embolic stroke indicate that the Ala312 allele is associated with a poor prognosis in high-risk subjects with atrial fibrillation to indicate that it may influence embolic disorders.142 The plausibility of these observations lies in the fact that position 312 in the Aα fibrinogen chain is very close to the factor XIII cross-linking and α2-antiplasmin incorporation sites. The biochemical consequences of these interactions are the subject of current investigation.

Factor XIII Val34Leu, cerebrovascular disease, and other associations

In comparison with MI and venous thromboembolism, the relationship between factor XIII Val34Leu and cerebrovascular disease has been investigated to a lesser extent (Table 3). The original paper on this subject by Catto et al143 demonstrated a higher prevalence of the Leu allele in subjects with primary intracranial hemorrhage (ICH) and no association with ischemic stroke. While the findings in ICH support the concept of a gene that can be both protective against thrombosis and involved in the pathogenesis of bleeding, the study involved only 62 patients with ICH. The findings in relation to ICH were not supported by a much larger study from Spain,144and this group reported no association between possession of Leu34 and ischemic stroke.133 However, a large, well-matched case-control study of cerebral infarction reported a major protective effect of Leu34, with interactions with smoking that modified risk of stroke.145 These findings were supported by a smaller study from Italy.129 A more recent study from the United States did not find a protective effect of Leu34 in a limited number of young women with cerebral infarction.130 Instead, the authors found that the Phe204 allele of factor XIII, which previously has been linked with an increased risk for miscarriage,102was associated with a mild increased risk of ischemic stroke. In an earlier report from the same authors, however, the Phe204 and Leu564 alleles was associated with an increased risk of hemorrhagic stroke.146 These apparently contradictory findings indicate that the relationship between factor XIII polymorphisms and cerebrovascular disease may be more complex, and further studies are warranted that take into account other genetic and environmental factors involved in the pathogenesis of the disease. With regard to other thrombotic disorders, a recent report from Austria has found a protective effect of homozygous factor XIII Leu34 on retinal artery thrombosis,147 with an odds ratio similar to that reported previously for the homozygous genotype in relation to deep vein thrombosis (Table 3).

The structure of the fibrin clot and the effects of cross-linking by factor XIII on fibrin structure are immensely complex. Fibrin clot structure in plasma samples from different individuals shows considerable variation, suggesting that many factors, both genetic and environmental, play a role in determining the stability and resistance of the clot to fibrinolysis. FactorXIII Val34Leu is a genetic determinant of fibrin structure/function, and fibrinogen Aα Thr312Ala and Bβ Arg448Lys are potential candidates, but the effects of additional determinants may be major. The concentrations of fibrinogen, metal ions, and many other factors may affect fibrin clot structure and interact with the genetic polymorphisms. Incorporation of constitutive proteins such as fibronectin into the clot may play an additional role in determining molecular structure. The true complexity of clot formation is only now becoming apparent, and future developments in this area may have profound effects on our understanding of the basic science and its translation into clinical practice.

Activation of factor XIII by thrombin and the roles that fibrin formation and the factor XIII B-subunit play in this reaction are intriguing processes. To date, apart from x-ray crystallography and kinetic data of the interaction between thrombin and factor XIII–derived peptides, little is known about the molecular and structural details of factor XIII activation. It is known that activation of factor XIII is regulated mainly by fibrin polymerization and the clot formation process, but the exact molecular mechanisms have so far remained unresolved.

Two animal studies have indicated the potential therapeutic relevance of factor XIII modulation. In ferrets, factor XIII–mediated fibrin-fibrin and α2-antiplasmin–fibrin cross-linking caused pulmonary emboli that were resistant to endogenous and exogenous tissue plasminogen activator–induced fibrinolysis.148 In a canine model of coronary thrombosis, inhibition of cross-linking by factor XIII promoted tissue plasminogen activator–induced thrombolysis of the clots.149 

The laboratory and clinical epidemiological studies presented in this review indicate that genetic and environmental modulation of the processes involved in fibrin structure/function are of importance in clot formation. Recent studies on factor XIII Val34Leu suggest that therapeutic targets exist within the final processes of the coagulation cascade that may be of clinical value in the management of thrombotic disorders and, potentially, in enhancing therapeutic and physiological fibrinolysis. The challenge is to acquire a fuller understanding of the biochemical processes and to support the development of research programs that may lead to therapeutic advances in this field.

Supported by British Heart Foundation grants PG/98104 (P.J.G., R.A.S.A.), PG/99082 (P.J.G., R.A.S.A.), and FS2000023 (P.J.G., R.A.S.A.); Medical Research Council grants G9900904 (P.J.G., R.A.S.A.) and G0000624 (P.J.G., R.A.S.A.); National Institutes of Health grant HL30954 (J.W.W.); National Cancer Institute grant CA 71753 (C.S.G.); Duke University SPORE in Breast Cancer grant CA68438 (C.S.G.); National Heart, Lung and Blood Institute grant HL28391 (C.S.G.); and an American Heart Association (North Carolina Affiliate) Grant-in-Aid (T.S.L.).

1
Schwartz
ML
Pizzo
SV
Hill
RL
McKee
PA
Human factor XIII from plasma and platelets: molecular weights, subunit structures, proteolytic activation, and cross-linking of fibrinogen and fibrin.
J Biol Chem.
248
1973
1395
1407
2
Chung
SI
Lewis
MS
Folk
JE
Relationships of the catalytic properties of human plasma and platelet transglutaminases (activated blood coagulation factor XIII) to their subunit structures.
J Biol Chem.
249
1974
940
950
3
Ashcroft
AE
Grant
PJ
Ariëns
RAS
A study of human coagulation factor XIII A-subunit by electrospray ionization mass spectrometry.
Rapid Commun Mass Spectrom.
14
2000
1607
1611
4
McDonagh
J
McDonagh
RP
Jr
Delage
JM
Wagner
RH
Factor XIII in human plasma and platelets.
J Clin Invest.
48
1969
940
946
5
Weisberg
LJ
Shiu
DT
Conkling
PR
Shuman
MA
Identification of normal human peripheral blood monocytes and liver as sites of synthesis of coagulation factor XIII a-chain.
Blood.
70
1987
579
582
6
Muszbek
L
Ádány
R
Kavai
M
Boda
Z
Lopaciuk
S
Monocytes of patients congenitally deficient in plasma factor XIII lack factor XIII subunit a antigen and transglutaminase activity.
Thromb Haemost.
59
1988
231
235
7
Ádány
R
Nemes
Z
Muszbek
L
Characterization of factor XIII containing-macrophages in lymph nodes with Hodgkin's disease.
Br J Cancer.
55
1987
421
426
8
Nagy
JA
Kradin
RL
McDonagh
J
Biosynthesis of factor XIII A and B subunits.
Adv Exp Med Biol.
231
1988
29
49
9
Wölpl
A
Lattke
H
Board
PG
et al
Coagulation factor XIII A and B subunits in bone marrow and liver transplantation.
Transplantation.
43
1987
151
153
10
Yee
VC
Pedersen
LC
Le Trong
I
Bishop
PD
Stenkamp
RE
Teller
DC
Three-dimensional structure of a transglutaminase: human blood coagulation factor XIII.
Proc Natl Acad Sci U S A.
91
1994
7296
7300
11
Weiss
MS
Metzner
HJ
Hilgenfeld
R
Two non-proline cis peptide bonds may be important for factor XIII function.
FEBS Lett.
423
1998
291
296
12
Yee
VC
Pedersen
LC
Bishop
PD
Stenkamp
RE
Teller
DC
Structural evidence that the activation peptide is not released upon thrombin cleavage of factor XIII.
Thromb Res.
78
1995
389
397
13
Lewis
SD
Janus
TJ
Lorand
L
Shafer
JA
Regulation of formation of factor XIIIa by its fibrin substrates.
Biochemistry.
24
1985
6772
6777
14
Schwartz
ML
Pizzo
SV
Hill
RL
McKee
PA
The subunit structures of human plasma and platelet factor XIII (fibrin-stabilizing factor).
J Biol Chem.
246
1971
5851
5854
15
Bohn
H
Haupt
H
Kranz
T
Die molekulare Struktur der fibrinstabilisierenden Faktoren des Menschen [Molecular structure of human fibrin stabilizing factors].
Blut.
25
1972
235
248
16
Ichinose
A
McMullen
BA
Fujikawa
K
Davie
EW
Amino acid sequence of the b subunit of human factor XIII, a protein composed of ten repetitive segments.
Biochemistry.
25
1986
4633
4638
17
Bottenus
RE
Ichinose
A
Davie
EW
Nucleotide sequence of the gene for the b subunit of human factor XIII.
Biochemistry.
29
1990
11195
11209
18
Takagi
T
Doolittle
RF
Amino acid sequence studies on factor XIII and the peptide released during its activation by thrombin.
Biochemistry.
13
1974
750
756
19
Lynch
GW
Pfueller
SL
Thrombin-independent activation of platelet factor XIII by endogenous platelet acid protease.
Thromb Haemost.
59
1988
372
377
20
Ando
Y
Imamura
S
Yamagata
Y
et al
Platelet factor XIII is activated by calpain.
Biochem Biophys Res Commun.
144
1987
484
490
21
Hornyak
TJ
Shafer
JA
Interactions of factor XIII with fibrin as substrate and cofactor.
Biochemistry.
31
1992
423
429
22
Naski
MC
Lorand
L
Shafer
JA
Characterization of the kinetic pathway for fibrin promotion of alpha-thrombin-catalyzed activation of plasma factor XIII.
Biochemistry.
30
1991
934
941
23
Janus
TJ
Lewis
SD
Lorand
L
Shafer
JA
Promotion of thrombin-catalyzed activation of factor XIII by fibrinogen.
Biochemistry.
22
1983
6269
6272
24
Greenberg
CS
Miraglia
CC
Rickles
FR
Shuman
MA
Cleavage of blood coagulation factor XIII and fibrinogen by thrombin during in vitro clotting.
J Clin Invest.
75
1985
1463
1470
25
Greenberg
CS
Achyuthan
KE
Fenton
JW
Factor XIIIa formation promoted by complexing of alpha-thrombin, fibrin, and plasma factor XIII.
Blood.
69
1987
867
871
26
Hornyak
TJ
Bishop
PD
Shafer
JA
Alpha-thrombin-catalyzed activation of human platelet factor XIII: relationship between proteolysis and factor XIIIa activity.
Biochemistry.
28
1989
7326
7332
27
Lorand
L
Gray
AJ
Brown
K
et al
Dissociation of the subunit structure of fibrin stabilizing factor during activation of the zymogen.
Biochem Biophys Res Commun.
56
1974
914
922
28
Chung
SI
Folk
JE
Kinetic studies with transglutaminases: the human blood enzymes activated coagulation factor 13 and the guinea pig hair follicle enzyme.
J Biol Chem.
247
1972
2798
2807
29
Greenberg
CS
Dobson
JV
Miraglia
CC
Regulation of plasma factor XIII binding to fibrin in vitro.
Blood.
66
1985
1028
1034
30
Weisel
JW
Stauffacher
CV
Bullitt
E
Cohen
C
A model for fibrinogen: domains and sequence.
Science.
230
1985
1388
1391
31
Weisel
JW
Medved
L
The structure and function of the αC domains of fibrinogen.
Ann N Y Acad Sci.
936
2001
312
327
32
Procyk
R
Bishop
PD
Kudryk
B
Fibrin–recombinant human factor XIII A-subunit association.
Thromb Res.
71
1993
127
138
33
Credo
RB
Curtis
CG
Lorand
L
Alpha-chain domain of fibrinogen controls generation of fibrinoligase (coagulation factor XIIIa): calcium ion regulatory aspects.
Biochemistry.
20
1981
3770
3778
34
Siebenlist
KR
Meh
DA
Mosesson
MW
Plasma factor XIII binds specifically to fibrinogen molecules containing gamma chains.
Biochemistry.
35
1996
10448
10453
35
Fornace
AJ
Jr
Cummings
DE
Comeau
CM
Kant
JA
Crabtree
GR
Structure of the human gamma-fibrinogen gene: alternate mRNA splicing near the 3′ end of the gene produces gamma A and gamma B forms of gamma-fibrinogen.
J Biol Chem.
259
1984
12826
12830
36
Wolfenstein-Todel
C
Mosesson
MW
Carboxy-terminal amino acid sequence of a human fibrinogen gamma-chain variant (gamma′).
Biochemistry.
20
1981
6146
6149
37
Meh
DA
Siebenlist
KR
Mosesson
MW
Identification and characterization of the thrombin binding sites on fibrin.
J Biol Chem.
271
1996
23121
23125
38
Achyuthan
KE
Characterization of the reciprocal binding sites on human α-thrombin and factor XIII A-chain.
Mol Cell Biochem.
178
1998
289
297
39
Folk
JE
Mechanism and basis for specificity of transglutaminase-catalyzed epsilon-(gamma-glutamyl) lysine bond formation.
Adv Enzymol Relat Areas Mol Biol.
54
1983
1
56
40
Loewy
AG
Dunathan
K
Kriel
R
Wolfinger
JHL
Fibrinase I: purification of substrate and enzyme.
J Biol Chem.
236
1961
2625
2633
41
Lorand
L
Ong
HH
Lipinski
B
Rule
NG
Downey
J
Jacobsen
A
Lysine as amine donor in fibrin crosslinking.
Biochem Biophys Res Commun.
25
1966
629
637
42
Matacic
S
Loewy
AG
The identification of isopeptide crosslinks in insoluble fibrin.
Biochem Biophys Res Commun.
30
1968
356
362
43
Hettasch
JM
Greenberg
CS
Analysis of the catalytic activity of human factor XIIIa by site-directed mutagenesis.
J Biol Chem.
269
1994
28309
28313
44
Hornyak
TJ
Shafer
JA
Role of calcium ion in the generation of factor XIII activity.
Biochemistry.
30
1991
6175
6182
45
Curtis
CG
Brown
KL
Credo
RB
et al
Calcium-dependent unmasking of active center cysteine during activation of fibrin stabilizing factor.
Biochemistry.
13
1974
3774
3780
46
Yee
VC
Le Trong
I
Bishop
PD
Pedersen
LC
Stenkamp
RE
Teller
DC
Structure and function studies of factor XIIIa by x-ray crystallography.
Semin Thromb Hemost.
22
1996
377
384
47
Catani
MV
Bernassola
F
Rossi
A
Melino
G
Inhibition of clotting factor XIII activity by nitric oxide.
Biochem Biophys Res Commun.
249
1998
275
278
48
Hettasch
JM
Peoples
KA
Greenberg
CS
Analysis of factor XIII substrate specificity using recombinant human factor XIII and tissue transglutaminase chimeras.
J Biol Chem.
272
1997
25149
25156
49
Grootjans
JJ
Groenen
PJ
de Jong
WW
Substrate requirements for transglutaminases: influence of the amino acid residue preceding the amine donor lysine in a native protein.
J Biol Chem.
270
1995
22855
22858
50
Achyuthan
KE
Dobson
JV
Greenberg
CS
Gly-Pro-Arg-Pro modifies the glutamine residues in the alpha- and gamma-chains of fibrinogen:inhibition of transglutaminase cross-linking.
Biochim Biophys Acta.
872
1986
261
268
51
Lorand
L
Parameswaran
KN
Murthy
SN
A double-headed Gly-Pro-Arg-Pro ligand mimics the functions of the E domain of fibrin for promoting the end-to-end crosslinking of gamma chains by factor XIIIa.
Proc Natl Acad Sci U S A.
95
1998
537
541
52
Spraggon
G
Everse
SJ
Doolittle
RF
Crystal structures of fragment D from human fibrinogen and its crosslinked counterpart from fibrin.
Nature.
389
1997
455
462
53
Weisel
JW
Francis
CW
Nagaswami
C
Marder
VJ
Determination of the topology of factor XIIIa-induced fibrin gamma-chain cross-links by electron microscopy of ligated fragments.
J Biol Chem.
268
1993
26618
26624
54
Purves
L
Purves
M
Brandt
W
Cleavage of fibrin-derived D-dimer into monomers by endopeptidase from puff adder venom (Bitis arietans) acting at cross-linked sites of the gamma-chain: sequence of carboxy-terminal cyanogen bromide gamma-chain fragments.
Biochemistry.
26
1987
4640
4646
55
Fowler
WE
Erickson
HP
Hantgan
RR
McDonagh
J
Hermans
J
Cross-linked fibrinogen dimers demonstrate a feature of the molecular packing in fibrin fibers.
Science.
211
1981
287
289
56
Selmayr
E
Deffner
M
Bachmann
L
Muller-Berghaus
G
Chromatography and electron microscopy of cross-linked fibrin polymers: a new model describing the cross-linking at the DD-trans contact of the fibrin molecules.
Biopolymers.
27
1988
1733
1748
57
Siebenlist
KR
Meh
DA
Wall
JS
Hainfeld
JF
Mosesson
MW
Orientation of the carboxy-terminal regions of fibrin gamma chain dimers determined from the crosslinked products formed in mixtures of fibrin, fragment D, and factor XIIIa.
Thromb Haemost.
74
1995
1113
1119
58
Cottrell
BA
Strong
DD
Watt
KW
Doolittle
RF
Amino acid sequence studies on the α chain of human fibrinogen: exact location of cross-linking acceptor sites.
Biochemistry.
18
1979
5405
5410
59
Fretto
LJ
Ferguson
EW
Steinman
HM
McKee
PA
Localization of the alpha-chain cross-link acceptor sites of human fibrin.
J Biol Chem.
253
1978
2184
2195
60
Matsuka
YV
Medved
LV
Migliorini
MM
Ingham
KC
Factor XIIIa-catalyzed cross-linking of recombinant αC fragments of human fibrinogen.
Biochemistry.
35
1996
5810
5816
61
Lorand
L
Factor XIII: structure, activation, and interactions with fibrinogen and fibrin.
Ann N Y Acad Sci.
936
2001
291
311
62
Sobel
JH
Gawinowicz
MA
Identification of the α chain lysine donor sites involved in factor XIIIa fibrin cross-linking.
J Biol Chem.
271
1996
19288
19297
63
Gaffney
PJ
Whitaker
AN
Fibrin crosslinks and lysis rates.
Thromb Res.
14
1979
85
94
64
McDonagh
RP
Jr
McDonagh
J
Duckert
F
The influence of fibrin crosslinking on the kinetics of urokinase-induced clot lysis.
Br J Haematol.
21
1971
323
332
65
Muller
MF
Ris
H
Ferry
JD
Electron microscopy of fine fibrin clots and fine and coarse fibrin films: observations of fibers in cross-section and in deformed states.
J Mol Biol.
174
1984
369
384
66
Francis
CW
Marder
VJ
Barlow
GH
Plasmic degradation of crosslinked fibrin: characterization of new macromolecular soluble complexes and a model of their structure.
J Clin Invest.
66
1980
1033
1043
67
Sakata
Y
Aoki
N
Cross-linking of alpha 2-plasmin inhibitor to fibrin by fibrin-stabilizing factor.
J Clin Invest.
65
1980
290
297
68
Kimura
S
Aoki
N
Cross-linking site in fibrinogen for alpha 2-plasmin inhibitor.
J Biol Chem.
261
1986
15591
15595
69
Kimura
S
Tamaki
T
Aoki
N
Acceleration of fibrinolysis by the N-terminal peptide of alpha 2-plasmin inhibitor.
Blood.
66
1985
157
160
70
Mimuro
J
Kimura
S
Aoki
N
Release of alpha 2-plasmin inhibitor from plasma fibrin clots by activated coagulation factor XIII: its effect on fibrinolysis.
J Clin Invest.
77
1986
1006
1013
71
Sakata
Y
Aoki
N
Significance of cross-linking of alpha 2-plasmin inhibitor to fibrin in inhibition of fibrinolysis and in hemostasis.
J Clin Invest.
69
1982
536
542
72
Mosher
DF
Schad
PE
Vann
JM
Cross-linking of collagen and fibronectin by factor XIIIa: localization of participating glutaminyl residues to a tryptic fragment of fibronectin.
J Biol Chem.
255
1980
1181
1188
73
Procyk
R
Adamson
L
Block
M
Blomback
B
Factor XIII catalyzed formation of fibrinogen-fibronectin oligomers: a thiol enhanced process.
Thromb Res.
40
1985
833
852
74
Procyk
R
Blomback
B
Factor XIII-induced crosslinking in solutions of fibrinogen and fibronectin.
Biochim Biophys Acta.
967
1988
304
313
75
Niewiarowska
J
Cierniewski
CS
Inhibitory effect of fibronectin on the fibrin formation.
Thromb Res.
27
1982
611
618
76
Okada
M
Blomback
B
Chang
MD
Horowitz
B
Fibronectin and fibrin gel structure.
J Biol Chem.
260
1985
1811
1820
77
Chow
TW
McIntire
LV
Peterson
DM
Importance of plasma fibronectin in determining PFP and PRP clot mechanical properties.
Thromb Res.
29
1983
243
248
78
Kamykowski
GW
Mosher
DF
Lorand
L
Ferry
JD
Modification of shear modulus and creep compliance of fibrin clots by fibronectin.
Biophys Chem.
13
1981
25
28
79
Barry
EL
Mosher
DF
Factor XIIIa-mediated cross-linking of fibronectin in fibroblast cell layers: cross-linking of cellular and plasma fibronectin and of amino-terminal fibronectin fragments.
J Biol Chem.
264
1989
4179
4185
80
Mosher
DF
Schad
PE
Cross-linking of fibronectin to collagen by blood coagulation factor XIIIa.
J Clin Invest.
64
1979
781
787
81
Cox
AD
Devine
DV
Factor XIIIa binding to activated platelets is mediated through activation of glycoprotein IIb-IIIa.
Blood.
83
1994
1006
1016
82
Hevessy
Z
Haramura
G
Boda
Z
Udvardy
M
Muszbek
L
Promotion of the crosslinking of fibrin and alpha 2-antiplasmin by platelets.
Thromb Haemost.
75
1996
161
167
83
Devine
DV
Bishop
PD
Platelet-associated factor XIII in platelet activation, adhesion, and clot stabilization.
Semin Thromb Hemost.
22
1996
409
413
84
Devine
DV
Andestad
G
Nugent
D
Carter
CJ
Platelet-associated factor XIII as a marker of platelet activation in patients with peripheral vascular disease.
Arterioscler Thromb.
13
1993
857
862
85
Dale
GL
Friese
P
Batar
P
et al
Stimulated platelets use serotonin to enhance their retention of procoagulant proteins on the cell surface.
Nature.
415
2002
175
179
86
Greenberg
CS
Birckbichler
PJ
Rice
RH
Transglutaminases: multifunctional cross-linking enzymes that stabilize tissues.
FASEB J.
5
1991
3071
3077
87
Korsgren
C
Cohen
CM
Organization of the gene for human erythrocyte membrane protein 4.2: structural similarities with the gene for the a subunit of factor XIII.
Proc Natl Acad Sci U S A.
88
1991
4840
4844
88
Board
PG
Webb
GC
McKee
J
Ichinose
A
Localization of the coagulation factor XIII A subunit gene (F13A) to chromosome bands 6p24–p25.
Cytogenet Cell Genet.
48
1988
25
27
89
Weisberg
LJ
Shiu
DT
Greenberg
CS
Kan
YW
Shuman
MA
Localization of the gene for coagulation factor XIII a-chain to chromosome 6 and identification of sites of synthesis.
J Clin Invest.
79
1987
649
652
90
Ichinose
A
Davie
EW
Characterization of the gene for the a subunit of human factor XIII (plasma transglutaminase), a blood coagulation factor.
Proc Natl Acad Sci U S A.
85
1988
5829
5833
91
Webb
GC
Coggan
M
Ichinose
A
Board
PG
Localization of the coagulation factor XIII B subunit gene (F13B) to chromosome bands 1q31–32.1 and restriction fragment length polymorphism at the locus.
Hum Genet.
81
1989
157
160
92
Morley
BJ
Campbell
RD
Internal homologies of the Ba fragment from human complement component Factor B, a class III MHC antigen.
EMBO J.
3
1984
153
157
93
Chung
LP
Gagnon
J
Reid
KB
Amino acid sequence studies of human C4b-binding protein: N-terminal sequence analysis and alignment of the fragments produced by limited proteolysis with chymotrypsin and the peptides produced by cyanogen bromide treatment.
Mol Immunol.
22
1985
427
435
94
Weis
JH
Morton
CC
Bruns
GA
et al
A complement receptor locus: genes encoding C3b/C4b receptor and C3d/Epstein-Barr virus receptor map to 1q32.
J Immunol.
138
1987
312
315
95
Lublin
DM
Lemons
RS
Le Beau
MM
et al
The gene encoding decay-accelerating factor (DAF) is located in the complement-regulatory locus on the long arm of chromosome 1.
J Exp Med.
165
1987
1731
1736
96
Lublin
DM
Liszewski
MK
Post
TW
et al
Molecular cloning and chromosomal localization of human membrane cofactor protein (MCP): evidence for inclusion in the multigene family of complement-regulatory proteins.
J Exp Med.
168
1988
181
194
97
Rodriguez de Cordoba
S
Rey-Campos
J
Dykes
DD
McAlpine
PJ
Wong
P
Rubinstein
P
Coagulation factor XIII B subunit is encoded by a gene linked to the regulator of complement activation (RCA) gene cluster in man.
Immunogenetics.
28
1988
452
454
98
Kompf
J
Luckenbach
C
Kloor
D
Krczal
D
Amorim
A
Ritter
H
Linkage analyses of human peptidase C (PEPC), human factor H (HF), and coagulation factor XIIIB (F13B).
Hum Genet.
83
1989
97
98
99
Mikkola
H
Syrjälä
M
Rasi
V
et al
Deficiency in the A-subunit of coagulation factor XIII: two novel point mutations demonstrate different effects on transcript levels.
Blood.
84
1994
517
525
100
Anwar
R
Stewart
AD
Miloszewski
KJ
Losowsky
MS
Markham
AF
Molecular basis of inherited factor XIII deficiency: identification of multiple mutations provides insights into protein function.
Br J Haematol.
91
1995
728
735
101
Suzuki
K
Henke
J
Iwata
M
et al
Novel polymorphisms and haplotypes in the human coagulation factor XIII A-subunit gene.
Hum Genet.
98
1996
393
395
102
Anwar
R
Gallivan
L
Edmonds
SD
Markham
AF
Genotype/phenotype correlations for coagulation factor XIII: specific normal polymorphisms are associated with high or low factor XIII specific activity.
Blood.
93
1999
897
905
103
Suzuki
K
Itawa
M
Ito
S
Matsui
K
Uchida
A
Mizoi
Y
Molecular basis for the subtypic differences of the “a” subunit of coagulation factor XIII with description of the genesis of the subtypes.
Hum Genet.
94
1994
129
135
104
Izumi
T
Hashiguchi
T
Castaman
G
et al
Type I factor XIII deficiency is caused by a genetic defect of its B subunit: insertion of triplet AAC in exon III leads to premature termination in the second Sushi domain.
Blood.
87
1996
2769
2774
105
Ichinose
A
Tsukamoto
H
Izumi
T
et al
Arg260-Cys mutation in severe factor XIII deficiency: conformational change of the A subunit is predicted by molecular modelling and mechanics.
Br J Haematol.
101
1998
264
272
106
Kida
M
Suori
M
Yamamoto
M
Saito
H
Ichinose
A
Transcriptional regulation of cell type-specific expression of the TATA-less A subunit gene for human coagulation factor XIII.
J Biol Chem.
274
1999
6138
6147
107
Polymeropoulos
MH
Rath
DS
Xiao
H
Merril
CR
Tetranucleotide repeat polymorphism at the human coagulation factor XIII A subunit gene (F13A1).
Nucleic Acids Res.
19
1991
4306
108
Kohler
HP
Stickland
MH
Ossei-Gerning
N
Carter
A
Mikkola
H
Grant
PJ
Association of a common polymorphism in the factor XIII gene with myocardial infarction.
Thromb Haemost.
79
1998
8
13
109
McCormack
LJ
Kain
K
Catto
AJ
Kohler
HP
Stickland
MH
Grant
PJ
Prevalence of FXIII V34L in populations with different cardiovascular risk [letter].
Thromb Haemost.
80
1998
523
524
110
Attié-Castro
FA
Zago
MA
Lavinha
J
et al
Ethnic heterogeneity of the factor XIII Val34Leu polymorphism.
Thromb Haemost.
84
2000
601
603
111
Kohler
HP
Ariëns
RAS
Whitaker
P
Grant
PJ
A common coding polymorphism in the FXIII A-subunit gene (FXIII Val34Leu) affects cross-linking activity [letter].
Thromb Haemost.
80
1998
704
112
Ariëns
RAS
Philippou
H
Nagaswami
C
Weisel
JW
Lane
DA
Grant
PJ
The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure.
Blood.
96
2000
988
995
113
Wartiovaara
U
Mikkola
H
Szôke
G
et al
Effect of Val34Leu polymorphism on the activation of the coagulation factor XIII-A.
Thromb Haemost.
84
2000
595
600
114
Balogh
I
Szôke
G
Kárpáti
L
et al
Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia.
Blood.
96
2000
2479
2486
115
Trumbo
TA
Maurer
MC
Examining thrombin hydrolysis of the factor XIII activation peptide segment leads to a proposal for explaining the cardioprotective effects observed with the factor XIII V34L mutation.
J Biol Chem.
275
2000
20627
20631
116
Sadasivan
C
Yee
VC
Interaction of the factor XIII activation peptide with α-thrombin: crystal structure of its enzyme-substrate analog complex.
J Biol Chem.
275
2000
36942
36948
117
Trumbo
TA
Maurer
MC
Thrombin hydrolysis of V29F and V34L mutants of factor XIII (28-41) reveals roles of the P9 and P4 positions in factor XIII activation.
Biochemistry.
41
2002
2859
2868
118
Weisel
JW
Fibrin assembly: lateral aggregation and the role of the two pairs of fibrinopeptides.
Biophys J.
50
1986
1079
1093
119
Weisel
JW
Veklich
Y
Gorkun
O
The sequence of cleavage of fibrinopeptides from fibrinogen is important for protofibril formation and enhancement of lateral aggregation in fibrin clots.
J Mol Biol.
232
1993
285
297
120
Mullin
JL
Gorkun
OV
Lord
ST
Decreased lateral aggregation of a variant recombinant fibrinogen provides insight into the polymerisation mechanism.
Biochemistry.
39
2000
9843
9849
121
Schroeder
V
Chatterjee
T
Kohler
HP
Influence of blood coagulation factor XIII and FXIII Val34Leu on plasma clot formation measured by thromboelastography.
Thromb Res.
104
2001
467
474
122
Board
PG
Genetic polymorphism of the B subunit of human coagulation factor XIII.
Am J Hum Genet.
32
1980
348
353
123
Kass
DH
Aleman
C
Batzer
MA
Deininger
PL
Identification of a human specific Alu insertion in the factor XIIIB gene.
Genetica.
94
1994
1
8
124
Komanasin
N
Futers
TS
Ariëns
RAS
Grant
PJ
A novel polymorphism in the factor XIII B subunit (His95Arg) relates to the dissociation of the A2B2 tetramer [abstract].
Thromb Haemost.
82 (suppl)
1999
38
125
Kohler
HP
Mansfield
MW
Clark
PS
Grant
PJ
Interaction between insulin resistance and factor XIII Val34Leu in patients with coronary artery disease [letter].
Thromb Haemost.
82
1999
1202
1203
126
Kohler
HP
Grant
PJ
Clustering of haemostatic risk factor with FXIIIVal34Leu in patients with myocardial infarction [letter].
Thromb Haemost.
80
1998
862
127
Wartiovaara
U
Perola
M
Mikkola
H
et al
Association of FXIII Val34Leu with decreased risk of myocardial infarction in Finnish males.
Atherosclerosis.
142
1999
295
300
128
Franco
RF
Pazin-Filho
A
Tavella
AH
Simões
MV
Marin-Neto
JA
Zago
MA
Factor XIII Val34Leu and the risk of myocardial infarction.
Haematologica.
85
2000
67
71
129
Gemmati
D
Serino
ML
Ongaro
A
et al
A common mutation in the gene for coagulation factor XIII-A (Val34Leu): a risk factor for primary intracerebral hemorrhage is protective against atherothrombotic diseases.
Am J Hematol.
67
2001
183
188
130
Reiner
AP
Frank
MB
Schwartz
SM
et al
Coagulation factor XIII polymorphisms and the risk of myocardial infarction and ischaemic stroke in young women.
Br J Haematol.
116
2002
376
382
131
Canavy
I
Henry
M
Morange
PE
et al
Genetic polymorphisms and coronary artery disease in the South of France.
Thromb Haemost.
83
2000
212
216
132
Aleksic
N
Ahn
C
Wang
YW
et al
Factor XIIIA Val34Leu polymorphism does not predict risk of coronary artery disease: the atherosclerosis risk in communities (ARIC) study.
Arterioscler Thromb Vasc Biol.
22
2002
348
352
133
Corral
J
González-Conejero
R
Iniesta
JA
Riviera
J
Martı́nez
C
Vicente
V
The FXIII Val34Leu polymorphism in venous and arterial thromboembolism.
Haematologica.
85
2000
293
297
134
Warner
D
Mansfield
M
Grant
PJ
Coagulation factor XIII and cardiovascular disease in UK Asian patients undergoing coronary angioplasty.
Thromb Haemost.
85
2001
408
411
135
Kohler
HP
Futers
TS
Grant
PJ
Prevalence of three common polymorphisms in the A-subunit gene of factor XIII in patients with coronary artery disease.
Thromb Haemost.
81
1999
511
515
136
Catto
AJ
Kohler
HP
Coore
J
Mansfield
MW
Stickland
MH
Grant
PJ
Association of a common polymorphism in the factor XIII gene with venous thrombosis.
Blood.
93
1999
906
908
137
Franco
RF
Reitsma
PH
Lourenço
D
et al
Factor XIII Val34Leu is a genetic factor involved in the aetiology of venous thrombosis.
Thromb Haemost.
81
1999
676
679
138
Renner
W
Köppel
H
Hoffmann
C
et al
Prothrombin G20210A, factor V Leiden, and factor XIII Val34Leu: common mutations of blood coagulation factors and deep vein thrombosis in Austria.
Thromb Res.
99
2000
35
39
139
Margaglione
M
Bossone
A
Brancaccio
V
Ciampa
A
Di Minno
G
Factor XIII Val34Leu polymorphism and risk of deep vein thrombosis.
Thromb Haemost.
84
2000
1118
1119
140
Morange
PE
Henry
M
Brunet
D
Aillaud
MF
Juhan-Vague
I
Factor XIIIV34L is not an additional genetic risk factor for venous thrombosis in Factor V Leiden carriers [letter].
Blood.
97
2001
1894
1895
141
Carter
AM
Catto
AJ
Kohler
HP
Ariëns
RAS
Stickland
MH
Grant
PJ
α-Fibrinogen Thr312Ala polymorphism and venous thromboembolism.
Blood.
96
2000
1177
1179
142
Carter
AM
Catto
AJ
Grant
PJ
The association of the α-fibrinogen Thr312Ala polymorphism with post-stroke mortality in subjects with atrial fibrillation.
Circulation.
99
1999
2423
2426
143
Catto
AJ
Kohler
HP
Bannan
S
Stickland
M
Carter
A
Grant
PJ
Factor XIII Val 34 Leu: a novel association with primary intracerebral hemorrhage.
Stroke.
29
1998
813
816
144
Corral
J
Iniesta
JA
González-Conejero
R
Villalón
Vicente
V
Polymorphisms of clotting factor modify the risk for primary intracranial hemorrhage.
Blood.
97
2001
2979
2982
145
Elbaz
A
Poirier
O
Canaple
S
Chédru
F
Cambien
F
Amarenco
P
The association between the Val34Leu polymorphism in the factor XIII gene and brain infarction.
Blood.
95
2000
586
591
146
Reiner
AP
Schwartz
SM
Frank
MB
et al
Polymorphisms of coagulation factor XIII subunit A and risk of nonfatal hemorrhagic stroke in young white women.
Stroke.
32
2001
2580
2587
147
Weger
M
Renner
W
Stanger
O
et al
Role of factor XIII Val34Leu polymorphism in retinal artery occlusion.
Stroke.
32
2001
2759
2761
148
Reed
GL
Houng
AK
The contribution of activated factor XIII to fibrinolytic resistance in experimental pulmonary embolism.
Circulation.
99
1999
299
304
149
Shebuski
RJ
Sitko
GR
Claremon
DA
Baldwin
JJ
Remy
DC
Stern
AM
Inhibition of factor XIIIa in a canine model of coronary thrombosis: effect on reperfusion and acute reocclusion after recombinant tissue-type plasminogen activator.
Blood.
75
1990
1455
1459
150
Valnickova
Z
Enghild
JJ
Human procarboxypeptidase U, or thrombin-activable fibrinolysis inhibitor, is a substrate for transglutaminases: evidence for transglutaminase-catalyzed cross-linking to fibrin.
J Biol Chem.
273
1998
27220
27224
151
Ritchie
H
Lawrie
LC
Crombie
PW
Mosesson
MW
Booth
NA
Cross-linking of plasminogen activator inhibitor 2 and alpha 2-antiplasmin to fibrin(ogen).
J Biol Chem.
275
2000
24915
24920
152
Ritchie
H
Lawrie
LC
Mosesson
MW
Booth
NA
Characterization of crosslinking sites in fibrinogen for plasminogen activator inhibitor 2 (PAI-2).
Ann N Y Acad Sci.
936
2001
215
218
153
Hada
M
Kaminski
M
Bockenstedt
P
McDonagh
J
Covalent crosslinking of von Willebrand factor to fibrin.
Blood.
68
1986
95
101
154
Bockenstedt
P
McDonagh
J
Handin
RI
Binding and covalent cross-linking of purified von Willebrand factor to native monomeric collagen.
J Clin Invest.
78
1986
551
556
155
Sane
DC
Moser
TL
Pippen
AM
Parker
CJ
Achyuthan
KE
Greenberg
CS
Vitronectin is a substrate for transglutaminases.
Biochem Biophys Res Commun.
157
1988
115
120
156
Skorstengaard
K
Halkier
T
Hojrup
P
Mosher
D
Sequence location of a putative transglutaminase cross-linking site in human vitronectin.
FEBS Lett.
262
1990
269
274
157
Bale
MD
Westrick
LG
Mosher
DF
Incorporation of thrombospondin into fibrin clots.
J Biol Chem.
260
1985
7502
7508
158
Francis
RT
McDonagh
J
Mann
KG
Factor V is a substrate for the transamidase factor XIIIa.
J Biol Chem.
261
1986
9787
9792
159
Huh
MM
Schick
BP
Schick
PK
Colman
RW
Covalent crosslinking of human coagulation factor V by activated factor XIII from guinea pig megakaryocytes and human plasma.
Blood.
71
1988
1693
1702
160
Mui
PT
Ganguly
P
Cross-linking of actin and fibrin by fibrin-stabilizing factor.
Am J Physiol.
233
1977
H346
H349
161
Cohen
I
Blankenberg
TA
Borden
D
Kahn
DR
Veis
A
Factor XIIIa-catalyzed cross-linking of platelet and muscle actin: regulation by nucleotides.
Biochim Biophys Acta.
628
1980
365
375
162
Cohen
I
Young-Bandala
L
Blankenberg
TA
Siefring
GE
Jr
Bruner-Lorand
J
Fibrinoligase-catalyzed cross-linking of myosin from platelet and skeletal muscle.
Arch Biochem Biophys.
192
1979
100
111
163
Asijee
GM
Muszbek
L
Kappelmayer
J
Polgar
J
Horvath
A
Sturk
A
Platelet vinculin: a substrate of activated factor XIII.
Biochim Biophys Acta.
954
1988
303
308
164
Cohen
I
Lim
CT
Kahn
DR
Glaser
T
Gerrard
JM
White
JG
Disulfide-linked and transglutaminase-catalyzed protein assemblies in platelets.
Blood.
66
1985
143
151

Author notes

Robert A. S. Ariëns, Academic Unit of Molecular Vascular Medicine, G-Floor, Martin Wing, The General Infirmary, Leeds LS1 3EX, United Kingdom; e-mail:r.a.s.ariens@leeds.ac.uk.

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