|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
REVIEW ARTICLE
From the Academic Unit of Molecular Vascular Medicine,
University of Leeds School of Medicine, United Kingdom; the Department
of Medicine and the Department of Pathology, Duke University Medical
Center, Durham, NC; and the Department of Cell and Developmental
Biology, University of Pennsylvania School of Medicine, Philadelphia.
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.
(Blood. 2002;100:743-754) Overall structure of factor XIII
The A-subunit is divided into 4 domains, designated the
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
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
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 Thrombin binding site
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 -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.10 The 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.
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 nonproline cis-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.49
Even 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 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
Fibrin -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 -chain of one fibrin molecule and Lys406 on the -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
Fibrin  -chains occurs more slowly than
cross-linking of the -chains. A number of residues have been reported to be involved in fibrin -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 -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- -aminocaproyl-Ala-Gln-Gln-Ile-Val, and the sites that
are involved in -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 C-domains in the fibrin clot.
The extent of
2-antiplasmin. Factor XIIIa rapidly cross-links 2-antiplasmin to the -chain of
fibrin.67,68 This cross-linking reaction occurs between
Gln2 in the amino terminus of 2-antiplasmin69 and
Lys303 in the fibrin -chain.68 The 2-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.72 However, when fibrin is present, fibronectin-fibrin complexes are the preferred cross-linking products.73 Fibronectin is cross-linked to the-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 Table 1, together with the potential physiological significance of their cross-linking.
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 of2-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.86 Erythrocyte protein band 4.2 has significant sequence homology to the transglutaminases and is also a member of the family.87 The 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.90The 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.101 Tyr204Phe 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.
Factor XIII Val34Leu Factor XIII Val34Leu occurs in the activation peptide, 3 amino acids from the thrombin-cleavage site between Arg37 and Gly38 (Figure 1). 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 0.01.110Despite the fact that the transition of valine to leucine is a
relatively conservative change 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 and Km 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 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 (Figure
5).112 In addition,
Schroeder et al121 recently reported that clot formation
time as measured by thromboelastography was significantly shortened in
factor XIII Leu34 samples.
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.123 In 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 (Table 3). 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
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 al135 failed 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 A 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 A fibrinogen chain is very
close to the factor XIII cross-linking and 2-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,144 and 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,102 was 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 A 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 pro |
Top
Abstract
Factor XIII structure and...
-sandwich,
the catalytic core, barrel 1, and barrel 2 (Figure
the only difference between the 2 amino
acids being an additional CH2 group present in the leucine
side-chain
1sec