Published online before print June 24, 2004, doi: 10.1161/01.ATV.0000136649.83297.bf
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2004 American Heart Association, Inc.
Brief Reviews |
Genetic and Environmental Determinants of Fibrin Structure and Function
Relevance to Clinical Disease
From the Academic Unit of Molecular Vascular Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UK.
Correspondence to Prof P.J. Grant, Academic Unit of Molecular Vascular Medicine, Martin Wing, The General Infirmary at Leeds, Leeds, LS1 3EX, UK. E-mail P.J.Grant{at}Leeds.ac.uk
 |
Abstract |
|---|
 Top Abstract IntroductionThe Formation of a...Abnormal Clot Architecture and...Genetic and Environmental...FibrinogenFactor XIIIOther Factors Influencing Clot...ConclusionReferences |
|---|
The formation of a fibrin clot is one of the key events in atherothrombotic vascular disease. The structure of the fibrin clot and the genetic and environmental factors that modify it have effects on its biological function. Alterations in fibrin structure and function have implications for the clinical presentation of vascular disease. This review briefly describes the key features involved in the formation of a fibrin clot, its typical structure, and function. This is followed by a review of the current literature on genetic and environmental influences on fibrin structure/function and the relationship to clinical disease.
The formation of a fibrin clot is one of the key events in atherothrombotic vascular disease. This review discusses how genetic and environmental factors alter fibrin structure and function and the implications this has for the clinical presentation of vascular disease.
Key Words: fibrin • hemostatis • genetic • environment • atherothrombosis
|
Introduction |
|---|
|
TopAbstractIntroductionThe Formation of a...Abnormal Clot Architecture and...Genetic and Environmental...FibrinogenFactor XIIIOther Factors Influencing Clot...ConclusionReferences |
|---|
Diseases associated with the development of thrombosis are a major cause of morbidity and mortality in the developed world. Atherothrombotic vascular disorders develop over many decades and involve the interaction of classic atherogenic risk factors such as diabetes, hyperlipidemia, and hypertension with abnormalities of the inflammatory and hemostatic systems. Arterial disease develops in a high-pressure, high-flow system, with lipid deposition and smooth muscle hyperplasia occurring to form an atherosclerotic plaque.1 Subsequently, the plaque becomes unstable and ruptures exposing a prothrombotic lipid core activating the clotting cascade and leading to the development of a platelet-rich fibrin blood clot and arterial thrombotic occlusion. The extent of this process determines clinical outcome, ranging from no clinically noticeable event to acute coronary artery syndromes including myocardial infarction (MI), cerebrovascular and peripheral vascular disease, or sudden death.
|
The Formation of a Fibrin Clot |
|---|
|
TopAbstractIntroductionThe Formation of a...Abnormal Clot Architecture and...Genetic and Environmental...FibrinogenFactor XIIIOther Factors Influencing Clot...ConclusionReferences |
|---|
Fibrin is the major protein constituent of the blood clot and is formed from fibrinogen, a glycoprotein that circulates largely inactively, in the blood stream. Fibrinogen consists of 6 polypeptide chains (A
, Bß, 
)2 held together by disulphide bonds in a molecule with bilateral symmetry (Figure 1). The molecule consists of 3 main structural regions,2,3 including a central region (E), which contains fibrinopeptides A and B and the amino acid termini of all 6 polypeptide chains, 2 distal regions (D) connected to the E region by 2 -helical coiled segments and the D regions containing the carboxyl termini of the Bß and chains, and those of the A chain, which extend to form relatively flexible C-domains, each ending in a globular domain.2,3
|
In situations of tissue injury and inflammation, thrombin is generated after cleavage of prothrombin by the Xase complex. Thrombin subsequently binds to fibrinogen and cleaves the amino termini of the fibrinogen A and Bß chains at region E. This results in the release of fibrinopeptides A and B from fibrinogen, producing fibrin and initiating fibrin clot formation. Release of fibrinopeptide A by thrombin is fast and exposes a polymerization site on the E region of fibrin.4,5 This combines with a complementary binding site on the chain in the D region of an adjacent fibrin molecule to form a double-stranded twisted protofibril of fibrin. Cleavage of fibrinopeptide B by thrombin is slower but also exposes a binding site in the E region. This has been proposed to bind to a complementary binding site on the ß chain in the D region. The cleavage rate of fibrinopeptide B has been associated with the rate of lateral aggregation of the protofibrils and the thickness of the fibrin fibers.5
While a critical mass of fibrin is polymerizing, thrombin simultaneously activates factor XIII by a calcium-dependent mechanism. Factor XIII is composed of 2 A and 2 B subunits; 90% of the A subunit is bound to the fibrin clot. Once activated, factor XIIIa is involved in cross-linking of the fibrin clot by transglutaminase reactions between glutamine and lysine residues on fibrin. The first cross links are formed between chains of 2 neighboring fibrin molecules in the longitudinal orientation of the fibrils.6,7 This results in the formation of 2 isopeptide bonds between glutamine 398 or 399 and lysine 406 that connect the D regions of 2 fibrin molecules longitudinally. Cross-linking of the fibrin -chains occurs more slowly than that of the chains. There are 4 glutamine residues potentially involved, and at least 15 lysine residues have been identified.8 This number of potential cross-linking sites allows for a highly complex and intricate network to be formed between neighboring C domains in the fibrin clot. These cross-links provide stability to the fibrin clot,9,10 and they seem to form a protective barrier preventing plasmin-degrading fibrin.11,12 The result of fibrin polymerization and FXIII-induced cross-linking is the formation of thick fibrin bundles and a complex branched network conferring strength, rigidity, and resistance to lysis to the fibrin clot.
The typical structure of a fibrin clot as visualized by electron microscopy is shown in Figure 2.
|
A relationship exists between fibrin clot structure and fibrinolysis such that clots composed of thick fibers, with a less tightly cross-linked, reduced number of branch points, and more permeable networks are lysed faster than clots containing thin fibers, with increased density and a more tightly knit cross-linked structure.13–17 Although individually, thin fibers are lysed quicker than thick fibers, it is the fibrin network configuration and the number of fibers per volume of clot that has a bigger impact on the fibrinolysis rate than fiber thickness alone.18 It is evident that there is considerable variation in the fibrin clot structure of different individuals, suggesting that both genetic and environmental factors have a role in determining the balance between stability and susceptibility of the clot to fibrinolysis.
|
Abnormal Clot Architecture and Atherothrombotic Vascular Disease |
|---|
|
TopAbstractIntroductionThe Formation of a...Abnormal Clot Architecture and...Genetic and Environmental...FibrinogenFactor XIIIOther Factors Influencing Clot...ConclusionReferences |
|---|
The fibrin clot network architecture is altered in several diseases associated with atherothrombosis, including MI and diabetes.19,20 After MI, fibrin clots have reduced permeability and a lower fiber mass-to-length ratio.13,21 There are independent associations between permeability and the extent and severity of coronary artery stenosis and also of fibrinolytic activity. Patients with severe coronary artery disease have more rigid clot structures and an elevated fiber mass-to-length ratio.22 It is of note that this is the case despite subjects being treated with aspirin, which has been shown to increase fibrin clot permeability23,24 and potentially enhance the response to fibrinolysis. The plasma from healthy male first-degree relatives of patients with premature coronary artery disease also form ex vivo fibrin clots with abnormal structure. These clots are less porous, have thicker fibers, and begin polymerization more quickly than matched controls.25 The differences are not attributable to classic risk factors or common polymorphisms. In subjects with type 1 diabetes mellitus, the fibrin clot is less porous but with no difference in fiber mass-to-length ratio.20 This is independent of fibrinogen concentration.
|
Genetic and Environmental Factors Altering Fibrin Structure |
|---|
|
TopAbstractIntroductionThe Formation of a...Abnormal Clot Architecture and...Genetic and Environmental...FibrinogenFactor XIIIOther Factors Influencing Clot...ConclusionReferences |
|---|
Because fibrin structure/function is one of the major final phenotypes arising from activation of the fluid phase of coagulation, it would be expected to be a synthesis of all the genetic and environmental interactions described in the coagulation cascade. However, despite the observation that individual coagulation factors have a relatively high degree of heritability,26 this does not appear to be the case for fibrin structure/function, in which the major influence appears to be environmental.27 Several factors influencing clot architecture have been identified (Figure 2) within the coagulation system, including altered fibrinogen concentrations,28 genetic variations in fibrinogen15 and factor XIII,29 and altered concentrations of thrombin and prothrombin.30 One of the challenges in this field is to increase our understanding of the mechanisms by which lifestyle changes (exercise, obesity, smoking) translate into increased cardiovascular risk through these pathways.
|
Fibrinogen |
|---|
|
TopAbstractIntroductionThe Formation of a...Abnormal Clot Architecture and...Genetic and Environmental...FibrinogenFactor XIIIOther Factors Influencing Clot...ConclusionReferences |
|---|
Fibrinogen Concentration
Elevated fibrinogen has consistently been demonstrated to be a major risk factor for thrombosis and cardiovascular disease.31,32 Fibrinogen is an acute phase protein and is increased in many conditions, including advancing age, female gender, smoking, diabetes mellitus, elevated low-density lipoprotein cholesterol and triglycerides, hypertension, inflammation, and infection.31 It is reduced by exercise/physical fitness, weight loss, and smoking cessation. Whether fibrinogen is just a marker of the inflammation related to vascular disease, or whether it is involved in actively mediating the vascular disease process is not entirely known, although recent studies using transgenic mice with hyperfibrinogenemia have suggested that it is a true modifier of vascular disease, augmenting fibrin deposition in certain organs and regulating fibrin turnover.33 Despite this uncertainty, it is clear that fibrinogen concentration per se has a profound effect on fibrin clot structure. For example, the rate of fibrinopeptide A cleavage increases with increasing fibrinogen concentration,34 and this is associated with a shorter lag phase and a more dense and tight fibrin network.35 Elevated fibrinogen levels also lead to the formation of thicker fibers28,36 and larger thrombi with tight and rigid network structures21 which reduces the ability of the clot to be deformed and fibrinolysed.37 It also interferes with the binding of plasminogen to its receptor, which in turn reduces fibrinolysis.31 It is of interest that fibrates, ß blockers, and angiotensin-converting enzyme inhibitors all lower fibrinogen.31 Their effect on fibrin clot structure and function is not known, although it would be expected that any intervention that lowers fibrinogen would tend to produce a less compact clot structure with thicker fibers.
Fibrinogen Genes
The genes for the 3 polypeptide chains making up fibrinogen are located together in a cluster on the distal arm of chromosome 4, bands q23-q32.38 The A gene, which consists of 5 exons, is located at the center of the fibrinogen cluster.38 It produces a polypeptide chain that is 625 residues long. The gene for the ß chain is located 13 kb downstream of that of A, contains 8 exons, which are transcribed in the opposite direction to those of the A and genes, and codes for a 461-residue polypeptide.39 The third and last gene of the fibrinogen cluster is located 10 kb upstream of the A gene and codes for a 411-residue chain.38
Variations in the Splicing of Fibrinogen Gene Transcripts
A/' Fibrinogen
A major functional splice variant of fibrinogen is known as A/' fibrinogen. It accounts for between 7% and 15% of the fibrinogen found in plasma.40 For the production of this variant, the transcript is alternatively spliced, leading to a negatively charged 16-residue extension at the -chain carboxyl terminus.41 Fibrinogen ' contains binding sites for thrombin42 and FXIII B subunit.43 Binding of FXIII B subunit to fibrinogen ' suggests that it acts as a carrier of FXIII, and by doing so it increases the local concentration of FXIII at the level of the fibrin clot, allowing for more cross-linking.44 Clots made with A/' fibrinogen certainly have a more highly cross-linked and stable fibrin structure and are more resistant to lysis than those made from A/A fibrinogen.44 They also demonstrate reduced fiber diameter, increased branching, and reduced pore size (Table).45 This seems clinically relevant because similar fibrin structures have previously been related to an increased risk of thrombosis,13,21,46 and patients with coronary artery disease have higher A/' fibrinogen levels, which is an effect that is independent of total fibrinogen levels.47
|
AEC Fibrinogen
The second major variation that occurs in splicing of the fibrinogen gene transcripts occurs in the A gene transcript, where alternative splicing introduces an additional sixth exon, leading to a massive 236-residue extension at the carboxyl terminus of the A chain. This extended A chain or AEC occurs in 
1% of total fibrinogen, and its molecular mass is increased by >50% compared with the normal A chain.48 Little is known about the physiological regulation of splicing for either the AEC or the ' variants.
Noncoding Polymorphisms of Fibrinogen Gene
There are several polymorphisms that occur in the fibrinogen genes. Most of them are located in the nontranslated regions of the genes. These include a TaqI polymorphism in the 3' region of the A gene, a BclI variation in the 3' region of the Bß gene, and –148C/T and –455G/A polymorphisms in the 5' promoter region of the Bß gene.49 The BclI polymorphism has been shown to associate with increased fibrinogen levels and is more common in subjects with severe coronary artery disease.50,51 The –455G/A substitution in the Bß gene occurs in an IL-6–responsive HNF1 element and has been associated with increased fibrinogen levels52 in a manner that is environment-dependent.53,54 In vitro studies of the Bß–455 A/G polymorphism have indicated that the substitution alters nuclear protein binding profiles, reporter luciferase gene expression, and that it may explain up to 11% of the variation in fibrinogen levels.55 On a clinical basis, it has been shown that the Bß–455 A/G polymorphism is associated with the development of coronary artery disease in type 2 diabetic subjects, independently of fibrinogen levels.56 The same polymorphism has been related to the progression of coronary artery disease57,58 and the development of cerebral infarcts,59but not in all studies (Table).60
Coding Polymorphisms of Fibrinogen Gene
A Thr312Ala Polymorphism
In addition to the noncoding variations, there are 2 coding polymorphisms in the fibrinogen cluster that introduce an amino acid change in the mature protein. One of these occurs in the A gene and leads to a substitution of threonine with alanine at residue 312 of the A chain.61 Thr312Ala is located in an area of the molecule that is important for the interaction of fibrinogen with factor XIII. Two of the factor XIII cross-linking sites, AGln328 and ALys303, are located in this area and are important for the cross-linking to another chain and 2 antiplasmin, respectively. The substitution of Thr312 with Ala leads to increased factor XIII-dependent chain cross-linking and stiffness of the clot. The ultrastructure of the clot demonstrates larger average fibrin fiber diameters for Ala312 clots, but with a similar number of branch points as Thr312 (Table).62
Clinical studies have reported that the Ala allele of the Thr312Ala polymorphism predisposes to embolization in arterial and venous systems. There is an association of the Ala allele with poststroke mortality in subjects with atrial fibrillation.63 It has also been associated with pulmonary embolism in subjects with deep vein thrombosis.64 It may be possible that stiffer clots as observed in vitro are more brittle and tend to fragment more easily.62
Bß Arg448Lys Polymorphism
The second coding polymorphism occurs in the Bß chain, where arginine 448 is substituted with lysine.61 This amino acid change is located in the C-terminal domain of the Bß polypeptide, where it could have an effect on the configuration of this domain. Preliminary data have shown that possession of the Lys448 allele is associated with lower clot permeability and a tighter, finer structure than possession of the Arg448 allele,65 although another study did not confirm this (Table).66 Clinically, this polymorphism has been associated with macrovascular disease50,67 in some but not all studies.
Genetic and Environmental Interaction on Fibrinogen Levels
Overall, the genetic influence on the variation of fibrinogen and fibrin is relatively large. Twin studies have demonstrated that the percentage of variation of fibrinogen attributable to genetic factors is 40% to 50%.26,27 A similar, although slightly lower, degree of heritability of fibrinogen of 34% has been found in family studies.68 Even a phenotype that is more complex, such as the ultrastructure of the fibrin clot, is susceptible to genetic variation.27 Although overall heritability of both fibrinogen and fibrin is considerable, the contribution of individual genetic polymorphisms on intermediate phenotypes such as protein structure and function or the plasma level of coagulation proteins appears to be relatively small.69 This may be one reason why associations between the clinical disease phenotype and single genetic polymorphisms in coagulation factors are inconsistent.49
|
Factor XIII |
|---|
|
TopAbstractIntroductionThe Formation of a...Abnormal Clot Architecture and...Genetic and Environmental...FibrinogenFactor XIIIOther Factors Influencing Clot...ConclusionReferences |
|---|
Additional genetic regulation of fibrin structure and function occurs through variations in proteins other than fibrinogen that are involved in the process of fibrin clot formation and that interact with the variations occurring in the fibrinogen genes described. An example is a polymorphism in the factor XIII A subunit (Val34Leu), which codes for an amino acid change close to the thrombin cleavage site at position 37.
FXIII Val34Leu Polymorphism
The substitution of valine with leucine is a relatively conservative amino acid change, but it occurs in an area that plays a critical role in the interaction between thrombin and factor XIII,70 so that cleavage of the FXIII activation peptide by thrombin is enhanced 2- to 3-fold in the Leu34 variant (Table).29,71,72 This enhanced activation rate of factor XIII Leu34 has been reported to influence fibrin structure and function29 in a manner that is dependent on the concentration of fibrinogen.65 Fibrin clots formed in the presence of FXIIILeu34 form quicker and have thinner fibers, smaller pores, and reduced permeability compared with the Val34 variant. It appears that early cross-linking of fibrin by FXIIILeu 34, which is activated at the time of fibrinopeptide A release, inhibits lateral aggregation of the fibrin fibers, whereas delayed cross-linking by FXIII34Val allows for more lateral aggregation before the cross-linking occurs.29 At high concentrations of fibrinogen, plasma samples homozygous for the Leu34 allele form clots with increased permeability and looser structures than do clots formed from plasma samples homozygous for the Val allele.65 Therefore, a protective effect of the Leu34 allele should emerge only in the presence of increased fibrinogen concentrations.
Clinically, possession of the FXIIILeu34 allele has been found to be lower in some (but not all) studies of patients with MI and cerebral infarction.8 Bearing in mind that fibrinogen concentrations are often increased in cardiovascular disease, it is possible that environmental factors alter fibrinogen concentrations and consequently the structure of the clot formed in the presence of the Leu34 allele to give a protective effect.
Factor XIII B Polymorphisms
Polymorphisms of the FXIII B subunit are uncommon, although His95Arg is relatively common and appears to reduce the risk of MI in women.73 However, its effect on fibrin structure and function is unknown (Table).
Prothrombin and Thrombin
Elevated levels of prothrombin have been associated with a risk of arterial and venous thrombosis,74–76 and a mutation in the 3'-untranslated region of the prothrombin coding gene is associated with increased prothrombin levels.75 Increased prothrombin results in increased thrombin generation, which affects fibrin clot structure.30 Clots produced in conditions of low thrombin concentration are composed of thicker fibers and are more porous, whereas those formed at higher thrombin concentrations have thinner and more tightly cross-linked fibers.30 It has not been determined whether the altered clot structure produced at different thrombin concentrations in vivo has clinical relevance, but many previous studies have shown that thin-fibered tightly cross-linked clots have increased resistance to fibrinolysis.14–17
|
Other Factors Influencing Clot Architecture |
|---|
|
TopAbstractIntroductionThe Formation of a...Abnormal Clot Architecture and...Genetic and Environmental...FibrinogenFactor XIIIOther Factors Influencing Clot...ConclusionReferences |
|---|
Aside from the major genetic and environmental influences described, there are other clinically relevant environmental factors that influence fibrin clot structure and function. Many have a well-established link to an increased risk of atherothrombotic vascular disease.
Cross-Linked Proteins and Circulating Salts
Activated factor XIII cross-links several other proteins to the chain of the fibrin molecule, including 2-antiplasmin, the major physiological inhibitor of plasmin,11 TAFI,77and plasminogen activator inhibitor-2.78,79 Cross-linking of these proteins makes the clot less susceptible to lysis. FXIIIa cross-links fibronectin, which alters the mechanical properties of the clot by increasing fiber thickness and clot permeability. It also promotes migration and adherence of cells into the clot, presumably aiding the wound healing process.80–83 Collagen is cross-linked to fibrin, which may stabilize the extracellular matrix forming at tissue injury sites.84 Actin, myosin, and vinculin when cross-linked cause clot retraction and stabilization of the platelet cytoskeleton.85–88
The effect of different salts on clot structure has also been investigated. Chloride appears to be the most important physiological modulator of fibrin polymerization, because chloride ions bind to fibrin and prevent the lateral aggregation of protofibrils, resulting in thinner fibers that are more curved.89 This effect is dependent on ambient pH.
Glucose and Treatment
Subjects with diabetes and insulin resistance are more likely to have atherothrombotic cardiovascular disease.90 Fibrinogen concentrations are higher in diabetes,91 which will contribute to a more prothrombotic fibrin clot structure as discussed. Studies in type I diabetic subjects have shown that they have tighter, less permeable fibrin clots with normal fiber thickness than do healthy controls, and this was independent of fibrinogen concentration.19,20 In vitro, adding glucose to plasma leads to the formation of clots with a tighter, less permeable fibrin network.19 Recent work in our laboratory suggests that ambient glucose levels independently affect fibrin clot architecture and that increasing glycosylated hemoglobin (HbA1c) is independently associated with the formation of tightly cross-linked, thin-fibered fibrin clots (Dunn, unpublished data). This may be caused by concomitant glycosylation of the proteins involved in fibrin clot formation.92 It is of interest that 4 to 6 months of insulin treatment with continuous subcutaneous insulin infusion in patients with longstanding type 1 diabetes led to an increase in fibrin gel porosity independent of improved glycemic control or insulin levels, but this appeared to be related to total cholesterol and plasma fibrinogen levels.93 Other drugs used to treat diabetes have effects on fibrin structure and function. Gliclazide increases fibrin fiber thickness but reduces permeability, overall rendering the clot more susceptible to fibrinolysis.94 Clots formed in the presence of dimethylbiguanide (metformin) lyse more quickly19 and have been shown to interfere with thrombin-induced FXIII activation, inhibit fibrinopeptide A and B release, and thus reduce FXIII cross-linking activity, resulting in thinner fibers but a reduced pore size.95
Lipids and Treatment
It has been shown that total cholesterol may determine fibrin clot structure,93 and fibrin gel porosity has been associated with lipoproteins in young patients sustaining MI.13 It is of interest that statins appear to reduce thrombin formation and inhibit FXIII activation, reducing the formation of a stable clot.96 This appears to be independent of the effect of cholesterol-lowering and may be related to an anti-inflammatory effect of this class of drugs. They do not, however, alter fibrinogen concentrations.97
Homocysteine
A high-plasma homocysteine is a risk factor for atherothrombotic vascular disease.98 In vitro, clots formed in the presence of homocysteine have thicker, shorter fibers with a more compact structure.99 Clots formed with fibrinogen from homocysteinemic plasma are more resistant to lysis.100 In addition, homocysteine binds to circulating fibronectin and hinders fibrin/fibronectin binding.101 This may reduce the amount of fibronectin in the clot, impairing wound healing.
Inflammatory Markers
Inflammatory markers are associated with an increased risk of vascular disease. Complement activation has been shown to induce alterations in fibrin structure, including the formation of thinner fibers with increased tensile strength arranged into tight networks that are resistant to fibrinolysis.102 These changes in turn appear to promote further activation of the complement system.102 The effect of C-reactive protein and cytokines on fibrin clot structure does not appear to have been investigated, although C-reactive protein has been shown to induce plasminogen activator inhibitor-1 release in vitro, which would inhibit fibrinolysis.103
Lifestyle Factors—Diet and Smoking
Work in this area has been limited. A westernized diet is known to contribute to the development of cardiovascular disease, possibly because of its high-fat and low-fiber content. A study has shown that the water-soluble dietary fiber pectin given as a supplement to hypercholesterolemic subjects alters the fibrin network favorably, making it more permeable and less rigid.104 This is independent of fibrinogen concentration but accompanied by a decrease in total cholesterol and lipoprotein A. Red wine,105 fish oil, and olive oil106 consumption have been shown to lower fibrinogen. Further studies would be needed to determine whether these changes have any therapeutic relevance to thrombotic disease. No studies have been performed on the effect of smoking on fibrin clot architecture, but smoking increases fibrinogen levels,107 and this is likely to influence fibrin characteristics.
|
Conclusion |
|---|
|
TopAbstractIntroductionThe Formation of a...Abnormal Clot Architecture and...Genetic and Environmental...FibrinogenFactor XIIIOther Factors Influencing Clot...ConclusionReferences |
|---|
Atherothrombotic vascular disease has reached epidemic proportions in the developed world and represents the major cause of morbidity and mortality in westernized populations. The final phenotypes of acute coronary syndromes, including MI, cerebrovascular disease, and acute limb ischemia are most commonly related to the development of a platelet-rich fibrin mesh on a damaged vessel wall, leading to occlusive thrombus formation. The fibrin clot plays a pivotal role in the pathophysiology of vascular disease, and it is becoming clear that the structure/function of the fibrin clot is complex with genetic and environmental determinants. However, the information known about this is relatively limited and further research is required to understand the factors that modify fibrin structure/function and the clinical implications of these alterations. More work also needs to be performed looking at the relationship of fibrin clot structure to its stability and how this relates to atherogenesis. The development of FXIII inhibitors by computational chemistry should also help to elucidate this further. We can now appreciate that alterations in gene expression and coding function, splice variants, and posttranslational modifications of protein products all influence fibrin structure/function. The extent to which classical risk factors for cardiovascular disease interact with these processes and the mechanisms that might underpin such associations have not been evaluated and represent a great challenge in this field. A fuller knowledge of the role of the proteome in generating the fibrin phenotype and the links with classical risk factors may provide major opportunities for the development of novel fibrin-directed therapeutics to work alongside the well-established antiplatelet agents. This raises the possibility of combined antiplatelet and fibrin-modifying agents to prevent and treat the atherothrombotic syndromes.
Received March 29, 2004; accepted June 15, 2004.
|
References |
|---|
|
TopAbstractIntroductionThe Formation of a...Abnormal Clot Architecture and...Genetic and Environmental...FibrinogenFactor XIIIOther Factors Influencing Clot...ConclusionReferences |
|---|
1. Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001; 104: 365–372.
2. Weisel JW, Medved L. The structure and function of the alpha C domains of fibrinogen. Ann N Y Acad Sci. 2001; 936: 312–327.[Medline] [Order article via Infotrieve]
3. Mosesson MW, Siebenlist KR, Meh DA. The structure and biological features of fibrinogen and fibrin. Ann N Y Acad Sci. 2001; 936: 11–30.[Medline] [Order article via Infotrieve]
4. Mullin JL, Gorkun OV, Binnie CG, Lord ST. Recombinant fibrinogen studies reveal that thrombin specificity dictates order of fibrinopeptide release. J Biol Chem. 2000; 275: 25239–25246.
5. 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. 1993; 232: 285–297.[CrossRef][Medline] [Order article via Infotrieve]
6. 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. 1993; 268: 26618–26624.
7. Spraggon G, Everse SJ, Doolittle RF. Crystal structures of fragment D from human fibrinogen and its crosslinked counterpart from fibrin. Nature. 1997; 389: 455–462.[CrossRef][Medline] [Order article via Infotrieve]
8. Ariens RA, Lai TS, Weisel JW, Greenberg CS, Grant PJ. Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms. Blood. 2002; 100: 743–754.
9. Gaffney PJ, Whitaker AN. Fibrin crosslinks and lysis rates. Thromb Res. 1979; 14: 85–94.[CrossRef][Medline] [Order article via Infotrieve]
10. McDonagh RP, Jr, McDonagh J, Duckert F. The influence of fibrin crosslinking on the kinetics of urokinase-induced clot lysis. Br J Haematol. 1971; 21: 323–332.[Medline] [Order article via Infotrieve]
11. Sakata Y, Aoki N. Cross-linking of alpha 2-plasmin inhibitor to fibrin by fibrin-stabilizing factor. J Clin Invest. 1980; 65: 290–297.
12. 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. 1980; 66: 1033–1043.
13. Fatah K, Silveira A, Tornvall P, Karpe F, Blomback M, Hamsten A. Proneness to formation of tight and rigid fibrin gel structures in men with myocardial infarction at a young age. Thromb Haemost. 1996; 76: 535–540.[Medline] [Order article via Infotrieve]
14. Gabriel DA, Muga K, Boothroyd EM. The effect of fibrin structure on fibrinolysis. J Biol Chem. 1992; 267: 24259–24263.
15. Collet JP, Soria J, Mirshahi M, Hirsch M, Dagonnet FB, Caen J, Soria C. Dusart syndrome: a new concept of the relationship between fibrin clot architecture and fibrin clot degradability: hypofibrinolysis related to an abnormal clot structure. Blood. 1993; 82: 2462–2469.
16. Carr ME, Jr., Alving BM. Effect of fibrin structure on plasmin-mediated dissolution of plasma clots. Blood Coagul Fibrinolysis. 1995; 6: 567–573.[Medline] [Order article via Infotrieve]
17. Collet JP, Park D, Lesty C, Soria J, Soria C, Montalescot G, Weisel JW. Influence of fibrin network conformation and fibrin fiber diameter on fibrinolysis speed: dynamic and structural approaches by confocal microscopy. Arterioscler Thromb Vasc Biol. 2000; 20: 1354–1361.
18. Collet JP, Lesty C, Montalescot G, Weisel JW. Dynamic changes of fibrin architecture during fibrin formation and intrinsic fibrinolysis of fibrin-rich clots. J Biol Chem. 2003; 278: 21331–21335.
19. Nair CH, Azhar A, Wilson JD, Dhall DP. Studies on fibrin network structure in human plasma. Part II–Clinical application: diabetes and antidiabetic drugs. Thromb Res. 1991; 64: 477–485.[CrossRef][Medline] [Order article via Infotrieve]
20. Jorneskog G, Egberg N, Fagrell B, Fatah K, Hessel B, Johnsson H, Brismar K, Blomback M. Altered properties of the fibrin gel structure in patients with IDDM. Diabetologia. 1996; 39: 1519–1523.[CrossRef][Medline] [Order article via Infotrieve]
21. Fatah K, Hamsten A, Blomback B, Blomback M. Fibrin gel network characteristics and coronary heart disease: relations to plasma fibrinogen concentration, acute phase protein, serum lipoproteins and coronary atherosclerosis. Thromb Haemost. 1992; 68: 130–135.[Medline] [Order article via Infotrieve]
22. Greilich PE, Carr ME, Zekert SL, Dent RM. Quantitative assessment of platelet function and clot structure in patients with severe coronary artery disease. Am J Med Sci. 1994; 307: 15–20.[Medline] [Order article via Infotrieve]
23. Williams S, Fatah K, Hjemdahl P, Blomback M. Better increase in fibrin gel porosity by low dose than intermediate dose acetylsalicylic acid. Eur Heart J. 1998; 19: 1666–1672.
24. He S, Blomback M, Yoo G, Sinha R, Henschen-Edman AH. Modified clotting properties of fibrinogen in the presence of acetylsalicylic acid in a purified system. Ann N Y Acad Sci. 2001; 936: 531–535.[Medline] [Order article via Infotrieve]
25. Mills JD, Ariens RA, Mansfield MW, Grant PJ. Altered fibrin clot structure in the healthy relatives of patients with premature coronary artery disease. Circulation. 2002; 106: 1938–1942.
26. De Lange M, Snieder H, Ariens RA, Spector TD, Grant PJ. The genetics of haemostasis: a twin study. Lancet. 2001; 357: 101–105.[CrossRef][Medline] [Order article via Infotrieve]
27. Dunn EJ, Ariens RA, De Lange M, Snieder H, Turney JH, Spector TD, Grant PJ. Genetics of fibrin clot structure: a twin study. Blood. 2004; 103: 1735–1740.
28. Blomback B, Carlsson K, Hessel B, Liljeborg A, Procyk R, Aslund N. Native fibrin gel networks observed by 3D microscopy, permeation and turbidity. Biochim Biophys Acta. 1989; 997: 96–110.[CrossRef][Medline] [Order article via Infotrieve]
29. Ariens RA, 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. 2000; 96: 988–995.
30. Wolberg AS, Monroe DM, Roberts HR, Hoffman M. Elevated prothrombin results in clots with an altered fiber structure: a possible mechanism of the increased thrombotic risk. Blood. 2003; 101: 3008–3013.
31. Koenig W. Fibrin(ogen) in cardiovascular disease: an update. Thromb Haemost. 2003; 89: 601–609.[Medline] [Order article via Infotrieve]
32. Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med. 1993; 118: 956–963.
33. Kerlin B, Cooley BC, Isermann BH, Hernandez I, Sood R, Zogg M, Hendrickson SB, Mosesson MW, Lord S, Weiler H. Cause-effect relation between hyperfibrinogenemia and vascular disease. Blood. 2004; 103: 1728–1734.
34. Okada M, Blomback B. Factors influencing fibrin gel structure studied by flow measurement. Ann N Y Acad Sci. 1983; 408: 233–253.[Medline] [Order article via Infotrieve]
35. Blomback B. Fibrinogen structure, activation, polymerization and fibrin gel structure. Thromb Res. 1994; 75: 327–328.[CrossRef][Medline] [Order article via Infotrieve]
36. Carr ME Jr, Hermans J. Size and density of fibrin fibers from turbidity. Macromolecules. 1978; 11: 46–50.[CrossRef][Medline] [Order article via Infotrieve]
37. Scrutton MC, Ross-Murphy SB, Bennett GM, Stirling Y, Meade TW. Changes in clot deformability–a possible explanation for the epidemiological association between plasma fibrinogen concentration and myocardial infarction. Blood Coagul Fibrinolysis. 1994; 5: 719–723.[Medline] [Order article via Infotrieve]
38. Kant JA, Fornace AJ Jr, Saxe D, Simon MI, McBride OW, Crabtree GR. Evolution and organization of the fibrinogen locus on chromosome 4: gene duplication accompanied by transposition and inversion. Proc Natl Acad Sci U S A. 1985; 82: 2344–2348.
39. Tuddenham EGD, Cooper DN. The molecular genetics of haemostasis and its inherited disorders. Oxford: Oxford University Press; 1994.
40. Mosesson MW, Finlayson JS, Umfleet RA. Human fibrinogen heterogeneities. 3. Identification of chain variants. J Biol Chem. 1972; 247: 5223–5227.
41. 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. 1984; 259: 12826–12830.
42. Meh DA, Siebenlist KR, Brennan SO, Holyst T, Mosesson MW. The amino acid sequence in fibrin responsible for high affinity thrombin binding. Thromb Haemost. 2001; 85: 470–474.[Medline] [Order article via Infotrieve]
43. Siebenlist KR, Meh DA, Mosesson MW. Plasma factor XIII binds specifically to fibrinogen molecules containing gamma chains. Biochemistry. 1996; 35: 10448–10453.[CrossRef][Medline] [Order article via Infotrieve]
44. Falls LA, Farrell DH. Resistance of gammaA/gamma’ fibrin clots to fibrinolysis. J Biol Chem. 1997; 272: 14251–14256.
45. Cooper AV, Standeven KF, Ariens RA. Fibrinogen gamma-chain splice variant gamma’ alters fibrin formation and structure. Blood. 2003; 102: 535–540.
46. Collet JP, Woodhead JL, Soria J, Soria C, Mirshahi M, Caen JP, Weisel JW. Fibrinogen Dusart: electron microscopy of molecules, fibers and clots, and viscoelastic properties of clots. Biophys J. 1996; 70: 500–510.[Medline] [Order article via Infotrieve]
47. Lovely RS, Falls LA, Al Mondhiry HA, Chambers CE, Sexton GJ, Ni H, Farrell DH. Association of gammaA/gamma’ fibrinogen levels and coronary artery disease. Thromb Haemost. 2002; 88: 26–31.[Medline] [Order article via Infotrieve]
48. Grieninger G. Contribution of the alpha EC domain to the structure and function of fibrinogen-420. Ann N Y Acad Sci. 2001; 936: 44–64.[Medline] [Order article via Infotrieve]
49. Lane DA, Grant PJ. Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood. 2000; 95: 1517–1532.
50. Behague I, Poirier O, Nicaud V, Evans A, Arveiler D, Luc G, Cambou JP, Scarabin PY, Bara L, Green F, Cambien F. Beta fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction. The ECTIM Study. Etude Cas-Temoins sur l’Infarctus du Myocarde. Circulation. 1996; 93: 440–449.
51. Zito F, Di Castelnuovo A, Amore C, D’Orazio A, Donati MB, Iacoviello L. Bcl I polymorphism in the fibrinogen beta-chain gene is associated with the risk of familial myocardial infarction by increasing plasma fibrinogen levels. A case-control study in a sample of GISSI-2 patients. Arterioscler Thromb Vasc Biol. 1997; 17: 3489–3494.
52. Humphries SE, Cook M, Dubowitz M, Stirling Y, Meade TW. Role of genetic variation at the fibrinogen locus in determination of plasma fibrinogen concentrations. Lancet. 1987; 1: 1452–1455.[CrossRef][Medline] [Order article via Infotrieve]
53. Thomas AE, Green FR, Humphries SE. Association of genetic variation at the beta-fibrinogen gene locus and plasma fibrinogen levels; interaction between allele frequency of the G/A-455 polymorphism, age and smoking. Clin Genet. 1996; 50: 184–190.[Medline] [Order article via Infotrieve]
54. Montgomery HE, Clarkson P, Nwose OM, Mikailidis DP, Jagroop IA, Dollery C, Moult J, Benhizia F, Deanfield J, Jubb M, World M, McEwan JR, Winder A, Humphries S. The acute rise in plasma fibrinogen concentration with exercise is influenced by the G-453-A polymorphism of the beta-fibrinogen gene. Arterioscler Thromb Vasc Biol. 1996; 16: 386–391.
55. Brown ET, Fuller GM. Detection of a complex that associates with the Bß fibrinogen G-455-A polymorphism. Blood. 1998; 92: 3286–3293.
56. Carter AM, Mansfield MW, Stickland MH, Grant PJ. Beta-fibrinogen gene-455 G/A polymorphism and fibrinogen levels. Risk factors for coronary artery disease in subjects with NIDDM. Diabetes Care. 1996; 19: 1265–1268.[Abstract]
57. De Maat MP, Kastelein JJ, Jukema JW, Zwinderman AH, Jansen H, Groenemeier B, Bruschke AV, Kluft C. -455G/A polymorphism of the beta-fibrinogen gene is associated with the progression of coronary atherosclerosis in symptomatic men: proposed role for an acute-phase reaction pattern of fibrinogen. REGRESS group. Arterioscler Thromb Vasc Biol. 1998; 18: 265–271.
58. Green FR. Fibrinogen polymorphisms and atherothrombotic disease. Ann N Y Acad Sci. 2001; 936: 549–559.[Medline] [Order article via Infotrieve]
59. Martiskainen M, Pohjasvaara T, Mikkelsson J, Mantyla R, Kunnas T, Laippala P, Ilveskoski E, Kaste M, Karhunen PJ, Erkinjuntti T. Fibrinogen gene promoter -455 A allele as a risk factor for lacunar stroke. Stroke. 2003; 34: 886–891.
60. Folsom AR, Aleksic N, Ahn C, Boerwinkle E, Wu KK. Beta-fibrinogen gene -455G/A polymorphism and coronary heart disease incidence: the Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol. 2001; 11: 166–170.[CrossRef][Medline] [Order article via Infotrieve]
61. Baumann RE, Henschen AH. Human fibrinogen polymorphic site analysis by restriction endonuclease digestion and allele-specific polymerase chain reaction amplification: identification of polymorphisms at positions A alpha 312 and B beta 448. Blood. 1993; 82: 2117–2124.
62. Standeven KF, Grant PJ, Carter AM, Scheiner T, Weisel JW, Ariens RA. Functional analysis of the fibrinogen Aalpha Thr312Ala polymorphism: effects on fibrin structure and function. Circulation. 2003; 107: 2326–2330.
63. Carter AM, Catto AJ, Grant PJ. Association of the alpha-fibrinogen Thr312Ala polymorphism with poststroke mortality in subjects with atrial fibrillation. Circulation. 1999; 99: 2423–2426.
64. Carter AM, Catto AJ, Kohler HP, Ariens RA, Stickland MH, Grant PJ. alpha-fibrinogen Thr312Ala polymorphism and venous thromboembolism. Blood. 2000; 96: 1177–1179.
65. Lim BC, Ariens RA, Carter AM, Weisel JW, Grant PJ. Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk. Lancet. 2003; 361: 1424–1431.[CrossRef][Medline] [Order article via Infotrieve]
66. Maghzal GJ, Brennan SO, George PM. Fibrinogen B beta polymorphisms do not directly contribute to an altered in vitro clot structure in humans. Thromb Haemost. 2003; 90: 1021–1028.[Medline] [Order article via Infotrieve]
67. Carter AM, Catto AJ, Bamford JM, Grant PJ. Gender-specific associations of the fibrinogen B beta 448 polymorphism, fibrinogen levels, and acute cerebrovascular disease. Arterioscler Thromb Vasc Biol. 1997; 17: 589–594.
68. Souto JC, Almasy L, Borrell M, Gari M, Martinez E, Mateo J, Stone WH, Blangero J, Fontcuberta J. Genetic determinants of hemostasis phenotypes in Spanish families. Circulation. 2000; 101: 1546–1551.
69. Freeman MS, Mansfield MW, Barrett JH, Grant PJ. Genetic contribution to circulating levels of hemostatic factors in healthy families with effects of known genetic polymorphisms on heritability. Arterioscler Thromb Vasc Biol. 2002; 22: 506–510.
70. Trumbo TA, Maurer MC. Thrombin hydrolysis of V29F and V34L mutants of factor XIII (28–41) reveals roles of the P(9) and P(4) positions in factor XIII activation. Biochemistry. 2002; 41: 2859–2868.[CrossRef][Medline] [Order article via Infotrieve]
71. Balogh I, Szoke G, Karpati L, Wartiovaara U, Katona E, Komaromi I, Haramura G, Pfliegler G, Mikkola H, Muszbek L. Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia. Blood. 2000; 96: 2479–2486.
72. Wartiovaara U, Mikkola H, Szoke G, Haramura G, Karpati L, Balogh I, Lassila R, Muszbek L, Palotie A. Effect of Val34Leu polymorphism on the activation of the coagulation factor XIII-A. Thromb Haemost. 2000; 84: 595–600.[Medline] [Order article via Infotrieve]
73. Reiner AP, Heckbert SR, Vos HL, Ariens RA, Lemaitre RN, Smith NL, Lumley T, Rea TD, Hindorff LA, Schellenbaum GD, Rosendaal FR, Siscovick DS, Psaty BM. Genetic variants of coagulation factor XIII, postmenopausal estrogen therapy, and risk of nonfatal myocardial infarction. Blood. 2003; 102: 25–30.
74. Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raghunathan TE, Vos HL. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women. Blood. 1997; 90: 1747–1750.
75. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996; 88: 3698–3703.
76. Giordano P, De Lucia D, Coppola B, Iolascon A. Homozygous prothrombin gene mutation and ischemic cerebrovascular disease: a case report. Acta Haematol. 1999; 102: 101–103.[CrossRef][Medline] [Order article via Infotrieve]
77. 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. 1998; 273: 27220–27224.
78. 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. 2000; 275: 24915–24920.
79. 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. 2001; 936: 215–218.[Medline] [Order article via Infotrieve]
80. Okada M, Blomback B, Chang MD, Horowitz B. Fibronectin and fibrin gel structure. J Biol Chem. 1985; 260: 1811–1820.
81. Chow TW, McIntire LV, Peterson DM. Importance of plasma fibronectin in determining PFP and PRP clot mechanical properties. Thromb Res. 1983; 29: 243–248.[CrossRef][Medline] [Order article via Infotrieve]
82. Kamykowski GW, Mosher DF, Lorand L, Ferry JD. Modification of shear modulus and creep compliance of fibrin clots by fibronectin. Biophys Chem. 1981; 13: 25–28.[CrossRef][Medline] [Order article via Infotrieve]
83. Barry EL, Mosher DF. Factor XIII cross-linking of fibronectin at cellular matrix assembly sites. J Biol Chem. 1988; 263: 10464–10469.
84. 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. 1980; 255: 1181–1188.
85. Mui PT, Ganguly P. Cross-linking of actin and fibrin by fibrin-stabilizing factor. Am J Physiol. 1977; 233: H346–H349.
86. 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. 1979; 192: 100–111.[CrossRef][Medline] [Order article via Infotrieve]
87. 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. 1980; 628: 365–375.[Medline] [Order article via Infotrieve]
88. Asijee GM, Muszbek L, Kappelmayer J, Polgar J, Horvath A, Sturk A. Platelet vinculin: a substrate of activated factor XIII. Biochim Biophys Acta. 1988; 954: 303–308.[CrossRef][Medline] [Order article via Infotrieve]
89. Di Stasio E, Nagaswami C, Weisel JW, Di Cera E. Cl- regulates the structure of the fibrin clot. Biophys J. 1998; 75: 1973–1979.[Medline] [Order article via Infotrieve]
90. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham Study. JAMA. 1979; 241: 2035–2038.
91. Ganda OP, Arkin CF. Hyperfibrinogenemia. An important risk factor for vascular complications in diabetes. Diabetes Care. 1992; 15: 1245–1250.[Abstract]
92. Lutjens A, te Velde AA, vd Veen EA, vd Meer J. Glycosylation of human fibrinogen in vivo. Diabetologia. 1985; 28: 87–89.[Medline] [Order article via Infotrieve]
93. Jorneskog G, Hansson LO, Wallen NH, Yngen M, Blomback M. Increased plasma fibrin gel porosity in patients with Type I diabetes during continuous subcutaneous insulin infusion. J Thromb Haemost. 2003; 1: 1195–1201.[CrossRef][Medline] [Order article via Infotrieve]
94. Dhall DP, Nair CH. Effects of gliclazide on fibrin network. J Diabetes Complications. 1994; 8: 231–234.[CrossRef][Medline] [Order article via Infotrieve]
95. Standeven KF, Ariens RA, Whitaker P, Ashcroft AE, Weisel JW, Grant PJ. The effect of dimethylbiguanide on thrombin activity, FXIII activation, fibrin polymerization, and fibrin clot formation. Diabetes. 2002; 51: 189–197.
96. Undas A, Brummel KE, Musial J, Mann KG, Szczeklik A. Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation. Circulation. 2001; 103: 2248–2253.
97. Balk EM, Lau J, Goudas LC, Jordan HS, Kupelnick B, Kim LU, Karas RH. Effects of statins on nonlipid serum markers associated with cardiovascular disease: a systematic review. Ann Intern Med. 2003; 139: 670–682.
98. Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA. 1992; 268: 877–881.
99. Lauricella AM, Quintana IL, Kordich LC. Effects of homocysteine thiol group on fibrin networks: another possible mechanism of harm. Thromb Res. 2002; 107: 75–79.[CrossRef][Medline] [Order article via Infotrieve]
100. Sauls DL, Wolberg AS, Hoffman M. Elevated plasma homocysteine leads to alterations in fibrin clot structure and stability: implications for the mechanism of thrombosis in hyperhomocysteinemia. J Thromb Haemost. 2003; 1: 300–306.[CrossRef][Medline] [Order article via Infotrieve]
101. Majors AK, Sengupta S, Willard B, Kinter MT, Pyeritz RE, Jacobsen DW. Homocysteine binds to human plasma fibronectin and inhibits its interaction with fibrin. Arterioscler Thromb Vasc Biol. 2002; 22: 1354–1359.
102. Shats-Tseytlina EA, Nair CH, Dhall DP. Complement activation: a new participant in the modulation of fibrin gel characteristics and the progression of atherosclerosis? Blood Coagul Fibrinolysis. 1994; 5: 529–535.[Medline] [Order article via Infotrieve]
103. Devaraj S, Xu DY, Jialal I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis. Circulation. 2003; 107: 398–404.
104. Veldman FJ, Nair CH, Vorster HH, Vermaak WJ, Jerling JC, Oosthuizen W, Venter CS. Dietary pectin influences fibrin network structure in hypercholesterolaemic subjects. Thromb Res. 1997; 86: 183–196.[CrossRef][Medline] [Order article via Infotrieve]
105. Mezzano D, Leighton F, Martinez C, Marshall G, Cuevas A, Castillo O, Panes O, Munoz B, Perez DD, Mizon C, Rozowski J, San Martin A, Pereira J. Complementary effects of Mediterranean diet and moderate red wine intake on haemostatic cardiovascular risk factors. Eur J Clin Nutr. 2001; 55: 444–451.[CrossRef][Medline] [Order article via Infotrieve]
106. Oosthuizen W, Vorster HH, Jerling JC, Barnard HC, Smuts CM, Silvis N, Kruger A, Venter CS. Both fish oil and olive oil lowered plasma fibrinogen in women with high baseline fibrinogen levels. Thromb Haemost. 1994; 72: 557–562.[Medline] [Order article via Infotrieve]
107. Meade TW, Imeson J, Stirling Y. Effects of changes in smoking and other characteristics on clotting factors and the risk of ischaemic heart disease. Lancet. 1987; 2: 986–988.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  A. Undas, P. Podolec, K. Zawilska, M. Pieculewicz, I. Jedlinski, E. Stepien, E. Konarska-Kuszewska, P. Weglarz, M. Duszynska, E. Hanschke, et al. Altered Fibrin Clot Structure/Function in Patients With Cryptogenic Ischemic Stroke Stroke, April 1, 2009; 40(4): 1499 - 1501. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Undas, I. Wiek, E. Stepien, K. Zmudka, and W. Tracz Hyperglycemia Is Associated With Enhanced Thrombin Formation, Platelet Activation, and Fibrin Clot Resistance to Lysis in Patients With Acute Coronary Syndrome Diabetes Care, August 1, 2008; 31(8): 1590 - 1595. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Undas, M. Kolarz, G. Kopec, and W. Tracz Altered fibrin clot properties in patients on long-term haemodialysis: relation to cardiovascular mortality Nephrol. Dial. Transplant., June 1, 2008; 23(6): 2010 - 2015. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Suntharalingam, K. Goldsmith, V. van Marion, L. Long, C. M. Treacy, F. Dudbridge, M. R. Toshner, J. Pepke-Zaba, J. C. J. Eikenboom, and N. W. Morrell Fibrinogen A{alpha} Thr312Ala polymorphism is associated with chronic thromboembolic pulmonary hypertension Eur. Respir. J., April 1, 2008; 31(4): 736 - 741. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. O. Pruissen, A. J. C. Slooter, F. R. Rosendaal, Y. van der Graaf, and A. Algra Coagulation factor XIII gene variation, oral contraceptives, and risk of ischemic stroke Blood, February 1, 2008; 111(3): 1282 - 1286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Cerhan, S. M. Ansell, Z. S. Fredericksen, N. E. Kay, M. Liebow, T. G. Call, A. Dogan, J. M. Cunningham, A. H. Wang, W. Liu-Mares, et al. Genetic variation in 1253 immune and inflammation genes and risk of non-Hodgkin lymphoma Blood, December 15, 2007; 110(13): 4455 - 4463. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zalewski, A. Undas, J. Godlewski, E. Stepien, and K. Zmudka No-Reflow Phenomenon After Acute Myocardial Infarction Is Associated With Reduced Clot Permeability and Susceptibility to Lysis Arterioscler. Thromb. Vasc. Biol., October 1, 2007; 27(10): 2258 - 2265. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Silveira and A. Hamsten Fibrin gel architecture influences endogenous fibrinolysis and may promote coronary artery disease. Arterioscler. Thromb. Vasc. Biol., November 1, 2006; 26(11): 2419 - 2420. [Full Text] [PDF]
|
|
|
|
|
|
J.P. Collet, Y. Allali, C. Lesty, M.L. Tanguy, J. Silvain, A. Ankri, B. Blanchet, R. Dumaine, J. Gianetti, L. Payot, et al. Altered Fibrin Architecture Is Associated With Hypofibrinolysis and Premature Coronary Atherothrombosis Arterioscler. Thromb. Vasc. Biol., November 1, 2006; 26(11): 2567 - 2573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Undas, J. Brozek, M. Jankowski, Z. Siudak, A. Szczeklik, and H. Jakubowski Plasma Homocysteine Affects Fibrin Clot Permeability and Resistance to Lysis in Human Subjects Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1397 - 1404. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||