Functional Analysis of the Fibrinogen Aα Thr312Ala Polymorphism

Standeven, Kristina F.; Grant, Peter J.; Carter, Angela M.; Scheiner, Thomas; Weisel, John W.; Ariëns, Robert A. S.

doi:10.1161/01.cir.0000066690.89407.ce

Cited by 122 publications

(110 citation statements)

References 18 publications

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“…65 It has been reported that the Ala312 allele is associated with more rigid and less porous fibrin gel structures. 66 Ala312 fibrin clots had thicker fibers and more extensive ␣-chain cross-linking than Thr312 clots. 66 These results suggested that Ala312 fibrin clots are more resistant to fibrinolysis, which might increase the risk for thrombosis.…”

Section: Discussionmentioning

confidence: 87%

“…66 Ala312 fibrin clots had thicker fibers and more extensive ␣-chain cross-linking than Thr312 clots. 66 These results suggested that Ala312 fibrin clots are more resistant to fibrinolysis, which might increase the risk for thrombosis. 56 However, because this polymorphism is located on FGA-H2, which is strongly linked to FGG-H2, it is not unlikely that the risk reported to be associated with this polymorphism 67 is in fact caused by linkage with FGG-H2.…”

Section: Discussionmentioning

confidence: 87%

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Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen γ′ levels

Willige

Visser

Houwing-Duistermaat

et al. 2005

Blood

229

260

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We investigated the association between haplotypes of fibrinogen alpha (FGA), beta (FGB), and gamma (FGG), total fibrinogen levels, fibrinogen ␥ (␥A/␥ plus ␥/␥) levels, and risk for deep venous thrombosis. In a population-based case-control study, the Leiden Thrombophilia Study, we typed 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) in this gene cluster. None of these haplotypes was associated with total fibrinogen levels. In each gene, one haplotype increased the thrombosis risk approximately 2-fold. After adjustment for linkage disequilibrium between the genes, only FGG-H2 homozygosity remained associated with risk (odds ratio [OR], 2.4; 95% confidence interval [95% CI], 1.5-3.9). FGG-H2 was also associated with reduced fibrinogen ␥ levels and reduced ratios of fibrinogen ␥ to total fibrinogen. Multivariate analysis showed that reduced fibrinogen ␥ levels and elevated total fibrinogen levels were both associated with an increased risk for thrombosis, even after adjustment for FGG-H2. A reduced fibrinogen ␥ to total fibrinogen ratio (less than 0.69) also increased the risk (OR, 2.4; 95% CI, 1.7-3.5)

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 87%

Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen γ′ levels

Willige

Visser

Houwing-Duistermaat

et al. 2005

Blood

229

260

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“…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.…”

Section: A␣ Thr312ala Polymorphismmentioning

confidence: 99%

“…64 It may be possible that stiffer clots as observed in vitro are more brittle and tend to fragment more easily. 62 …”

Section: A␣ Thr312ala Polymorphismmentioning

confidence: 99%

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Genetic and Environmental Determinants of Fibrin Structure and Function

Scott

Ariëns

Grant

2004

ATVB

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138

129

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Abstract-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. Key Words: fibrin Ⅲ hemostatis Ⅲ genetic Ⅲ environment Ⅲ atherothrombosis D iseases 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 ClotFibrin 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␣, B␤, ␥) 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 B␤ 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 B␤ 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 adjac...

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Association of genetic polymorphisms in the fibrinogen and platelet glycoprotein genes with unstable angina in Chinese patients

Hong

et al. 2004

Clinical Cardiology

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Functional Analysis of the Fibrinogen Aα Thr312Ala Polymorphism

Cited by 122 publications

References 18 publications

Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen γ′ levels

Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen γ′ levels

Genetic and Environmental Determinants of Fibrin Structure and Function

Association of genetic polymorphisms in the fibrinogen and platelet glycoprotein genes with unstable angina in Chinese patients

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