Elevated plasma fibrinogen γ′ concentration is associated with myocardial infarction: effects of variation in fibrinogen genes and environmental factors

Mannila, Maria Nastase; Lovely, Rehana Sultana; Kazmierczak, Steven C.; Eriksson, Per; Samnegård, Ann; Farrell, David H.; Hamsten, Anders; Silveira, Angela

doi:10.1111/j.1538-7836.2007.02406.x

Cited by 88 publications

(87 citation statements)

References 27 publications

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“…91 No association of this SNP was found with risk of MI. 94 SNP 9340T3C was associated with increased ␥A/␥Ј fibrinogen levels, again confirmed in other studies, 84,87,91 and a slight decrease in DVT risk. 81 In addition, 9340T3C was associated with a reduced risk in a Swedish MI study, 94 a Dutch study on ischemic stroke, 87 but not in a Dutch study on MI.…”

Section: Determinants Of the ␥A/␥ Fibrinogen Levelsupporting

confidence: 71%

“…Similarly, Mannila et al found that the ␥A/␥Ј fibrinogen level was significantly higher in MI patients than in age-and sex-matched healthy controls; and although there was a weak correlation between ␥A/␥Ј and total fibrinogen level in both patients and controls, they did not find a significant difference in the ␥Ј fibrinogen/ total fibrinogen ratio between patients and controls. 84 In contrast to the elevated plasma ␥A/␥Ј fibrinogen levels found in patients with arterial disease, patients with deep venous thrombosis (DVT) have reduced ␥A/␥Ј fibrinogen levels and reduced ␥Ј fibrinogen/total fibrinogen ratio compared with healthy controls. 81 Persons with a ␥Ј fibrinogen/total fibrinogen ratio below the 10th percentile, as measured in the control group, had a 2.4-fold increased risk of DVT in the Leiden Thrombophilia Study.…”

Section: Fibrinogen ␥ Chain As Modifier Of Thrombosis Riskmentioning

confidence: 95%

“…83 Correspondingly, Mosesson et al showed that in healthy persons, expression of the ␥Ј 427L or ␥Ј 423P chains was not significantly influenced by gender, age, and ethnicity. 82 The first real attempt to identify genetic and environmental determinants of the plasma ␥A/␥Ј fibrinogen level was presented by Mannila et al 84 In control persons, they showed that FGG 9340T3C (10.4%), fibrinogen (3.4%), and FGA 2224G3A (2.2%) emerged as independent predictors, together accounting for 16% of the variation in ␥A/␥Ј fibrinogen level. In post-MI patients, fibrinogen (9.2%), FGG 9340T3C (5.9%), FGA 2224G3A (3.9%), high-density lipoproteincholesterol (1.4%), insulin (1.1%), and sex (0.9%) emerged as independent determinants, together accounting for 22.4% of variation in ␥A/␥Ј fibrinogen.…”

Section: Determinants Of the ␥A/␥ Fibrinogen Levelmentioning

confidence: 99%

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The pleiotropic role of the fibrinogen γ′ chain in hemostasis

Willige

Standeven

Philippou

et al. 2009

Blood

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Section: Determinants Of the ␥A/␥ Fibrinogen Levelsupporting

confidence: 71%

Section: Fibrinogen ␥ Chain As Modifier Of Thrombosis Riskmentioning

confidence: 95%

Section: Determinants Of the ␥A/␥ Fibrinogen Levelmentioning

confidence: 99%

See 1 more Smart Citation

The pleiotropic role of the fibrinogen γ′ chain in hemostasis

Willige

Standeven

Philippou

et al. 2009

Blood

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“…In particular, the reduced ␥Ј/␥A ratio occurring in certain fibrinogen polymorphisms, such as FGG-H2, was not associated with either acute myocardial infarction (53) or ischemic stroke. Instead, increased ␥Ј levels were shown to be positively associated with an increased risk for both acute myocardial infection and ischemic stroke (54,55). However, this association was shown to be strengthened by the presence of increased levels of plasma fibrinogen concentration (54,55) and by FGG 9340T and FGA 2224G polymorphisms (54,55).…”

Section: Discussionmentioning

confidence: 94%

“…Instead, increased ␥Ј levels were shown to be positively associated with an increased risk for both acute myocardial infection and ischemic stroke (54,55). However, this association was shown to be strengthened by the presence of increased levels of plasma fibrinogen concentration (54,55) and by FGG 9340T and FGA 2224G polymorphisms (54,55). Other factors, such as total fibrinogenemia (56), the ability of the ␥Ј chain to protect thrombin by the heparin-antithrombin inhibition (3), and to confer to fibrin clots resistance to fibrinolytic degradation, may represent confounding factors in these studies.…”

Section: Discussionmentioning

confidence: 99%

Fibrinogen-elongated γ Chain Inhibits Thrombin-induced Platelet Response, Hindering the Interaction with Different Receptors

Lancellotti

Rutella

Filippis

et al. 2008

Journal of Biological Chemistry

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The expression of the elongated fibrinogen ␥ chain, termed ␥, derives from alternative splicing of mRNA and causes an insertion sequence of 20 amino acids. This insertion domain interacts with the anion-binding exosite (ABE)-II of thrombin. This study investigated whether and how ␥ chain binding to ABE-II affects thrombin interaction with its platelet receptors, i.e. glycoprotein Ib␣ (GpIb␣), protease-activated receptor (PAR) 1, and PAR4. Both synthetic ␥ peptide and fibrinogen fragment D*, containing the elongated ␥ chain, inhibited thrombin-induced platelet aggregation up to 70%, with IC 50 values of 42 ؎ 3.5 and 0.47 ؎ 0.03 M, respectively. Solid-phase binding and spectrofluorimetric assays showed that both fragment D* and the synthetic ␥ peptide specifically bind to thrombin ABE-II and competitively inhibit the thrombin binding to GpIb␣ with a mean K i ≈ 0.5 and ≈35 M, respectively. Both these ␥ chain-containing ligands allosterically inhibited thrombin cleavage of a synthetic PAR1 peptide, of native PAR1 molecules on intact platelets, and of the synthetic chromogenic peptide D-Phe-pipecolyl-Arg-p-nitroanilide. PAR4 cleavage was unaffected. In summary, fibrinogen ␥ chain binds with high affinity to thrombin and inhibits with combined mechanisms the platelet response to thrombin. Thus, its variations in vivo may affect the hemostatic balance in arterial circulation.Fibrinogen is a key molecule in both primary and secondary hemostasis, because of its role in forming the platelet plug by connecting activated platelets and in forming plasma fibrin clot upon thrombin cleavage. Fibrinogen consists of two symmetric half-molecules, each containing a set of three different polypeptide chains termed A␣, B␤, and ␥. The latter contains several sites that interact with different ligands such as other fibrin(ogen) molecules, coagulation enzymes, growth factors, and integrins (1). The product of thrombin digestion of fibrinogen, i.e. fibrin, binds with a considerable specificity thrombin, so that in the early studies fibrin was termed antithrombin I (2). Thrombin has a divalent interaction with two classes of binding sites on fibrin, one of low affinity in the E domain and the other of high affinity in the D domain of fibrin(ogen) molecules (3). Binding of thrombin to fibrinogen involves sequences of both A␣ and B␤ chain, which contain recognition sites in the fibrinogen E domain. These recognition sites are still able to interact with thrombin after cleavage of fibrinopeptide A and B and form the low affinity binding site for the enzyme. The D domains contain a ␥ chain variant, termed ␥Ј, arising from an alternative mRNA splicing (4), resulting in an elongated chain composed of 427 instead of 411 residues. The inserted region at the C terminus is composed of 20 amino acids ( 408 VRPEH-PAETEYDSLYPEDDL 427 ), rich of acidic side chains and two sulfate anions linked to Tyr 418 and Tyr 422 (5). The elongated ␥ chain, termed ␥Ј, mainly heterodimerizes in the fibrinogen molecule with the more abundant ␥A chain, thus generating ...

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Fibrin Matrices as (Injectable) Biomaterials: Formation, Clinical Use, and Molecular Engineering

Roberts

Bukhary

Leon‐Valdivieso

et al. 2019

Macromolecular Bioscience

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This review focuses on fibrin, starting from biological mechanisms (its production from fibrinogen and its enzymatic degradation), through its use as a medical device and as a biomaterial, and finally discussing the techniques used to add biological functions and/or improve its mechanical performance through its molecular engineering. Fibrin is a material of biological (human, and even patient's own) origin, injectable, adhesive, and remodellable by cells; further, it is nature's most common choice for an in situ forming, provisional matrix. Its widespread use in the clinic and in research is therefore completely unsurprising. There are, however, areas where its biomedical performance can be improved, namely achieving a better control over mechanical properties (and possibly higher modulus), slowing down degradation or incorporating cell-instructive functions (e.g., controlled delivery of growth factors).

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Elevated plasma fibrinogen γ′ concentration is associated with myocardial infarction: effects of variation in fibrinogen genes and environmental factors

Cited by 88 publications

References 27 publications

The pleiotropic role of the fibrinogen γ′ chain in hemostasis

The pleiotropic role of the fibrinogen γ′ chain in hemostasis

Fibrinogen-elongated γ Chain Inhibits Thrombin-induced Platelet Response, Hindering the Interaction with Different Receptors

Fibrin Matrices as (Injectable) Biomaterials: Formation, Clinical Use, and Molecular Engineering

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