Note on the Adsorption of Thrombin on Fibrin

Seegers, Walter H.; Nieft, Marie; Loomis, Eugene C.

doi:10.1126/science.101.2629.520

Cited by 119 publications

(65 citation statements)

References 6 publications

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“…51,52,55 Studies on ␥A/␥Ј fibrin(ogen) indicated that this binding site functioned as a thrombin inhibitor 56,57 and, importantly, contributed to the antithrombin activity that develops during fibrin formation (antithrombin 1). 58,59 Thrombin interacts with the carboxy terminal sequence of the ␥Ј chain through its exosite 2, 26,27,57 which prevents the participation of this exosite in the binding of thrombin to heparin 60 and which recently was found to be responsible for the observation that thrombin-induced FPA generation was slower with ␥A/␥Ј fibrinogen than with ␥A/␥A fibrinogen. 61 Experiments in which thrombin generation was measured in afibrinogenemia plasma and fibrinogen-depleted plasma supplemented with ␥A/␥A fibrinogen or ␥A/␥Ј fibrinogen showed that ␥A/␥Ј fibrinogen had a more profound effect in down-regulating thrombin generation than ␥A/␥A fibrinogen.…”

Section: Discussionmentioning

confidence: 99%

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

230

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: 99%

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

230

260

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“…One of these involves inhibition of thrombin activity, which was first reported as antithrombin I more than 50 years ago by Seegers et al 26,27 For comprehensive reviews on this topic, see Mosesson. 28,29 The thrombin clotting time was increased by addition of phosphorylated ␥Ј V408-L427 peptide in a purified system, 30 but the ␥Ј peptide was added at a 80-to 320-fold molar excess over ␥A/␥A fibrinogen, compared with a 0.1 molar ratio in vivo.…”

Section: Thrombin Bindingmentioning

confidence: 99%

The pleiotropic role of the fibrinogen γ′ chain in hemostasis

Willige

Standeven

Philippou

et al. 2009

Blood

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“…This haplotype is associated with a significantly increased risk for venous thrombosis (6). Biochemical studies showed that ␥Ј chains bind to ␣-thrombin with high affinity (8) and that the 408 -427 region of ␥Ј chain binds to the anion-binding exosite (ABE) 2 -II of thrombin (1,9). Moreover, fibrinopeptide B cleavage by thrombin from ␥Ј/␥A fibrinogen is slower than in ␥A/␥A fibrinogen (10).…”

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confidence: 99%

“…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).…”

mentioning

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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Note on the Adsorption of Thrombin on Fibrin

Cited by 119 publications

References 6 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

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

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