Characterization of the Binding of Factor Xa to Fibrinogen/Fibrin Derivatives and Localization of the Factor Xa Binding Site on Fibrinogen

Iino, Masaki; Takeya, Hiroyuki; Takemitsu, Tetsushi; Nakagaki, Tomohiro; Gabazza, Esteban C.; Suzuki, Koji

doi:10.1111/j.1432-1033.1995.tb20785.x

Cited by 18 publications

(11 citation statements)

References 35 publications

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“…A vitamin K‐dependent clotting factor, Xa , has been shown to bind to fibrin and to fibrin/fibrinogen degradation products 136. Xa bound specifically to a peptide corresponding to Aα 82D to 123K, a site that is located between the E and D domains, and quite distinct from the thrombin binding sites.…”

Section: Other Binding Interactionsmentioning

confidence: 99%

“…135 A vitamin K-dependent clotting factor, Xa, has been shown to bind to fibrin and to fibrin/fibrinogen degradation products. 136 Xa bound specifically to a peptide corresponding to Aα 82D to 123K, a site that is located between the E and D domains, and quite distinct from the thrombin binding sites. Tissue factor pathway inhibitor binds to fibrin via a C-terminal region that is rich in Arg and Lys residues, but the location of the binding site in fibrin has not been determined.…”

Section: Other Binding Interactionsmentioning

confidence: 99%

See 1 more Smart Citation

The Structure and Biological Features of Fibrinogen and Fibrin

Mosesson

Siebenlist

Meh

2001

Annals of the New York Academy of Sciences

561

349

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Fibrinogen and fibrin play important, overlapping roles in blood clotting, fibrinolysis, cellular and matrix interactions, inflammation, wound healing, and neoplasia. These events are regulated to a large extent by fibrin formation itself and by complementary interactions between specific binding sites on fibrin(ogen) and extrinsic molecules including proenzymes, clotting factors, enzyme inhibitors, and cell receptors. Fibrinogen is comprised of two sets of three polypeptide chains termed Aα, Bβ, and γ, that are joined by disulfide bridging within the N‐terminal E domain. The molecules are elongated 45‐nm structures consisting of two outer D domains, each connected to a central E domain by a coiled‐coil segment. These domains contain constitutive binding sites that participate in fibrinogen conversion to fibrin, fibrin assembly, crosslinking, and platelet interactions (e.g., thrombin substrate, Da, Db, γXL, D:D, αC, γA chain platelet receptor) as well as sites that are available after fibrinopeptide cleavage (e.g., E domain low affinity non‐substrate thrombin binding site); or that become exposed as a consequence of the polymerization process (e.g., tPA‐dependent plasminogen activation). A constitutive plasma factor XIII binding site and a high affinity non‐substrate thrombin binding site are located on variant γ′ chains that comprise a minor proportion of the γ chain population. Initiation of fibrin assembly by thrombin‐mediated cleavage of fibrinopeptide A from Aα chains exposes two EA polymerization sites, and subsequent fibrinopeptide B cleavage exposes two EB polymerization sites that can also interact with platelets, fibroblasts, and endothelial cells. Fibrin generation leads to end‐to‐middle intermolecular Da to EA associations, resulting in linear double‐stranded fibrils and equilaterally branched trimolecular fibril junctions. Side‐to‐side fibril convergence results in bilateral network branches and multistranded thick fiber cables. Concomitantly, factor XIII or thrombin‐activated factor XIIIa introduce intermolecular covalent ε‐(γ glutamyl)lysine bonds into these polymers, first creating γ dimers between properly aligned C‐terminal γXL sites, which are positioned transversely between the two strands of each fibrin fibril. Later, crosslinks form mainly between complementary sites on γ chains (forming γ‐polymers), and even more slowly among γ dimers to create higher order crosslinked γ trimers and tetramers, to complete the mature network structure.

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Section: Other Binding Interactionsmentioning

confidence: 99%

Section: Other Binding Interactionsmentioning

confidence: 99%

The Structure and Biological Features of Fibrinogen and Fibrin

Mosesson

Siebenlist

Meh

2001

Annals of the New York Academy of Sciences

561

349

View full text Add to dashboard Cite

show abstract

“…We showed in this study that factor Xa induced mesangial cell proliferation and plays the important role in the coagulation cascades by the result of fibrin deposition on the mesangial surface, and that factor Xa could cause a mitogenic effect in an ERK-dependent manner in human mesangial cells. It is assumed that factor Xa binds to the fibrin clot and thereby contributes to further activation of the coagulation system [46][47][48]. After factor Xa stimulates fibrin deposition through the formation of thrombinase, clot-binding factor Xa continues to activate prothrombin to thrombin.…”

Section: Discussionmentioning

confidence: 99%

Role of coagulation factor Xa and protease-activated receptor 2 in human mesangial cell proliferation

Tanaka¹,

Arai²,

Liu³

et al. 2005

Kidney International

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“…Slightly modified from Weitz prothrombinase (FX/FVa/phospholipids and Ca++) activate prothrombin resulting in sustained thrombin generation. This procedure is thought to be important for the thrombogenicity of blood clots [16,17]. Clot-bound FXa and thrombin are not accessible to the inhibitory effect of AT and the ATdependent FXa inhibitors (i.e., fondaparinux and heparin) or thrombin inhibitors (i.e., heparins).…”

Section: The Physiological Importance Of Fibrin Bound Fxa and Thrombinmentioning

confidence: 99%

Heterogeneity of Synthetic Factor Xa Inhibitors

Gerotziafas

Samama²

2005

CPD

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Heparins and vitamin K antagonists are the landmarks of antithrombotic treatment. Both of them were discovered by serendipity; they are multi-targeted drugs and share several limitations. New molecules have been designed in order to be both more selective concerning their biological target and more homogeneous in their biochemical structure aiming at an improved benefit/risk ratio in the treatment of thrombotic disease. In this article, we will review the pharmacological characteristics of the new synthetic direct or antithrombin dependent inhibitors of FXa in the light of the modern concept of blood coagulation process. We will also present the most recent data from the clinical trials with synthetic inhibitors of FXa. Among them, the synthetic pentasaccharide fondaparinux is the first synthetic and specific FXa inhibitor, which has been approved by health authorities in Europe and in the USA for the prophylaxis of venous thromboembolism in major orthopaedic surgery and is being approved for the treatment of pulmonary embolism and DVT as a single daily subcutaneous injection. The phase II dose-finding trial of the "meta-pentasaccharide" idraparinux administered subcutaneously once weekly in the secondary prevention of VTE has been completed. DX-9065a is the first direct synthetic inhibitor which has been studied in patients with coronary disease. Razaxaban, BAY59-7939, ZK-807834 and JTV-803 are orally active direct FXa inhibitors, which have been studied in phase II trials. Several other synthetic direct inhibitors of FXa (such as FXV673, YM60828, KFA-1411) are in a pre-clinical stage of research. From a clinical point of view, the results of recent trials with the synthetic specific FXa inhibitors clearly show that the inhibition of FXa is a critical point in the antithrombotic strategy.

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Characterization of the Binding of Factor Xa to Fibrinogen/Fibrin Derivatives and Localization of the Factor Xa Binding Site on Fibrinogen

Cited by 18 publications

References 35 publications

The Structure and Biological Features of Fibrinogen and Fibrin

The Structure and Biological Features of Fibrinogen and Fibrin

Role of coagulation factor Xa and protease-activated receptor 2 in human mesangial cell proliferation

Heterogeneity of Synthetic Factor Xa Inhibitors

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