Fucosylated chondroitin sulfate inhibits plasma thrombin generation via targeting of the factor IXa heparin-binding exosite

Buyue, Yang; Sheehan, John P.

doi:10.1182/blood-2009-02-203661

Cited by 57 publications

(57 citation statements)

References 42 publications

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“…This glycosaminoglycan has high anticoagulant properties, which may open new avenues for the development of antithrombotic agents [3,6,7,8]. The sulfated polysaccharide also displays several other pharmacological activities, such as anti-human immunodeficiency virus (anti-HIV) activity [9], attenuation of renal fibrosis through a P-selectin-mediated mechanism [10].…”

Section: Introductionmentioning

confidence: 99%

Preparation and Characterization of O-Acylated Fucosylated Chondroitin Sulfate from Sea Cucumber

Gao

Shao

et al. 2012

Marine Drugs

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Fucosylated chondroitin sulfate (FuCS), a kind of complex glycosaminoglycan from sea cucumber, has potent anticoagulant activity. In order to understand the relationship between structures and activity, the depolymerized FuCS (dFuCS) was chosen to prepare its derivates by selective substitution at OH groups. Its O-acylation was carried out in a homogeneous way using carboxylic acid anhydrides. The structures of O-acylated derivatives were characterized by NMR. The results indicated that the 4-O-sulfated fucose residues may be easier to be acylated than the other ones in the sulfated fucose branches. But the O-acylation was always accompanied by the β-elimination, and the degree of elimination was higher as that of acylation was higher. The results of clotting assay indicated that the effect of partial O-acylation of the dFuCS on their anticoagulant potency was not significant and the O-acylation of 2-OH groups of 4-O-sulfated fucose units did not affect the anticoagulant activity.

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Section: Introductionmentioning

confidence: 99%

Preparation and Characterization of O-Acylated Fucosylated Chondroitin Sulfate from Sea Cucumber

Gao

Shao

et al. 2012

Marine Drugs

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“…1), which is a complex acidic polysaccharide isolated from sea cucumber, has recently attracted considerable attention because of its various bioactivities (14). Notably, FG has potent anticoagulant and antithrombotic activities due to its inhibition of the intrinsic tenase (15)(16)(17). However, the native polysaccharide has side effects such as factor XII (FXII) activation, platelet aggregation, and serious bleeding (18).…”

mentioning

confidence: 99%

Discovery of an intrinsic tenase complex inhibitor: Pure nonasaccharide from fucosylated glycosaminoglycan

Zhao

Xiao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

116

152

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Selective inhibition of the intrinsic coagulation pathway is a promising strategy for developing safer anticoagulants that do not cause serious bleeding. Intrinsic tenase, the final and rate-limiting enzyme complex in the intrinsic coagulation pathway, is an attractive but less explored target for anticoagulants due to the lack of a pure selective inhibitor. Fucosylated glycosaminoglycan (FG), which has a distinct but complicated and ill-defined structure, is a potent natural anticoagulant with nonselective and adverse activities. Herein we present a range of oligosaccharides prepared via the deacetylationdeaminative cleavage of FG. Analysis of these purified oligosaccharides reveals the precise structure of FG. Among these fragments, nonasaccharide is the minimum fragment that retains the potent selective inhibition of the intrinsic tenase while avoiding the adverse effects of native FG. In vivo, the nonasaccharide shows 97% inhibition of venous thrombus at a dose of 10 mg/kg in rats and has no obvious bleeding risk. This nonasaccharide may therefore serve as a novel promising anticoagulant.T hrombotic disease is seriously harmful to human health and is one of the major causes of death in modern society (1). Despite their long-term and widespread use as anticoagulants, heparin, low-molecular-weight heparin (LMWH), and coumarins still have a major unresolved issue: the risk of serious bleeding during therapy (1-3). It is generally recognized that the risk of bleeding associated with these agents is related to the nonselectivity of their anticoagulant activity. Therefore, selective inhibitors of human factor Xa (FXa) and thrombin (FIIa), such as dabigatran, rivaroxaban, and apixaban, which have predictable pharmacokinetics, have recently been developed; however, these agents have not effectively reduced the risk of bleeding in clinical applications (4-7).Components of the intrinsic coagulation pathway are promising targets for antithrombotic therapy because they are important for thrombosis but are not required for hemostasis (1,8). The development of new anticoagulant agents that inhibit components of the intrinsic pathway and that have a lower risk of causing bleeding has thus become a research focus (9-11). Factor IXa (FIXa), a serine protease, and factor VIIIa (FVIIIa), a protein cofactor, form a Ca 2+ -and phospholipid surface-dependent complex referred to as the intrinsic tenase complex, which efficiently converts zymogen factor X (FX) to FXa (1,12,13). Because the intrinsic tenase is the final and rate-limiting enzyme complex in the intrinsic pathway, the development of inhibitors of this enzyme complex is important for meeting clinical demands (1). However, limited progress has been achieved due to the unavailability of selective inhibitors with welldefined structures.Fucosylated glycosaminoglycan (FG; 1 in Fig. 1), which is a complex acidic polysaccharide isolated from sea cucumber, has recently attracted considerable attention because of its various bioactivities (14). Notably, FG has potent anticoagula...

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“…In contrast, thrombin generation remained unchanged without (checked bar) or with anti-protein S antibody (open bar) in the presence of high TF. As discussed before, thrombin generation is largely independent of fIX in the presence of excess TF (4-5 pmol/L) 32 but highly dependent on fIX in the presence of limiting TF. Our studies further confirmed that protein S inhibits thrombin generation by inhibiting the fIX pathway of fX generation.…”

Section: Effect Of Protein S On Thrombin Generation Initiated By Limimentioning

confidence: 70%

“…The magnitude of plasma thrombin generation is highly dependent on fIX in the presence of limiting TF (0.2-0.4 pmol/L) and largely independent of fIX in the presence of excess TF (≈4-5 pmol/L). 32 With protein S-depleted plasma, addition of increasing concentrations of protein S decreased thrombin generation in the presence of 0.4 pmol/L TF ( Figure 3A). The plot of peak thrombin generation as a function of increasing protein S concentration ( Figure 3A, inset, solid circles) shows that, as protein S concentration increased, thrombin generation progressively decreased.…”

Section: Effect Of Protein S On Thrombin Generation Initiated By Limimentioning

confidence: 93%

“…[30][31][32] To monitor the effect of protein S exclusively on the fVIIa/TF-dependent pathway, protein S-deficient plasma (40 µL) was incubated with Technothrombin RC reagent (10 µL), having a high TF concentration (5 pmol/L TF/8.0 µmol/L phospholipid) and different concentrations of protein S. To determine the effect of protein S on the fIXa/fVIIIa pathway, a thrombin generation assay was performed using Technothrombin RB reagent with a low TF concentration (0.4 pmol/L TF/8 µmol/L phospholipids) instead of RC reagent, in the absence and presence of anti-TFPI inhibitor, keeping all other conditions unchanged. Thrombin generation curves were analyzed to determine peak thrombin generated and total thrombin generated, as described.…”

Section: Thrombin Generation Assaymentioning

confidence: 99%

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Inhibition of Intrinsic Xase by Protein S

Chattopadhyay

Sengupta

Majumder

2012

ATVB

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Objective-Protein S is a vitamin K-dependent plasma protein that functions in the feedback regulation of thrombin generation. Our goal was to determine how protein S regulates the intrinsic pathway of blood coagulation. Methods and Results-We used plasma, including platelet-rich plasma, and in vitro methods to determine how the intrinsic pathway of blood coagulation is regulated by protein S. We obtained the following results: (1) activated partial thromboplastin time assays with protein S-supplemented plasma confirmed that protein S prolongs clotting time; (2) a modified activated partial thromboplastin time assay with factor IX (fIX)-deficient plasma confirmed that protein S affects fIX-initiated clotting; (3) a fIXa/factor VIIIa (fVIIIa)-mediated thrombin generation assay with either platelet-rich plasma or factor-deficient plasma, initiated with a limiting amount of tissue factor, was regulated by protein S; (4) in the presence of phosphatidylserine vesicles, protein S inhibited fIXa in the absence and presence of fVIIIa; and (5) protein S altered only the K M for factor X activation by fIXa in the absence of fVIIIa and both k cat and K M in the presence of fVIIIa. Conclusion-From our findings, it can be concluded that protein S inhibits fIXa in the presence or absence of fVIIIa in an activated protein C-independent way. (Arterioscler Thromb Vasc Biol. 2012;32:2387-2393.)

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Fucosylated chondroitin sulfate inhibits plasma thrombin generation via targeting of the factor IXa heparin-binding exosite

Cited by 57 publications

References 42 publications

Preparation and Characterization of O-Acylated Fucosylated Chondroitin Sulfate from Sea Cucumber

Preparation and Characterization of O-Acylated Fucosylated Chondroitin Sulfate from Sea Cucumber

Discovery of an intrinsic tenase complex inhibitor: Pure nonasaccharide from fucosylated glycosaminoglycan

Inhibition of Intrinsic Xase by Protein S

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