scholarly journals Structure and anticoagulant properties of sulfated glycosaminoglycans from primitive Chordates

2002 ◽  
Vol 74 (1) ◽  
pp. 105-112 ◽  
Author(s):  
MAURO S. G. PAVÃO
Keyword(s):  
Dermatan Sulfate ◽  
Thrombus Formation ◽  
Anticoagulant Activity ◽  
The Body ◽  
Heparin Cofactor Ii ◽  
Styela Plicata ◽  
Iduronic Acid ◽  
Bleeding Effect

Dermatan sulfates and heparin, similar to the mammalian glycosaminoglycans, but with differences in the degree and position of sulfation were previously isolated from the body of the ascidian Styela plicata and Ascidia nigra. These differences produce profound effects on their anticoagulant properties. S. plicata dermatan sulfate composed by 2-O-sulfatedalpha-L-iduronic acid and 4-O-sulfated N-acetyl-beta-D-galactosamine residues is a potent anticoagulant due to a high heparin cofactor II activity. Surprisingly, it has a lower potency to prevent thrombus formation on an experimental model and a lower bleeding effect in rats than the mammalian dermatan sulfate. In contrast, A. nigra dermatan sulfate, also enriched in 2-O-sulfated alpha-L-iduronic acid, but in this case sulfated at O-6 of the N-acetyl-beta-D-galactosamine units, has no in vitro or in vivo anticoagulant activity, does not prevent thrombus formation but shows a bleeding effect similar to the mammalian glycosaminoglycan. Ascidian heparin, composed by 2-O-sulfated alpha-L-iduronic acid, N- and 6-O-sulfated glucosamine (75%) and alpha-L-iduronic acid, N- and 6-O-sulfated glucosamine (25%) disaccharide units has an anticoagulant activity 10 times lower than the mammalian heparin, is about 20 times less potent in the inhibition of thrombin by antithrombin, but has the same heparin cofactor II activity as mammalian heparin.

Unbalanced Effects of Dermatan Sulfates with Different Sulfation Patterns on Coagulation, Thrombosis and Bleeding

2001 ◽  
Vol 86 (11) ◽  
pp. 1215-1220 ◽  
Author(s):  
C. P. Vicente ◽  
P. Zancan ◽  
L. L. Peixoto ◽  
R. Alves-Sá ◽  
F. S. Araújo ◽  
...  
Keyword(s):  
Dermatan Sulfate ◽  
Thrombus Formation ◽  
Anticoagulant Activity ◽  
Sulfated Polysaccharides ◽  
Heparin Cofactor Ii ◽  
Iduronic Acid ◽  
Bleeding Effect ◽  
Mammalian Counterpart

SummaryWe compared the anticoagulant, antithrombotic and bleeding effects of highly sulfated dermatan sulfates from invertebrates and their mammalian counterpart. An invertebrate dermatan sulfate containing 2-O-sulfated α-L-iduronic acid and 4-O-sulfated N-acetyl-β-D-galactosamine residues is a potent anticoagulant due to a high heparin cofactor II activity. It inhibits thrombin due to the formation of a covalent complex with heparin cofactor II, as in the case of mammalian dermatan sulfate, but the effect occurs at lower concentrations for the invertebrate polysaccharide. Surprisingly, the invertebrate dermatan sulfate has a lower potency to prevent thrombus formation on an experimental model and a lower bleeding effect in rats than the mammalian dermatan sulfate. In contrast, another invertebrate dermatan sulfate, also enriched in 2-O-sulfated α-L-iduronic acid, but in this case sulfated at O-6 position of the N-acetyl-β-D-galactosamine units, has no in vitro or in vivo anticoagulant activity, does not prevent thrombus formation but shows a bleeding effect similar to the mammalian glycosaminoglycan. Overall, these results demonstrate unbalanced effects of dermatan sulfates with different sulfation patterns on coagulation, thrombosis and bleeding, and raise interesting questions concerning the relationship among these three biological actions of sulfated polysaccharides.

scholarly journals Antithrombotic properties of a dermatan sulfate hexadecasaccharide fractionated by affinity for heparin cofactor II

Blood ◽  
1993 ◽  
Vol 81 (7) ◽  
pp. 1771-1777 ◽  
Author(s):  
P Sie ◽  
D Dupouy ◽  
C Caranobe ◽  
M Petitou ◽  
B Boneu
Keyword(s):  
Catalytic Activity ◽  
Dermatan Sulfate ◽  
Anticoagulant Activity ◽  
Gel Filtration ◽  
Heparin Cofactor Ii ◽  
High Affinity ◽  
Suitable Target ◽  
The Relationship

Abstract The relationship between the antithrombotic activity of dermatan sulfate (DS) in vivo and its catalytic effect on the inhibition of thrombin by heparin cofactor II (HC II) in vitro was investigated. DS was depolymerized by Smith degradation and the fragments obtained were separated by gel filtration. The fragment of minimal size with full catalytic activity was a hexadecasaccharide, which was further fractionated by affinity for immobilized HC II. Only a small proportion by weight (6.7%) was recovered in the high-affinity fraction, which had about 10 times more catalytic activity than the unfractionated oligosaccharide; the change in activity was primarily caused by the removal of inert materials, recovered in the low-affinity fraction. 1H- NMR spectra indicated strengthening of the signal given by Ido A (2S04) in the high-affinity fraction compared with that of the low-affinity fraction. The anticoagulant activity of the high-affinity fraction was exclusively HC II-dependent. The antithrombotic potency was evaluated in rabbits using the Wessler-thromboplastin model. Half-maximal prevention of thrombosis was obtained after injection of 250 micrograms/kg DS, of 500 micrograms/kg hexadecasaccharide, or of 60 micrograms/kg of its high-affinity fraction. The low-affinity fraction was ineffective at the highest dose tested (1,200 micrograms/kg) and did not potentiate the effect of the high-affinity fraction. These results show that the antithrombotic effect of DS is essentially dependent on HC II binding and activation and that HC II is therefore a suitable target for antithrombotic drugs.

scholarly journals Antithrombotic properties of a dermatan sulfate hexadecasaccharide fractionated by affinity for heparin cofactor II

Blood ◽  
1993 ◽  
Vol 81 (7) ◽  
pp. 1771-1777
Author(s):  
P Sie ◽  
D Dupouy ◽  
C Caranobe ◽  
M Petitou ◽  
B Boneu
Keyword(s):  
Catalytic Activity ◽  
Dermatan Sulfate ◽  
Anticoagulant Activity ◽  
Gel Filtration ◽  
Heparin Cofactor Ii ◽  
High Affinity ◽  
Suitable Target ◽  
The Relationship

The relationship between the antithrombotic activity of dermatan sulfate (DS) in vivo and its catalytic effect on the inhibition of thrombin by heparin cofactor II (HC II) in vitro was investigated. DS was depolymerized by Smith degradation and the fragments obtained were separated by gel filtration. The fragment of minimal size with full catalytic activity was a hexadecasaccharide, which was further fractionated by affinity for immobilized HC II. Only a small proportion by weight (6.7%) was recovered in the high-affinity fraction, which had about 10 times more catalytic activity than the unfractionated oligosaccharide; the change in activity was primarily caused by the removal of inert materials, recovered in the low-affinity fraction. 1H- NMR spectra indicated strengthening of the signal given by Ido A (2S04) in the high-affinity fraction compared with that of the low-affinity fraction. The anticoagulant activity of the high-affinity fraction was exclusively HC II-dependent. The antithrombotic potency was evaluated in rabbits using the Wessler-thromboplastin model. Half-maximal prevention of thrombosis was obtained after injection of 250 micrograms/kg DS, of 500 micrograms/kg hexadecasaccharide, or of 60 micrograms/kg of its high-affinity fraction. The low-affinity fraction was ineffective at the highest dose tested (1,200 micrograms/kg) and did not potentiate the effect of the high-affinity fraction. These results show that the antithrombotic effect of DS is essentially dependent on HC II binding and activation and that HC II is therefore a suitable target for antithrombotic drugs.

scholarly journals Vascular dermatan sulfate regulates the antithrombotic activity of heparin cofactor II

Blood ◽  
2008 ◽  
Vol 111 (8) ◽  
pp. 4118-4125 ◽  
Author(s):  
Li He ◽  
Tusar K. Giri ◽  
Cristina P. Vicente ◽  
Douglas M. Tollefsen
Keyword(s):  
Carotid Artery ◽  
Dermatan Sulfate ◽  
Thrombus Formation ◽  
Wild Type ◽  
Heparin Cofactor Ii ◽  
Arterial Endothelium ◽  
Carotid Arterial ◽  
Deficient Mice

AbstractHeparin cofactor II (HCII)–deficient mice form occlusive thrombi more rapidly than do wild-type mice following injury to the carotid arterial endothelium. Dermatan sulfate (DS) and heparan sulfate (HS) increase the rate of inhibition of thrombin by HCII in vitro, but it is unknown whether vascular glycosaminoglycans play a role in the antithrombotic effect of HCII in vivo. In this study, we found that intravenous injection of either wild-type recombinant HCII or a variant with low affinity for HS (K173H) corrected the abnormally short thrombosis time of HCII-deficient mice, while a variant with low affinity for DS (R189H) had no effect. When HCII was incubated with frozen sections of the mouse carotid artery, it bound specifically to DS in the adventitia. HCII was undetectable in the wall of the uninjured carotid artery, but it became concentrated in the adventitia following endothelial injury. These results support the hypothesis that HCII interacts with DS in the vessel wall after disruption of the endothelium and that this interaction regulates thrombus formation in vivo.

INFLUENCE OF THE SULFATION PATTERN ON CERTAIN BIOLOGICAL PROPERTIES OF GALACTOSAMINOGLYCANS

1987 ◽  
Author(s):  
B Casu ◽  
L Marchese ◽  
A Naggi ◽  
G Torri ◽  
J Fareed ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Dermatan Sulfate ◽  
Anticoagulant Activity ◽  
Chlorosulfonic Acid ◽  
Biological Properties ◽  
Sulfated Polysaccharides ◽  
Low Molecular Weight ◽  
Antithrombotic Activity

In order to investigate the influence of charge distribution and chain length on the biological properties of sulfated polysaccharides, additional sulfate groups were introduced into the galactosaminoglycans, chondriotin sulfate and dermatan sulfate. Using a flexible method (with sulfuric acid and chlorosulfonic acid) for concurrent sulfation and controlled depolymerization, numerous products were obtained and characterized by chemical, enzymatic and nuclear magnetic resonance spectroscopic methods. The biologic actions of these products were profiled in both in vitro and in vivo assays for antithrombotic activity. Despite a weaker in vitro anticoagulant activity, low molecular weight over sulfated galactosaminoglycans produced significant dose-dependent antithrombotic actions in animal models which were similar to the actions observed with oversulfated low molecular weight heparins. These results suggest that a significant antithrombotic activity can be elicited through non-specific interactions of polysulfates with cellular and plasma components, and that clusters of sulfate groups such as the 4-6 disulfate group on D-galactosaminoglycan residues may be important for these interactions. Furthermore, these results, also suggest that supersulfation of glycosaminogly-cans results in products with biologic activity distinct from the native material.

INCREASED SULFATION IMPROVES THE ABILITY OF VESSEL WALL GLYCOSA-MINOGLYCANS TO REGULATE THROMBIN ACTIVITY AND PROTHROMBIN ACTIVATION IN PLASMA

1987 ◽  
Author(s):  
F A Ofosu ◽  
G J Modi ◽  
M A Blajchman ◽  
M R Buchanan ◽  
E A Johnson
Keyword(s):  
Vessel Wall ◽  
Dermatan Sulfate ◽  
Heparin Cofactor Ii ◽  
Thrombin Inhibition ◽  
Antithrombotic Effects ◽  
The Relationship ◽  
Functional Attribute ◽  
Prothrombin Activation

Studies have shown that dermatan sulfate (DS), heparan sulfate (HS) and chondroitin-4-sulfate (C4S), have antithrombotic properties. The sulfate to carboxylate ratios of these three glycosaminoglycans (GAGs) are approximately half that of heparin (HEP) and the gravimetric dose of each of the three GAGs required to achieve antithrombotic effects in vivo comparable to HEP can be 10 times or more than that of HEPT Since antithrombotic effects depend on the ability of a GAG to catalyse thrombin inhibition and/or to inhibit prothrombin activation, we determined the relationship between the extent of sulfation of various GAGs and their effects on these two reactions in normal plasma. In addition to the three GAGs, DS, HS and C4S were resulfated in vitro to yield DS-S, HS-S and C4S-S, each with a sulfate to carboxylate ratio comparable to that of heparin. As summarized below, increased sulfation improved the ability of a GAG to catalyse thrombin inhibition and to inhibit prothrombin activation. Increasing the degree of sulfation primarily improved the ability of a GAG to accelerate the inhibition of thrombin by heparin cofactor II. The degree of sulfation, therefore, appears to be an important functional attribute of the ability of vessel wall GAGs to regulate the formation and activity of thrombin in plasma.

Prevention of Intravascular Thrombus Formation on Plastic Catheters with Heparin-Benzalkonium Complex: in Vivo and in Vitro Studies

1979 ◽  
Vol 41 (03) ◽  
pp. 537-543
Author(s):  
Roger W Evans ◽  
Mark W Pasmantier ◽  
Morton Coleman ◽  
Franklin S Wagner ◽  
Robert C Flair
Keyword(s):  
Organic Solvent ◽  
Thrombus Formation ◽  
Anticoagulant Activity ◽  
Model System ◽  
Quaternary Ammonium Compound ◽  
Ammonium Compound ◽  
In Vitro Testing ◽  
In Vivo Animal Model

SummaryA complex of heparin and a quaternary ammonium compound dissolved in an organic solvent was investigated for its potential ability to prevent clotting on the surface of plastic catheters. Despite the complexing of heparin to ammonium, anticoagulant activity remained on in vitro testing. Both the heparin complex and its organic solvent alone partially prevented catheter thrombus formation when tested in an in vivo animal model system. Neither, however, was totally effective in preventing thrombosis.

scholarly journals Nanoencapsulation Enhances Anticoagulant Activity of Adenosine and Dipeptide IleTrp

Nanomaterials ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 1191
Author(s):  
Trung Dinh Nguyen ◽  
The Ngoc Nguyen ◽  
Trang Thuy Thi Nguyen ◽  
Igor A. Ivanov ◽  
Khoa Cuu Nguyen ◽  
...  
Keyword(s):  
Biological Activity ◽  
Bleeding Time ◽  
Anticoagulant Activity ◽  
The Body ◽  
Clot Formation ◽  
Pluronic P123 ◽  
Transmission Electron ◽  
Clot Formation Time

It is well-known that drugs administered into an organism intravenously or through the gastrointestinal tract are degraded by enzymes of the body, reducing their therapeutic effect. One of the ways to decrease this undesirable process is through the inclusion of drugs in nanomaterials. Earlier strong anticoagulant activity was demonstrated for dipeptide IleTrp (IW) and adenosine (Ado). In this work, the effect of inclusion in nanomaterials on the biological activity of IW and Ado was studied. For this purpose, Ado and IW were incorporated into thermosensitive nanogel composed of pluronic P123-grafted heparin. The prepared nanocarrier was characterized by transmission electron microscopy, dynamic light scattering, and ζ-potential. Biological activity was determined by measuring the bleeding time from mouse tail in vivo and the time of clot formation in vitro. It was found that encapsulation of Ado and IW into nanomaterial significantly increased their effects, resulting in an increase in the bleeding time from mouse tail and clot formation time. Thus, inclusion of low molecular weight anticoagulants Ado and IW into nanomaterials may be considered a way to increase their biological activity.

Impaired Fibrinolysis as an Essential Contribution to Thrombosis in Patients with Lupus Anticoagulant

1989 ◽  
Vol 61 (02) ◽  
pp. 175-177 ◽  
Author(s):  
D A Tsakiris ◽  
G A Marbet ◽  
P E Makris ◽  
L Settas ◽  
F Duckert
Keyword(s):  
Defense Mechanism ◽  
Anticoagulant Activity ◽  
Plasminogen Activator Inhibitor ◽  
Control Group ◽  
Heparin Cofactor Ii ◽  
Significant Difference ◽  
Essential Contribution ◽  
Activator Inhibitor

SummaryLupus anticoagulants (LA) are IgG or IgM antibodies against phospholipids which in vivo represent an important thrombophilic factor despite their in vitro anticoagulant activity. We investigated the fibrinolytic system of 20 patients with connective tissue disease and positive LA, compared to a control group of 24 age- and disease-matched patients without LA. There was no statistically significant difference of alpha2-antiplasmin, plasminogen, fibrinogen, t-PA activity, D-dimers and heparin cofactor II, between the two groups. Although t-PA was uniformly low in both groups, plasminogen activator inhibitor activity (PAI) was significantly higher in LA cases (p <0.001). Increased PAI levels represent an inhibitory factor of the fibrinolytic defense mechanism, which together with other functional deviations may contribute to the thrombophilic tendency of LA patients.

scholarly journals Antithrombotic Effect and Mechanism of Radix Paeoniae Rubra

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Pingyao Xie ◽  
Lili Cui ◽  
Yuan Shan ◽  
Wen-yi Kang
Keyword(s):  
Protocatechuic Acid ◽  
Thrombus Formation ◽  
Anticoagulant Activity ◽  
Blood Stasis ◽  
Plasma Viscosity ◽  
Antithrombotic Effect ◽  
Active Compounds ◽  
Antithrombotic Effects

The compounds of Radix Paeoniae Rubra (RPR) were isolated and identified by bioassay-guided method, and antithrombotic effects and mechanism were investigated by the acute blood stasis rat model. The RPR extract was evaluated by APTT, TT, PT, and FIB assays in vitro. Results indicated that RPR extract exhibited the anticoagulant activity. In order to find active compounds, six compounds were isolated and identified, and four compounds, paeoniflorin (Pae), pentagalloylglucose (Pen), albiflorin (Ali), and protocatechuic acid (Pro), exhibited the anticoagulant activity in vitro. Therefore, the antithrombosis effects of RPR extract and four active compounds were investigated in vivo by measuring whole blood viscosity (WBV), plasma viscosity (PV), APTT, PT, TT, and FIB. Meanwhile, the levels of TXB2, 6-Keto-PGF1α, eNOS, and ET-1 were detected. Results suggested that RPR extract and four active compounds had the inhibition effect on thrombus formation, and the antithrombotic effects were associated with the regulation of vascular endothelium active substance, activating blood flow and anticoagulation effect.

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