Comparative Study on the Antithrombotic Efficacy of Four Low-Molecular-Weight Heparins in Three Different Models of Experimental Venous Thrombosis

Monreal, Manuel; Silveira, Pierre Galvagni; Monreal, Luís; Monasterio, J; Anglés, A.; Lafoz, E.; Lorente, Laura

doi:10.1159/000216209

Cited by 11 publications

(7 citation statements)

References 19 publications

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“…The rats were anaesthetized and opened abdomen by a midline incision. IVC thrombosis was performed with IVC ligation below the level of the renal veins [40][41][42]. Three hours after the ligation, saline with or without drugs (31.5 pmol/kg) was administered through a catheter inserted into the jugular vein.…”

Section: Thrombolytic Activity Of Sfh In Inferior Vena Cava (Ivc) Thrmentioning

confidence: 99%

Locally activity-released bifunctional fusion protein enhances antithrombosis and alleviates bleeding risk

Shi

Yu²,

Liu³

et al. 2007

J Thromb Thrombolysis

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Despite the fact that lytic therapy of thromboembolic disorder has been achieved, reocclusion of the damaged vessels and bleeding complication frequently reduce the therapeutic effect. In order to prevent the vessel reocclusion and enhance the therapeutic effect, combining the anticoagulant with the thrombolytic was assumed. Herein, we propose that restraining but locally releasing anticoagulant activity in the vicinity of thrombus is a way to alleviate the bleeding risk. A bifunctional fusion protein, termed as SFH (Staphylokinase (SAK) linked by FXa recognition peptide at N-terminus of Hirudin (HV)), was designed. SFH retained thrombolytic activity but no anticoagulant activity in thrombus-free blood due to the extension of the N-terminus of HV. However, it could locally liberate intact HV and exhibit anticoagulant activity when FXa or fresh thrombus was present. At equimolar dose, both improved antithrombotic and thrombolytic effects of SFH were observed in kappa-carrageenin inducing mouse-tail thrombosis model and rat inferior vena cava thrombosis model, respectively. Moreover, we observed significantly lower bleeding risk in mice and rats treated with SFH than with the mixture of SAK and HV with monitoring TT (P < 0.01), aPTT (P < 0.05) and PT (P < 0.05), and bleeding time (P < 0.05). In conclusion, SFH is a promising bifunctional therapeutic candidate with lower bleeding risk.

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Section: Thrombolytic Activity Of Sfh In Inferior Vena Cava (Ivc) Thrmentioning

confidence: 99%

Locally activity-released bifunctional fusion protein enhances antithrombosis and alleviates bleeding risk

Shi

Yu²,

Liu³

et al. 2007

J Thromb Thrombolysis

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“…A lack of correlation between plasma anti-Xa activity and antithrombotic effect has also been demonstrated for other heparin-like oligosaccharides (20). Similarly, over recent years, it has become apparent that neither the observed inhibition of factor Xa nor that of thrombin are sufficient to explain the antithrombotic effect of LMWH and the relevance of this is the subject of much debate (21,22,23). Much of the apparent confusion has probably arisen from the comparison of the kinetics of plasma anti-Xa and anti-IIa activities and the observed antithrombotic effect.…”

Section: Discussionmentioning

confidence: 99%

The Antithrombotic Potential of Dalteparin in Man Assessed Indirectly by Wessler’s Technique

et al. 1996

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SummaryThe aim of this study was to demonstrate the effectiveness of a new experimental approach for assessing the antithrombotic potential of low molecular weight heparins (LMWH) such as dalteparin. In this approach, sera obtained from healthy volunteers treated with various i.v. doses of dalteparin (30, 60 or 120 anti-Xa IU/kg) or placebo (physiological saline) were used as the thrombogenic challenge in a Wessler’s stasis model of experimental venous thrombosis in the rat. Sera from placebo-treated volunteers showed a stable thrombogenic activity (0.25 ml/kg of serum producing thrombi of about 50 mg wet weight). Sera from healthy volunteers having previously received dalteparin however demonstrated dose- and time-related reductions in their thrombogenic activity. Half-lives of these effects were 300, 444 and >480 min for 30,60 and 120 anti-Xa IU/kg dalteparin respectively. These values were significantly higher than the corresponding anti-Xa and anti-IIa half-lives.

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“…The thrombolytic effect and bleeding risk of STH were evaluated with clot weights and two anticoagulant parameters, activated partial thromboplastin time (APTT) and thrombin time (TT), in a modified IVC thrombosis model (18,19). In brief, after anesthesia, the left jugular vein of the rat was separated and cannulated for drug administration and blood collection.…”

Section: Thrombolytic Effect and Bleeding Risk Of Sth In Vivo Inferiomentioning

confidence: 99%

A fusion protein with improved thrombolytic effect and low bleeding risk

Wang¹,

Zhang²,

Wang³

et al. 2009

Thromb Haemost

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To resolve the therapeutic dilemma between efficacy of thrombolysis and bleeding risk associated with the use of a combination of thrombolytic and anticoagulant treatments, we created a fusion protein. Staphylokinase was fused to the N-terminus of hirudin using thrombin recognition sequence as linker peptide, resulting in a fusion protein STH. We hypothesised that STH would be cleaved by thrombin at the thrombus site, releasing staphylokinase and hirudin to perform bifunctionally, and attenuating bleeding risk. SDS-PAGE and Western blot analyses indicated that the linker peptide could be specially recognised and cleaved by thrombin. Amidolytic and thromboelastogram assays showed that the N-terminus of hirudin in STH was blocked by staphylokinase and linker peptide, impeding hirudin's anticoagulant activity. Once cleaved, STH displayed 35.7% of the anticoagulant activity of equimolar hirudin and exhibited anticoagulant effects in the fibrin clot lysis assay. Thrombin-binding and fibrin clot lysis assays showed that the C-terminus of hirudin retained its high affinity for thrombin. Moreover, STH showed improved thrombolytic effects and a lower bleeding risk in animals. Thus, STH may have the capacity to perform bifunctionally and release anticoagulant activity in a thrombus-targeted manner in vivo, which may reduce the bleeding risk that often accompanies high thrombolytic efficacy in the treatment of thromboembolic diseases.

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Comparative Study on the Antithrombotic Efficacy of Four Low-Molecular-Weight Heparins in Three Different Models of Experimental Venous Thrombosis

Cited by 11 publications

References 19 publications

Locally activity-released bifunctional fusion protein enhances antithrombosis and alleviates bleeding risk

Locally activity-released bifunctional fusion protein enhances antithrombosis and alleviates bleeding risk

The Antithrombotic Potential of Dalteparin in Man Assessed Indirectly by Wessler’s Technique

A fusion protein with improved thrombolytic effect and low bleeding risk

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