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Job Harenberg - One of the best experts on this subject based on the ideXlab platform.

B J Biemond - One of the best experts on this subject based on the ideXlab platform.

  • enhancement of rabbit jugular vein thrombolysis by neutralization of factor xi in vivo evidence for a role of factor xi as an anti fibrinolytic factor
    Journal of Clinical Investigation, 1998
    Co-Authors: M C Minnema, Laurent O Mosnier, Philip W Friederich, Marcel Levi, P A K Von Dem Borne, B J Biemond, C E Hack, B N Bouma, Ten H Cate
    Abstract:

    Recent in vitro studies have shown that fibrinolytic activity may be attenuated by a thrombin-activatable fibrinolysis inhibitor (TAFI), which is activated by thrombin, generated via the intrinsic pathway of coagulation in a factor XI-dependent way. Thus factor XI may play a role in the regulation of endogenous fibrinolysis. The aim of this study was to investigate the effect of in vivo inhibition of factor XI and TAFI in an experimental Thrombosis Model in rabbits. Incorporation of anti-factor XI antibodies in jugular vein thrombi resulted in an almost twofold increase in endogenous thrombolysis compared with a control antibody. A similar effect was observed when the anti-factor XI antibody was administered systemically. Inhibition of TAFI activity also resulted in a twofold increase in clot lysis whereas inhibition of both factor XI and TAFI activity had no additional effect. Thus, we provide the first in vivo evidence for enhanced thrombolysis through inhibition of clotting factor XI, demonstrating a novel role for the intrinsic pathway of coagulation. Furthermore we demonstrate that inhibition of TAFI had a similar effect on thrombolysis. We postulate that inhibition of factor XI activity enhances thrombolysis because of diminished indirect activation of TAFI.

  • apolipoprotein a attenuates endogenous fibrinolysis in the rabbit jugular vein Thrombosis Model in vivo
    Circulation, 1997
    Co-Authors: B J Biemond, Philip W Friederich, Marcel Levi, Marlys L Koschinsky, Waheed Sangrar, Harry R Buller, Jan Ten W Cate
    Abstract:

    Background In many case-control as well as epidemiological studies, increased lipoprotein(a) [Lp(a)] levels are considered to constitute an independent risk factor for premature coronary artery and cerebrovascular disease. Lp(a) resembles an LDL particle with an additional linked protein [apolipoprotein(a), apo(a)], whose molecular structure has been demonstrated to be homologous to the fibrinolytic proenzyme plasminogen. Because of the high similarity between plasminogen and apo(a), apo(a) may potentially interfere in the fibrinolytic system by competing with plasminogen for fibrin binding sites. In vitro studies have demonstrated that Lp(a) indeed competes with plasminogen binding to fibrin and inhibits tissue plasminogen activator (TPA)-mediated activation of plasminogen. No direct in vivo studies to test this hypothesis have been performed. Methods and Results To test this hypothesis, we studied the effect of a recombinant form of apo(a) on endogenous and TPA-mediated thrombolysis in an in vivo Model of experimental venous Thrombosis. Thrombi containing either 16 μg r-apo(a), 8 μg r-apo(a), or vehicle (HEPES-buffered saline, control) were formed in the jugular veins of a rabbit and showed significantly reduced endogenous thrombolysis after 60 minutes in a dose-dependent fashion, ID 2.7±0.9% and 4.6±1.8%, respectively, versus 7.4±1.6% of that of the control. High concentrations of incorporated apo(a) significantly reduced TPA-induced thrombolysis (12.2±2.5% versus 22.2±2.6% in the control thrombi), but no effect of lower concentrations of incorporated r-apo(a) was demonstrated on the exogenous TPA-induced thrombolysis. Conclusions The present study demonstrates the attenuation of endogenous fibrinolysis by apo(a) in an in vivo Model of experimental venous Thrombosis, lending support to the proposed mechanism of impaired fibrinolysis by which Lp(a) may contribute to atherothrombotic disorders.

  • comparison of sustained antithrombotic effects of inhibitors of thrombin and factor xa in experimental Thrombosis
    Circulation, 1996
    Co-Authors: B J Biemond, Philip W Friederich, M Levi, George P Vlasuk, H R Buller, J Ten W Cate
    Abstract:

    Background In the pathogenesis of (recurrent) Thrombosis, clot-associated thrombin appears to play an important role. Antithrombin III–independent thrombin inhibitors have been shown to neutralize clot-bound thrombin effectively. We compared the sustained antithrombotic effects and the effects on endogenous fibrinolysis of several of these agents with recombinant tick anticoagulant peptide (rTAP), a selective factor Xa inhibitor, and low-molecular-weight heparin (LMWH) in an experimental venous Thrombosis Model. Methods and Results Rabbits received either recombinant hirudin (rHir), Hirulog-1, CVS#995 (a novel direct inhibitor of thrombin), rTAP, LMWH, or saline. The effect on thrombus growth was assessed by measuring the accretion of 125I-labeled fibrinogen onto preformed nonradioactive thrombi, and the effect on endogenous fibrinolysis was assessed by measuring the decline in radioactivity of preformed 125I-labeled thrombi in rabbit jugular veins. All direct thrombin inhibitors induced a sustained antit...

  • thrombolysis and reocclusion in experimental jugular vein and coronary artery Thrombosis effects of a plasminogen activator inhibitor type 1 neutralizing monoclonal antibody
    Circulation, 1995
    Co-Authors: B J Biemond, Marcel Levi, Ruben Coronel, Michiel J Janse, J Ten W Cate, H Pannekoek
    Abstract:

    Background Thrombolytic therapy for acute myocardial infarction is often complicated by reocclusion of the initially reperfused artery. Platelets have been shown to play an important role in this process. We determined the contribution of plasminogen activator inhibitor type 1 (PAI-1), stored in the α-granules of platelets, to thrombolysis resistance and to reocclusion. Methods and Results In a rabbit jugular vein Thrombosis Model, the effect of a PAI-1–neutralizing monoclonal antibody (CLB-2C8) on thrombolysis and thrombus growth was assessed. The effect on reperfusion, reocclusion, and duration of vessel patency was studied in a canine Model of coronary artery Thrombosis superimposed on a high-grade stenosis and endothelial damage. In the rabbit jugular vein Model, the intravenous administration of 1 mg/kg anti–PAI-1 antibody significantly enhanced the endogenous thrombolysis from 5.5±1.3% in the animals treated with a nonspecific monoclonal antibody (control) to 13.7±2.6% in the animals treated with th...

Yi Kong - One of the best experts on this subject based on the ideXlab platform.

  • a novel direct factor xa inhibitory peptide with anti platelet aggregation activity from agkistrodon acutus venom hydrolysates
    Scientific Reports, 2015
    Co-Authors: Meimei Chen, Xin Ming, Yahui Chen, Ying Wang, Yi Kong
    Abstract:

    Snake venom is a natural substance that contains numerous bioactive proteins and peptides, nearly all of which have been identified over the last several decades. In this study, we subjected snake venom to enzymatic hydrolysis to identify previously unreported bioactive peptides. The novel peptide ACH-11 with the sequence LTFPRIVFVLG was identified with both FXa inhibition and anti-platelet aggregation activities. ACH-11 inhibited the catalytic function of FXa towards its substrate S-2222 via a mixed Model with a Ki value of 9.02 μM and inhibited platelet aggregation induced by ADP and U46619 in a dose-dependent manner. Furthermore, ACH-11 exhibited potent antithrombotic activity in vivo. It reduced paralysis and death in an acute pulmonary Thrombosis Model by 90% and attenuated Thrombosis weight in an arterio-venous shunt Thrombosis Model by 57.91%, both at a dose of 3 mg/kg. Additionally, a tail cutting bleeding time assay revealed that ACH-11 did not prolong bleeding time in mice at a dose of 3 mg/kg. Together, our results reveal that ACH-11 is a novel antithrombotic peptide exhibiting both FXa inhibition and anti-platelet aggregation activities, with a low bleeding risk. We believe that it could be a candidate or lead compound for new antithrombotic drug development.

  • isolation and characterization of a novel antithrombotic peptide from enzymatic hydrolysate of agkistrodon acutus venom
    International Journal of Peptide Research and Therapeutics, 2015
    Co-Authors: Meimei Chen, Yahui Chen, Ying Wang, Yi Kong
    Abstract:

    Snake venoms contain a large variety of proteins and peptides that affect the hemostasis and Thrombosis. Numerous antithrombotic peptides have been found in snake venom. However, few studies have been performed on the proteolysis of snake venom for obtaining bioactive peptides. In this study, the Agkistrodon acutus venom was hydrolyzed using four commercial proteases (pepsin, papain, neutrase, and alcalase) and the hydrolysate was tested for antiplatelet aggregation activity. The pepsin hydrolysate, exhibiting the highest activity, was further purified by gel filtration and reversed-phase high performance liquid chromatography. A novel antithrombotic peptide SP-14 was obtained, and its sequence was identified as SHIHGDYSSPSGAP using tandem electrospray mass spectrometry. SP-14 inhibited U46619-induced rabbit platelet aggregation in a dose-dependent manner. It reduced the mortality of mice in acute pulmonary Thrombosis Model and decreased thrombus weight in rat arteriovenous shunt Model, while with lower bleeding risk than aspirin. Therefore, SP-14 may be beneficial for new antithrombotic drug design and development.

  • a novel anti platelet aggregation tripeptide from agkistrodon acutus venom isolation and characterization
    Toxicon, 2009
    Co-Authors: Yi Kong, Jianli Huo, Jin Xiong
    Abstract:

    AAP, a tripeptide that inhibited rabbit platelet aggregation, was isolated from Agkistrodon acutus venom by ion-exchange, gel filtration and reverse-phase chromatography. Amino acid sequences which determined mainly by amino acid analyses and NMR spectroscopy indicated it was a tripeptide including pyroglutamic acid, asparagine and tryptophane residues. The ESMS experiment assigned a molecular weight of 429 Da. AAP inhibited rabbit platelet aggregation induced by ADP, PAF-acether, collagen and thrombin, the IC(50)s were 178 microM, 332 microM, 179 microM and 203 microM, respectively. AAP also inhibited thrombus formation in vivo Thrombosis Model and prevented the combination between fibrinogen and GP IIb/IIIa. Besides, AAP was not toxic after intravenous injection into mice at a higher dose. Those studies might be helpful to delineate unknown mechanisms involved in platelet aggregation and serve as a Model for developing antithrombotic agents.

Benedict R. Lucchesi - One of the best experts on this subject based on the ideXlab platform.

  • prevention of carotid artery Thrombosis by oral platelet gpiib iiia antagonist in dogs
    Stroke, 1997
    Co-Authors: Shaker A. Mousa, Benedict R. Lucchesi
    Abstract:

    Background and Purpose Current antithrombotic therapy in acute ischemic stroke and myocardial infarction in which a combination of antiplatelet agents (aspirin) and anticoagulants (heparin) was used led to partial reduction of acute thrombotic complications. Recent advances in antiplatelet research led to the discovery of the platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), the final common pathway for platelet aggregation. The present study was undertaken to determine the oral antithrombotic efficacy of a potent and specific platelet GPIIb/IIIa antagonist, DMP728, in an electrically induced carotid artery Thrombosis Model in dogs. Based on the powerful antiplatelet efficacy of this mechanism in inhibiting all agonist-induced platelet aggregation as well as in inhibiting platelet procoagulant activity (thrombin generation and hence fibrin formation), an orally active antagonist for this integrin receptor might have potential benefits in stroke. Methods Anesthetized dogs were instrumented for monitorin...

Kaweh Zokai - One of the best experts on this subject based on the ideXlab platform.