Antithrombotic actions of argatroban in rat models of venous, ‘mixed’ and arterial thrombosis, and its effects on the tail transection bleeding time

Berry, Catherine; Girard, Denise; Lochot, Sylvette; Lecoffre, Catherine

doi:10.1111/j.1476-5381.1994.tb17126.x

Cited by 94 publications

(63 citation statements)

References 25 publications

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“…Indeed, this is the ®rst demonstration to our knowledge of the antithrombotic activity of a PAI-1 inhibitor in both arterial and venous thrombosis models in the same species. Moreover, MA33H1 exerted antithrombotic activity at the same doses in both venous and Berry et al (1994). arterial thrombosis, which distinguishes PAI-1 inhibition from anticoagulants where higher doses are required for antithrombotic ecacy in animal models of arterial thrombosis compared to models of venous thrombosis in the rat (Freund et al, 1990;Talbot et al, 1991;Berry et al, 1994). Furthermore, the antithrombotic eect of MA33H1 in the venous thrombosis model was abolished in the presence of tranexamic acid, which inhibits endogenous ®brinolysis by blocking the binding of plasminogen to ®brin via the high anity lysine binding site (Hoylaerts et al, 1981).…”

Section: Discussionmentioning

confidence: 99%

“…Table 3 shows the activity of MA33H1 in the arterial thrombosis and tail-transection bleeding models in the rat compared with that of heparin and the synthetic thrombin inhibitor argatroban in the same models and using the same mode of administration, i.e. intravenous infusion so that the eects of dierences in pharmacokinetics would be minimized (Berry et al, 1994). In these models, it would seem that MA33H1 and, by inference, PAI-1 inhibitors would have a better therapeutic margin than anticoagulant agents as antithrombotic agents in arterial thrombosis.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, these antibodies are able to cross-react with rabbit and porcine PAI-1 (Debrock & Declerck 1997). We therefore decided to examine the cross-reactivity of one of these antibodies, MA33H1, with rat PAI-1, and, if sucient cross-reactivity was obtained, to evaluate the ability of MA33H1 to prevent thrombus formation in models of venous and arterial thrombosis in the rat, which we have previously shown to be sensitive to heparin and the thrombin inhibitor argatroban (Berry et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

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Antithrombotic activity of a monoclonal antibody inducing the substrate form of plasminogen activator inhibitor type 1 in rat models of venous and arterial thrombosis

Berry¹,

Lunven²,

Lechaire³

et al. 1998

British J Pharmacology

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1 Elevated plasminogen activator inhibitor 1 (PAI-1) is a risk factor for thrombosis, and inhibitors of the interaction between PAI-1 and tissue plasminogen activator (t-PA) have antithrombotic and prothrombolytic activity in animals. We describe the antithrombotic eects in the rat of a monoclonal antibody (MA33H1) which converts PAI-1 to a non-inhibitory substrate. 2 The activity of MA33H1 against rat PAI-1 was con®rmed using two-chain t-PA and a chromogenic substrate. MA33H1 was evaluated in rat venous (thromboplastin+stasis in the abdominal vena cava) and arterial (electric current applied to a carotid artery) thrombosis models. The eects on tailtransection bleeding time were studied. 3 MA33H1 at 100 ng ml 71 inhibited both human (44.1%) and rat PAI-1 (49.7%). This eect was concentration-dependent. Its eect on human PAI-1 was not signi®cantly inhibited by 1 mg ml 71 ®brin or a &7 fold molar excess of vitronectin (1 nM). Inhibition of rat PAI-1 was unchanged by ®brin, but vitronectin reduced inhibition from 0.5 nM. 4 In the venous thrombosis model, MA33H1 signi®cantly reduced thrombus weights by 38 and 58.6% at 50 and 100 mg kg 71 min 71 i.v. respectively. This eect was inhibited by tranexamic acid. In the arterial model, MA33H1 signi®cantly increased the delay to occlusive thrombus formation by 58 and 142% at 50 and 100 mg kg 71 min 71 i.v., and did not aect bleeding time at 300 mg kg 71 min 71 i.v. 5 Thus, a monoclonal antibody which transforms PAI-1 to a t-PA substrate prevents thrombus formation in the rat with no eect on bleeding time at a higher dose.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antithrombotic activity of a monoclonal antibody inducing the substrate form of plasminogen activator inhibitor type 1 in rat models of venous and arterial thrombosis

Berry¹,

Lunven²,

Lechaire³

et al. 1998

British J Pharmacology

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“…In rats, rivaroxaban reduced thrombosis in a carotid to contralateral jugular 45 arteriovenous shunt model with a polyethylene catheter with a nylon thread inside. This evaluation also included combining rivaroxaban with heparin, with low-molecular-weight heparin, with aspirin, with various nonsteroidal anti-inflammatory drugs, with clopidogrel, with clopidogrel and aspirin, and with warfarin.…”

Section: Rivaroxaban (2011; Nda 202439 and 22406)mentioning

confidence: 99%

Animal Models of Thrombosis From Zebrafish to Nonhuman Primates

Jagadeeswaran

Cooley

Gross

et al. 2016

Circulation Research

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Thrombosis is a leading cause of morbidity and mortality worldwide. Animal models are used to understand the pathological pathways involved in thrombosis and to test the efficacy and safety of new antithrombotic drugs. In this review, we will first describe the central role a variety of animal models of thrombosis and hemostasis has played in the development of new antiplatelet and anticoagulant drugs. These include the widely used P2Y 12 antagonists and the recently developed orally available anticoagulants that directly target factor Xa or thrombin. Next, we will describe the new players, such as polyphosphate, neutrophil extracellular traps, and microparticles, which have been shown to contribute to thrombosis in mouse models, particularly venous thrombosis models. Other mouse studies have demonstrated roles for the factor XIIa and factor XIa in thrombosis. This has spurred the development of strategies to reduce their levels or activities as a new approach for preventing thrombosis. Finally, we will discuss the emergence of zebrafish as a model to study thrombosis and its potential use in the discovery of novel factors involved in thrombosis and hemostasis. Animal models of thrombosis from zebrafish to nonhuman primates are vital in identifying pathological pathways of thrombosis that can be safely targeted with a minimal effect on hemostasis. Future studies should focus on understanding the different triggers of thrombosis and the best drugs to prevent each type of thrombotic event. (Circ Res.

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“…Argatroban, a direct thrombin inhibitor, induces predictable anticoagulant effects (13) and a lower incidence of bleeding complications compared with heparin, as observed in a rat model (14). In addition, its hepatic clearance may be superior in ASMVT therapy over other anticoagulants (15), when adjusting the dose to achieve an activated partial thromboplastin time (aPTT) to a target value.…”

Section: Introductionmentioning

confidence: 99%

Early initiation of argatroban therapy in the management of acute superior mesenteric venous thrombosis

Zeng

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Acute superior mesenteric venous thrombosis (ASMVT) is an intractable disease with poor prognosis. Argatroban, a direct thrombin inhibitor, may be a novel anticoagulant method in the therapy of ASMVT. The aim of the present study was to assess the efficacy and safety of early argatroban therapy in ASMVT patients. The current retrospective study reviewed a consecutive series of ASMVT patients receiving early argatroban therapy during hospitalization between March 2013 and April 2014, with 18 ASMVT patients included in the study. Of these, 16 patients without hepatic dysfunction underwent anticoagulant therapy with argatroban with a mean dose of 1.57±0.34 µg/kg/min and a mean duration of 12.2±3.7 days, while their activated partial thromboplastin time (aPTT) was elevated to 1.95±0.26 times the baseline value. In addition, 2 hepatic dysfunction patients received therapy with a dose of 0.41 µg/kg/min and 0.46 µg/kg/min, and with aPTT of 1.68 and 1.62 times the baseline value, respectively. Overall, 94% (n=17) of the patients presented clinical improvement, while 88% (n=16) of patients presented partially or completely dissolved thrombus in contrast-enhanced computed tomography images. The incidence of surgery and bowel resection was 6% (excluding 1 case with intestinal necrosis detected on admission). Furthermore, 11% (n=2) of patients experienced a bleeding episode, however no major bleeding or mortality occurred during hospitalization. During the follow-up, the mortality and the recurrence rate were 6% and 11%, respectively. In conclusion, early initiation of argatroban treatment may be an effective and safe therapy in ASMVT, manifesting efficient resolution of the thrombus, rapid improvement of symptoms, low incidence of bowel resection and bleeding complication, and low mortality rate.

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Antithrombotic actions of argatroban in rat models of venous, ‘mixed’ and arterial thrombosis, and its effects on the tail transection bleeding time

Cited by 94 publications

References 25 publications

Antithrombotic activity of a monoclonal antibody inducing the substrate form of plasminogen activator inhibitor type 1 in rat models of venous and arterial thrombosis

Antithrombotic activity of a monoclonal antibody inducing the substrate form of plasminogen activator inhibitor type 1 in rat models of venous and arterial thrombosis

Animal Models of Thrombosis From Zebrafish to Nonhuman Primates

Early initiation of argatroban therapy in the management of acute superior mesenteric venous thrombosis

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