Thrombin generation and inactivation in the presence of antithrombin III and heparin

Lindhout, Théo; Baruch, Dominique; Schoen, Pieter; Franssen, Jo; Hemker, H. Cœnraad

doi:10.1021/bi00368a019

Cited by 62 publications

(38 citation statements)

References 21 publications

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“…As a result, the generation of factor Xa will be reduced hence producing a pattern of factor X deficiency. On the other hand, the initial product of factor II conversion, meizothrombin, is not inhibited by antithrombin/ heparin [14,25], so that factor VIII will still be activated, and an inhibition of subse quently formed factor Ila will only be a sec ondary event.…”

Section: Discussionmentioning

confidence: 99%

Kinetic Analysis of the Clotting System in the Presence of Heparin and Depolymerized Heparin

Heuck¹,

Baumann²

1991

Pathophysiol Haemos Thromb

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The kinetics of the activation of the plasmatic clotting system in the presence of heparin and depolymerized heparin (Kabi 2165), respectively, was compared with the kinetics of activation in plasma with isolated factor deficiency. Measurements were made with a chromogenic substrate method using Tos-Gly-Pro-Arg-p-nitroanilide acetate. The extinction curves were analyzed to determine the characteristics of a curve that was fitted to the experimental data to sufficiently describe the slope of the curves by constants. In the activated extrinsic clotting system, the action of heparin and depolymerized heparin results in a distribution pattern for the two relevant constants, K(l), defining the time of the point of inflection of the curve, and K(2), relating to the slope of the curve at the point of inflection, which is identical with the pattern observed in plasma with factor II deficiency. This distribution pattern can be explained by an inhibitory reaction on factor Ila, which is accelerated by the anticoagulant. In contrast, the pattern of K(2)/K(l) for the activated intrinsic system is identical with the pattern for plasma with factor X deficiency. Qualitative differences in the action of heparin and depolymerized heparin are not evident. The investigation confirms that the molecular action of heparin and depolymerized heparin as accelerators of the plasmatic clotting system is qualitatively the same. However, their action in the extrinsic and intrinsic system has different effects. Furthermore, the study reveals that constant K(2) is a more sensitive indicator to measure low heparin and depolymerized heparin activities than K(l) or its equivalent, the clotting time.

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Section: Discussionmentioning

confidence: 99%

Kinetic Analysis of the Clotting System in the Presence of Heparin and Depolymerized Heparin

Heuck¹,

Baumann²

1991

Pathophysiol Haemos Thromb

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“…Consequently, not only does locally formed thrombin become inactivated by FPRCH2C1, but the resultant inactive complex, FPRCH2-thrombin, occupies the platelet thrombin receptors of ambient platelets to prevent subsequent activation by thrombin. Second, FPRCH2C1 may inactivate platelet-bound meizothrombin (33) during thrombin generation. Since thrombin formation is generally a process associated with the cell surface, particularly the platelet membrane, covalent inactivation by FPRCH2C1 may occur after the activating cleavage but before thrombin is freed from the platelet-bound fragment 1.2.…”

Section: Discussionmentioning

confidence: 99%

Interruption of acute platelet-dependent thrombosis by the synthetic antithrombin D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone.

Hanson

Harker

1988

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

257

103

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Since the antithrombin action of heparin fails to interrupt arterial thrombosis, a mediating role for thrombin (EC 3.4.21.5) in the formation of high-shear platelet-dependent thrombus has been unproven. To determine whether thrombin is important in acute arterial thrombus formation and to assess the therapeutic potential of inhibiting its action, the effects of the synthetic covalent antithrombin D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone (FPRCH2CI) on arterial-flow vascular graft thrombosis and occlusion have been studied in a nonhuman primate model. Continuous intravenous infusion of FPRCH2CI (100 nmol/kg per min) into vascular graft-bearing baboons (Papio anubis) abolished (s) vascular graft "'Inplatelet deposition, (ii) vascular graft occlusion, (iii) thrombusassociated in vivo release of platelet-specific proteins and fibrinopeptides, (iv) platelet hemostatic plug formation, (v) thrombin-induced platelet aggregation ex vivo, and (vW) thrombin-induced blood clotting. The effects of FPRCH2CI largely disappeared within 15 min after the infusion had been discontinued. FPRCH2C1 produced no detectable cardiovascular or other acute side effects. In contrast, sustained comparably anticoagulating levels of heparin had no effect upon "1In-platelet graft deposition, graft occlusion, platelet function as measured by the bleeding time, platelet aggregation ex vivo, or release of platelet-specific proteins in vivo. We conclude that thrombin is the principal mediator of platelet-dependent hemostatic plug formation and of the formation of plateletdependent high-flow acute graft thrombosis and occlusion. Moreover, FPRCH2C1 or other synthetic antithrombins may provide effective antithrombotic therapy for both arterial and venous thrombosis by simultaneously inhibiting platelet activation and fibrin formation.Heparin therapy prevents stasis-type venous thrombosis by accelerating the plasma antithrombin III-mediated inhibition of thrombin (EC 3.4.21.5), thereby preventing fibrin formation (1). By contrast, heparin fails to interrupt plateletmediated, high-shear, arterial thrombosis or hemostatic plug formation, implying that these platelet-dependent processes are largely independent of thrombin generation (2-4). Moreover, standard preparations of heparin may contain fractions that activate platelets (5) and may on occasion contribute to the development of arterial thrombosis (6-8). Indeed, several alternate pathways have been characterized by which platelets may undergo thrombin-independent activation to form thrombus under high-shear flow conditions. For example, collagen, adenosine diphosphate, thromboxane A2j and platelet-activating factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) mediate platelet activation in vivo (9)(10)(11)(12) To clarify in vivo the role of thrombin in the activation of platelets during the formation of hemostatic plugs and acute high-shear, platelet-dependent thrombosis, a small molecular weight synthetic inhibitor of thrombin has been administered in a baboon model of arteri...

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“…Heparin is well known to form a complex with plasma antithrombin III, and then this complex neutralizes thrombin. Argatroban, on the other hand, binds directly to the active sites of the thrombin molecule (23). Hanson and Harker (24) have shown that argatroban, which is a relatively small molecule, can diffuse into the thrombus and interact with thrombin that is bound to platelet receptors.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effect of Clopidogrel, Vapiprost and Argatroban on the Middle Cerebral Artery Thrombosis in the Rat

Umemura

Kawai

Ishiga

et al. 1995

Japanese Journal of Pharmacology

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ABSTRACT-This study investigated the roles of thromboxane A2 (TXA2), ADP and thrombin in middle cerebral artery (MCA) thrombosis in the rat. The rat MCA was occluded by a thrombus induced by the photochemical reaction of rose bengal by green light that causes endothelial damage followed by platelet adhesion, aggregation and formation of a platelet and fibrin-rich thrombus at the site of the photochemical reaction. Vapiprost, a specific TXA2-receptor antagonist; clopidogrel, which has the thienopyridine structure of ticlopidine and is a more potent inhibitor of ADP-induced platelet aggregation than ticlopidine; argatroban, a specific thrombin inhibitor; or heparin was administered intravenously before rose bengal injection. The MCA local blood flow was monitored by a laser Doppler flowmeter. The MCA was occluded by thrombus about 5 min after the initiation of the photochemical reaction. Vapiprost, clopidogrel and argatroban all significantly prolonged the time taken for the thrombotic occlusion of the MCA, but in this respect, heparin was ineffective. Our observations suggest that vapiprost and clopidogrel are useful antithrombotic agents against platelet and fibrin-rich thrombi. The effect of argatroban is attributable to inhibition of thrombin-induced platelet activation and fibrin generation. The thrombosis model described in this study is useful for understanding the mechanism(s) of thrombogenesis in the rat MCA and may be applied to other mammalian species.

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Thrombin generation and inactivation in the presence of antithrombin III and heparin

Cited by 62 publications

References 21 publications

Kinetic Analysis of the Clotting System in the Presence of Heparin and Depolymerized Heparin

Kinetic Analysis of the Clotting System in the Presence of Heparin and Depolymerized Heparin

Interruption of acute platelet-dependent thrombosis by the synthetic antithrombin D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone.

Inhibitory Effect of Clopidogrel, Vapiprost and Argatroban on the Middle Cerebral Artery Thrombosis in the Rat

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