Pharmacologic modulation of thrombin generation associated with human clots by human purified antithrombin alone or in the presence of low molecular weight heparin or unfractionated heparin

Meddahi, Sadia; Bara, L.; Fessi, Hatem; Samama, M

doi:10.1097/00001721-200001000-00006

Cited by 6 publications

(6 citation statements)

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“…In the absence of prothrombin When clots were incubated in the recalcified Owren buffer solution, no significant variation of clot-associated thrombin concentration was observed during the incubation period as previously described [14].…”

Section: Effect Of Antithrombin Alone Low-molecular-weight Heparin Omentioning

confidence: 99%

“…Effect of purified human antithrombin alone or lowmolecular-weight heparin compared with unfractionated heparin on clot-associated factor Xa and on clot-bound factor IIa The techniques to determine clot-associated FXa and clot-induced thrombin generation were described previously [14]: Standard clots were prepared by recalcification of frozen platelet-poor citrated plasma as described above.…”

Section: Determination Of Clot-induced Factor Iia Generation and Clotmentioning

confidence: 99%

“…Measurement of thrombin concentrations present on the clots and in the reaction mixtures Chromogenic activity of the clots and the reaction mixtures were determined by using a CBS 3447 at 0.75 nmol/l as described previously [14].…”

Section: Determination Of Clot-induced Factor Iia Generation and Clotmentioning

confidence: 99%

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Is the inhibition of both clot-associated thrombin and factor Xa more clinically relevant than either one alone?

Meddahi

Samama²

2009

Blood Coagulation &Amp; Fibrinolysis

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The procoagulant activity of a thrombus is essentially due to clot-associated factor IIa and factor Xa activities.The aim of this review is to underline that specific antithrombin and anti-Xa drugs, such as r-hirudin and DX 9065a, respectively, are complementary, and could be used in combination in clinical trials in patients with acute arterial thrombosis such as coronary syndromes. After standardization of the in-vitro techniques for clot-bound thrombin and clot-associated factor Xa, we have studied the anticoagulant effect of unfractionated heparin and a low-molecular heparin in an in-vitro model. We have confirmed the inability of heparins to inhibit clot-bound thrombin and clot-associated factor Xa. We have compared r-hirudin, a direct thrombin inhibitor, with DX9065a, a direct factor Xa inhibitor. We have observed that r-hirudin inhibited clot-bound thrombin but not clot-bound factor Xa. After r-hirudin treatment interruption, a hypercoagulation rebound has been reported and it could be in relation with the persistence of factor Xa activity in the clot. We have demonstrated that DX9065a inhibits clot-bound factor Xa but does not inhibit clot-bound factor IIa. The complementary effect of DX9065a and r-hirudin is demonstrated in this experimental model. It is likely that several other combinations of drugs may also exhibit an increase of the antithrombotic activity which could be of interest in clinical implication for the treatment of several groups of patients at high risk of arterial thrombosis.

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Section: Effect Of Antithrombin Alone Low-molecular-weight Heparin Omentioning

confidence: 99%

Section: Determination Of Clot-induced Factor Iia Generation and Clotmentioning

confidence: 99%

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Is the inhibition of both clot-associated thrombin and factor Xa more clinically relevant than either one alone?

Meddahi

Samama²

2009

Blood Coagulation &Amp; Fibrinolysis

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“…This limitation is compounded by the fact that the heparin/antithrombin complex also is unable to inhibit factor Xa incorporated within the prothrombinase complex [29,30]. Thus, platelet-rich thrombi sequester factor Xa that retains activity in the face of the heparin/antithrombin complex [31,32]. This platelet-bound factor Xa converts prothrombin to thrombin, which also is protected from heparin inhibitors once it binds to fibrin.…”

Section: Potential Advantages Of Parenteral Direct Thrombin Inhibitormentioning

confidence: 99%

Pharmacology and Clinical Potential of Direct Thrombin Inhibitors

Linkins¹,

Weitz²

2005

CPD

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Direct thrombin inhibitors represent a new class of anticoagulants that bind directly to thrombin and block the enzyme's interactions with its substrates. These agents have been developed, at least in part, to overcome the limitations of heparin and vitamin K antagonists. This paper (a) reviews why thrombin is an ideal target for new anticoagulants, (b) describes the pharmacological profiles of the various direct thrombin inhibitors, (c) outlines the potential mechanistic advantages of parenteral direct thrombin inhibitors over heparin, (d) defines the potential benefits of ximelagatran, the first orally active direct thrombin inhibitor, over vitamin K antagonists, and (e) provides clinical perspective on the strengths and weaknesses of the various parenteral and oral direct thrombin inhibitors.

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“…During this process, thrombin becomes incorporated into the evolving fibrin clot and becomes a nidus for activation of coagulant factors and fibrin accretion [1]. Historically, thrombosis prevention has been through administration of heparin, which catalyzes the inhibition of thrombin by antithrombin (AT) [2].…”

Section: Introductionmentioning

confidence: 99%

An Antithrombin-Heparin Complex Increases the Anticoagulant Activity of Fibrin Clots

Smith

Mewhort-Buist

Berry

et al. 2008

Research Letters in Biochemistry

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Clotting blood contains fibrin-bound thrombin, which is a major source of procoagulant activity leading to clot extension and further activation of coagulation. When bound to fibrin, thrombin is protected from inhibition by antithrombin (AT) + heparin but is neutralized when AT and heparin are covalently linked (ATH). Here, we report the surprising observation that, rather than yielding an inert complex, thrombin-ATH formation converts clots into anticoagulant surfaces that effectively catalyze inhibition of thrombin in the surrounding environment.

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Pharmacologic modulation of thrombin generation associated with human clots by human purified antithrombin alone or in the presence of low molecular weight heparin or unfractionated heparin

Cited by 6 publications

References 0 publications

Is the inhibition of both clot-associated thrombin and factor Xa more clinically relevant than either one alone?

Is the inhibition of both clot-associated thrombin and factor Xa more clinically relevant than either one alone?

Pharmacology and Clinical Potential of Direct Thrombin Inhibitors

An Antithrombin-Heparin Complex Increases the Anticoagulant Activity of Fibrin Clots

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