Comparative Studies on Various Assays for the Laboratory Evaluation of r-Hirudin

Walenga, Jeanine M.; Hoppensteadt, Debra; Koza, Michael J.; Pifarré, R; Fareed, Jawed

doi:10.1055/s-2007-1002597

Cited by 25 publications

(19 citation statements)

References 12 publications

(19 reference statements)

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“…The use of ACT for measuring the effect of these compounds has, however, been found to be relatively unsuitable [32]. In this study, a strong correlation between melagatran plasma concentration and ACT, but not APTT was found.…”

Section: Discussioncontrasting

confidence: 47%

Melagatran attenuates fibrin and platelet deposition in a porcine coronary aartery over-stretch injury model

Scherstén

Wahlund

Björnheden

et al. 2003

Blood Coagulation & Fibrinolysis

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Melagatran is the active form of the oral direct thrombin inhibitor, ximelagatran. The purpose of this study was to compare the effects of different doses of melagatran with heparin or placebo on platelet deposition and relative fibrin content after coronary angioplasty in pigs. After 125I-labelled fibrinogen and autologous 111Indium-labelled platelets had been infused a balloon injury was performed in the left anterior descending and the right coronary arteries. Pigs were randomized to receive either heparin 200 IU/kg bolus plus 20 IU/kg per h infusion (n = 7); melagatran 1 mg/kg bolus plus 0.33 mg/kg per h infusion (n = 7); melagatran bolus 0.5 mg/kg plus 0.17 mg/kg per h infusion (n = 7); melagatran 0.15 mg/kg bolus plus 0.05 mg/kg per h infusion (n = 6) or saline (n = 4). Seventy-five minutes after the angioplasty, the pigs were euthanized and the injured vessel segments were measured in a gamma counter. Compared with placebo, platelet deposition and relative fibrin content were reduced after both heparin and melagatran, in the latter case with a dose-response relationship. Melagatran reduced platelet deposition and relative thrombus size in a dose-dependent manner when compared with placebo after coronary angioplasty in pigs. No statistically significant difference between melagatran and heparin was found.

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Section: Discussioncontrasting

confidence: 47%

Melagatran attenuates fibrin and platelet deposition in a porcine coronary aartery over-stretch injury model

Scherstén

Wahlund

Björnheden

et al. 2003

Blood Coagulation & Fibrinolysis

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“…In order to be able to predict bleeding ten dency or complications, respectively, in hu mans there has been a lot of discussion on which species and model should be chosen and what parameters are appropriate [12,21,23]. We decided to follow the coagulation sta tus in rabbits and to assess the bleeding time prolongation in rats after r-hirudin applica tion.…”

Section: Discussionmentioning

confidence: 99%

Investigation of Activated Prothrombin Complex Concentrate as Potential Hirudin Antidote in Animal Models

Diehl

Römisch²,

Hein³

et al. 1995

Pathophysiol Haemos Thromb

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The specific thrombin inhibitor r-hirudin (HBW 023) has been demonstrated to be effective in preventing thrombosis in preclinical models. Up to now, no bleeding complications have been observed using therapeutically effective doses in animal studies. However, in case of inadvertent overdosing the occurrence of undesired impairment of coagulation cannot be excluded. As a potential antidote an activated prothrombin complex concentrate (APC) was tested on its ability to normalize blood coagulation. APC given as bolus injections 5 min after termination of 1-hour r-hirudin infusions of 0.1, 0.3, 1.0 and 3.0 mg/kg neutralized the r-hirudin-induced prolongation of whole blood coagulation time in rabbits completely within 5 min without any clot formation in the blood vessels or capillaries of the heart, kidneys, or lungs. Furthermore, bleeding time prolongation induced by bolus application of 3.0 and 30.0 mg/kg r-hirudin was significantly inhibited by APC within 5 min. These results suggest that administration of APC may be an effective way to reverse the effects of r-hirudin in the coagulation system in case of inadvertent overdosing of r-hirudin.

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“…[71][72][73][74][75][76] The usefulness of the activated partial-thromboplastin time seems limited by its poor linearity and reproducibility, especially when heparin or a vitamin K antagonist is coadministered. [71][72][73][77][78][79] The ecarin clotting time better reflects the actual plasma concentration of DTIs, but this test is not widely available. [74][75][76][77][80][81][82] heparin-induced thrombocytopenia remaining issues The new england journal of medicine…”

Section: Monitoring Activitymentioning

confidence: 99%

“…[71][72][73][77][78][79] The ecarin clotting time better reflects the actual plasma concentration of DTIs, but this test is not widely available. [74][75][76][77][80][81][82] heparin-induced thrombocytopenia remaining issues The new england journal of medicine …”

mentioning

confidence: 99%

Direct Thrombin Inhibitors

2005

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irect thrombin inhibitors (dti s ) are a new class of anticoagulants that bind directly to thrombin and block its interaction with its substrates. Some DTIs -such as recombinant hirudins, bivalirudin, and ximelagatran, either alone or in combination with melagatran -have undergone extensive evaluation in phase 3 trials for the prevention and treatment of arterial and venous thrombosis. The evidence concerning the clinical applicability of other DTIs, such as argatroban and dabigatran, is limited to phase 2 studies. Four parenteral DTIs have been approved by the Food and Drug Administration (FDA) in North America: hirudin and argatroban for the treatment of heparin-induced thrombocytopenia, bivalirudin as an alternative to heparin in percutaneous coronary intervention, and desirudin as prophylaxis against venous thromboembolism in hip replacement. This review discusses FDA-approved DTIs as well as those under evaluation in phase 2 or 3 clinical trials. coagulation cascade and generation of thrombinAfter injury to a vessel wall, tissue factor is exposed on the surface of the damaged endothelium. The interaction of tissue factor with plasma factor VII activates the coagulation cascade, producing thrombin by stepwise activation of a series of proenzymes ( Fig. 1). Thrombin is central in the clotting process: it converts soluble fibrinogen to fibrin; activates factors V, VIII, and XI, which generates more thrombin; and stimulates platelets. Furthermore, by activating factor XIII, thrombin favors the formation of cross-linked bonds among the fibrin molecules, stabilizing the clot. The coagulation cascade is regulated by natural anticoagulants, such as tissue factor pathway inhibitor, the protein C and protein S system, and antithrombin, all of which help to restrict the formation of the hemostatic plug to the site of injury. differences from heparinsThrombin-inhibiting drugs can block the action of thrombin by binding to three domains: the active site or catalytic site and two exosites (Fig. 2). Located next to the active site, exosite 1 acts as a dock for substrates such as fibrin, thereby orienting the appropriate peptide bonds in the active site. Exosite 2 serves as the heparin-binding domain. 1 Thrombin is inhibited indirectly by low-molecular-weight heparins, because these drugs strongly catalyze the function of antithrombin. A heparin-thrombin-antithrombin complex is formed in which heparin binds simultaneously to exosite 2 in thrombin and to antithrombin. Furthermore, heparin can act as a bridge between thrombin and fibrin by binding both to fibrin and exosite 2 (Fig. 2). Because both thrombin exosites are occupied within this fibrin-heparin-thrombin complex, the enzymatic activity of thrombin is relatively protected from inactivation by the heparin-antithrombin complex. 2-4 Thus, heparins have a reduced capacity for the inhibition of fibrin-bound thrombin, which ap- pears to be detrimental, because active thrombin further triggers thrombus growth.Since DTIs act independently of antithrombin, they can inhibit t...

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Comparative Studies on Various Assays for the Laboratory Evaluation of r-Hirudin

Cited by 25 publications

References 12 publications

Melagatran attenuates fibrin and platelet deposition in a porcine coronary aartery over-stretch injury model

Melagatran attenuates fibrin and platelet deposition in a porcine coronary aartery over-stretch injury model

Investigation of Activated Prothrombin Complex Concentrate as Potential Hirudin Antidote in Animal Models

Direct Thrombin Inhibitors

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