Activated Clotting Time as an Appropriate Test to Compare Heparin and Direct Thrombin Inhibitors Such as Hirudin or Ro 46-6240 in Experimental Arterial Thrombosis

Carteaux, Jean‐Pierre; Gast, Alain; Tschopp, Thomas B.; Roux, Sébastiên

doi:10.1161/01.cir.91.5.1568

Cited by 44 publications

(28 citation statements)

References 40 publications

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“…Fourth, as the most potent physiological agonist of platelet activation, thrombin formed at the damaged site may be important in thrombus formation, as evidenced by the positive antithrombotic effect of direct thrombin inhibitors in models similar to that used in the present study. 17,25 Consequently, inhibition of thrombin or the production of thrombin may play an important role in the antithrombotic effect of enoxaparin in this study. Recent data suggest that enoxaparin inhibits coagulation factor VIIa generation in vitro to a greater extent than does heparin.…”

Section: Discussionmentioning

confidence: 87%

Inhibition of Repetitive Thrombus Formation in the Stenosed Canine Coronary Artery by Enoxaparin, But Not by Unfractionated Heparin

Leadley¹,

Kasiewski²,

Bostwick³

et al. 1998

ATVB

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Abstract-Experiments were designed to compare the antithrombotic efficacy of enoxaparin and unfractionated heparin (UH) in a model of platelet-dependent cyclic flow reductions (CFRs) in the stenosed canine circumflex coronary artery. Low-molecular-weight heparins (LMWHs) are safe and effective in the prevention and treatment of venous thromboembolism. The present experiments were designed to evaluate the potential use of LMWHs in arterial thrombotic indications by comparing the antithrombotic effect of an LMWH with that of UH in an animal model of unstable angina. After establishment of consistent CFRs by experimentally induced vascular stenosis and damage, vehicle (saline), enoxaparin, or UH was administered intravenously as a loading dose plus a continuous infusion for 1 hour. The inhibition of CFRs was taken as an indicator of antithrombotic efficacy. Enoxaparin inhibited repetitive platelet thrombus formation in a dose-dependent manner, with significant inhibition of CFRs achieved at 0.5 mg/kgϩ5 g/kg per minute. This dose of enoxaparin resulted in anti-Xa levels of 0.9 to 1.0 IU/mL, anti-IIa levels of 0.2 to 0.3 IU/mL, activated partial thromboplastin time (APTT) of 1.3-fold over baseline, and a 1.4-fold increase (NS) in template bleeding time. Near-complete abolishment of CFRs was achieved with enoxaparin at 1.0 mg/kgϩ10 g/kg per minute. This dose of enoxaparin produced anti-Xa levels of 2 to 2.2 IU/mL, anti-IIa levels of 0.5 to 0.6 IU/mL, an increase in APTT of 1.4-to 1.5-fold over baseline, and a 1.9-fold increase (PϽ0.05) in template bleeding time. In contrast, UH had no significant effect on CFRs at a dose (100 U/kgϩ10 U/kg per minute) that resulted in anti-Xa levels of 1.2 to 1.6 IU/mL, anti-IIa levels of 1.8 to 2.4 IU/mL, an increase in APTT greater than 10-fold over baseline, and a 2.

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Section: Discussionmentioning

confidence: 87%

Inhibition of Repetitive Thrombus Formation in the Stenosed Canine Coronary Artery by Enoxaparin, But Not by Unfractionated Heparin

Leadley¹,

Kasiewski²,

Bostwick³

et al. 1998

ATVB

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“…type and source of reagents, including batch‐to‐batch variations, type of instrument used for clot detection, citrate concentration in the test tube, and type of test tube [12–18]. In addition, anticoagulants with differing mechanism of action produce different levels of antithrombotic effect and bleeding at the same level of APTT [3, 8, 19–22]. Antithrombotic effects have been demonstrated for inogatran at plasma concentrations of 0.3–3 µmol l −1 in experimental rat models [20, 22, 23].…”

Section: Introductionmentioning

confidence: 99%

Population modelling of the effect of inogatran, at thrombin inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery disease

Cullberg

Eriksson

Larsson

et al. 2001

Brit J Clinical Pharma

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Aims The purpose of this study was to characterize the relationship between the degree of anticoagulation, assessed by APTT, and the plasma concentration of inogatran in healthy subjects and in patients with coronary artery disease. Methods Data from ®ve phase I studies in 78 healthy males and two phase II multicentre studies in 948 patients of both sexes with unstable angina pectoris or non-Q-wave myocardial infarction were evaluated. A total of 3296 pairs of concentration-APTT samples were obtained before, during, and after intravenous infusions of inogatran. Mixed effects modelling was used for population pharmacodynamic analysis of the drug effect and for describing the variability in baseline APTT. Results The population mean baseline APTT was 29 s, but large variations between individuals (s.d. 3.6 s) were observed. The variability between studies (1.3 s) and centres (1.8 s) were of less importance, though statistically signi®cant. APTT increased in a nonlinear manner with increasing inogatran concentration and the relationship was well described by a combined linear and E max model. A signi®cant part of the overall variability could be ascribed to the APTT reagent and equipment used at the different study centres. These method-dependent differences were compensated for by including the lower limit of the normal reference range as a covariate, affecting both baseline and E max , in the model. For the typical healthy subject and patient, the method-corrected population mean parameters were: APTT baseline 35 and 31 s, slope 8.0 and 5.8 s l mmol x1 , E max 36 and 34 s, and EC 50 0.54 and 0.72 mmol l x1 , respectively. The model predicted plasma concentration needed to double the APTT from the baseline value was 1.25 and 1.45 mmol l x1 in the healthy volunteer and patient, respectively. Conclusions The nonlinear relationship between APTT and inogatran concentration in plasma was well described by a combined linear and E max model. Pooling of data was made possible by incorporating a centre-speci®c characteristic of the assay method in the model. Patients had lower baseline APTT and appeared to have less pronounced effect of inogatran than young healthy subjects.

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“…This has been compensated for by including the lower limit of the reference range as a covariate in the PK/PD model [14]. We also used ACT, a bedside test done on whole blood, which has been shown to be a good predictor of the antithrombotic activity of direct thrombin inhibitors like hirudin in a model of arterial thrombosis [17] and is routinely used to monitor heparinization during interventional cardiovascular procedures. A linear increase in ACT with the S 18326 concentrations was observed after infusion of 0.5 mg and 3 mg S 18326.…”

Section: Discussionmentioning

confidence: 99%

Dose‐effect relationship for several coagulation markers during administration of the direct thrombin inhibitor S 18326 in healthy subjects

Gaussem

Dubar

Bonniec

et al. 2002

Brit J Clinical Pharma

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Aims We conducted a phase I placebo-controlled trial with two i.v. doses (0.5 mg h x1 and 3 mg h x1 ) of S 18326, a selective thrombin inhibitor that interacts with the catalytic site of thrombin, with the aim to study the relationships between increasing plasma levels of S 18326 and changes in coagulation tests and thrombin generation markers. Methods Thirty-six healthy male volunteers were divided into three groups. In each group, 10 volunteers were randomly assigned to receive S 18326 and two to receive a placebo. Following a bolus of 4.5 mg, doses were 0.5 mg h x1 in the ®rst group and 3 mg h x1 in the two other groups, administered as an i.v. infusion for 24 h. Blood was drawn repeatedly up to 36 h after the bolus, and tested for the activated clotting time (ACT) and activated partial thromboplastin time (APTT). The APTT reagent was chosen among ®ve commercial reagents to yield a linear increase in the clotting time among possible therapeutic S 18326 concentrations in vitro. To accurately measure the thrombin-inhibiting effects of low doses of S 18326 (<0.5 mM), we developed a speci®c chromogenic assay. We also measured F1+2 prothrombin fragment levels to assess the effect of S 18326 on thrombin generation in vivo. Results A two-compartment pharmacokinetic model was ®tted to the S 18326 plasma concentration vs time data by using population pharmacokinetic methods. Results of the pharmacodynamic-pharmacokinetic relationships showed that both the ACT and APTT methods yielded a linear increase according to the S 18326 concentration measured using a highly sensitive analytical method. At the end of infusion, ACT was prolonged 1.20 and 1.95-fold in the 0.5 mg h x1 and the 3 mg h x1 groups, respectively, and APTT was prolonged 1.27 and 2.75-fold. Thrombin inhibition plateaued above 0.5 mM of S 18326 according to an Emax model, con®rming that the test was highly sensitive. F1+2 levels fell signi®cantly after the 24 h S 18326 infusion (0.83 nM to 0.6 nM and 0.80 nM to 0.44 nM in the 0.5 mg h x1 and the 3 mg h x1 groups, respectively), but remained stable after the placebo infusion. Conclusions Our results support speci®c monitoring of the thrombin inhibitor S 18326 with ACT and APTT to establish the safety range of the drug in further studies. Moreover, the fall in F1+2 prothrombin fragments suggests that S 18326 effectively reduces the retroactivation of factors V and VIII by thrombin.

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Activated Clotting Time as an Appropriate Test to Compare Heparin and Direct Thrombin Inhibitors Such as Hirudin or Ro 46-6240 in Experimental Arterial Thrombosis

Cited by 44 publications

References 40 publications

Inhibition of Repetitive Thrombus Formation in the Stenosed Canine Coronary Artery by Enoxaparin, But Not by Unfractionated Heparin

Inhibition of Repetitive Thrombus Formation in the Stenosed Canine Coronary Artery by Enoxaparin, But Not by Unfractionated Heparin

Population modelling of the effect of inogatran, at thrombin inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery disease

Dose‐effect relationship for several coagulation markers during administration of the direct thrombin inhibitor S 18326 in healthy subjects

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