Argatroban: a direct thrombin inhibitor with reliable and predictable anticoagulant actions.

Pharmacological strategies aimed at the prevention of thrombotic complications are in continuous development. Argatroban is a synthetic small molecule derived from l-arginine with specific antithrombotic activity. Argatroban is a direct thrombin inhibitor that binds avidly and reversibly to the catalytic site of thrombin and that does not require other cofactors to exert its antithrombotic action. Due to its selective inhibitory mechanism, argatroban blocks both circulating and clot-bound thrombin. A rapid onset of its anticoagulant action is achieved after intravenous administration. The short elimination half-life of argatroban (52+/-16 minutes) ensures a rapid restoration of hemostasis upon cessation of treatment. Argatroban produces a predictable dose response, and its anticoagulant actions can be monitored easily through the routine coagulation tests activated partial thromboplastin time (aPTT) and activated clotting time (ACT). The specific mechanism of action and favorable pharmacokinetic profile of argatroban suggest that it could be beneficial in all indications where other intravenous anticoagulants are used. Results from clinical studies performed to date show that, when administered to patients with heparin-induced thrombocytopenia (HIT) or HIT with thrombosis (HITTS) in two large-scale, nonrandomized, prospective trials, argatroban reduced a combined endpoint of morbidity and mortality when compared with historical controls. Argatroban was well tolerated in clinical trials of patients with HIT and caused no increase in bleeding risk compared with historical controls. Argatroban does not induce the formation of antibodies that can neutralize its anticoagulant effect, prolong its half-life or enhance its activity. The U.S. Food and Drug Administration has approved the use of this drug as an alternative antithrombotic treatment for patients with HIT as well as for patients with or at risk for HIT undergoing percutaneous coronary interventions. In 2004 (Sweden), 2005 (Germany, the Netherlands, Austria and Iceland) and 2006 (Denmark) argatroban was approved for anticoagulation in adult patients with heparin-induced thrombocytopenia type II who require parenteral antithrombotic therapy.

No impact of factor IX Ala-10 mutations in acenocoumarol-treated southern Europeans.

Increased risk of bleeding during oral anticoagulant (OA) treatment may be related to mutations in the precursor of coagulation factor IX. Missense mutations at Ala-10 (Ala-10Thre and Ala-10Val) in the factor IX propeptide lead to impaired carboxylation of factor IX. When patients carrying these mutations are treated with coumarins, functional factor IX levels decrease significantly, leading to an excessively prolonged activated partial thromboplastin time (aPTT) and an increased bleeding risk. Mutations at Ala-10 have been described in northern-European patients, but it is not known whether geographical differences play a role in the prevalence of these mutations. We aimed to analyze the prevalence of mutations at Ala-10 in factor IX in southern-European patients on OA treatment. Patients attending the Oral Anticoagulant Unit of the Hospital Clinic were prospectively included. The aPTT was determined at their normal International Normalized Ratio (INR) control. When the aPTT was excessively prolonged for the INR value, determination of factor IX and genotyping for Ala-10 mutations was performed. A total of 2360 patients were included (1289 men, 1071 women; mean age, 70.5 +/- 12.1 years). Twenty-four patients (16 men, eight women; mean age, 61.0 +/- 16.2 years) had an aPTT over that expected for the INR. The mean aPTT was 69.6 +/- 16.2 s. Only one patient presented with a factor IX level lower than 10%. None of the 24 patients carried mutations at Ala-10. Mutations at Ala-10 in factor IX were non-existent in the southern-European population analyzed, and thus, do not represent a relevant cause of bleeding during OA treatment.

Pharmacogenetics of acenocoumarol: cytochrome P450 CYP2C9 polymorphisms influence dose requirements and stability of anticoagulation.

BACKGROUND AND OBJECTIVES: Cytochrome P4502C9 (CYP2C9) is the main enzyme implicated in coumarinic metabolism. Variant alleles, CYP2C9*2 and CYP2C9*3, have been related to decreased enzymatic activity, but their clinical relevance in acenocoumarol metabolism has not been established. We investigated CYP2C9 polymorphisms in relation to acenocoumarol dose requirement, stability of anticoagulation and bleeding. DESIGN AND METHODS: CYP2C9 genotyping was performed in 325 acenocoumarol-treated patients (INR target between 2.0 and 3.0) and in an additional group of 84 patients with repeated bleeding. RESULTS: Patients with the wild-type CYP2C9*1/*1 genotype (n=169) required a higher maintenance dose of acenocoumarol (17.1 8.7 mg/week) than did patients with the CYP2C9*2 (14.6 6.4 mg/week, p<0.05, N=97) or the CYP2C9*3 allele (11.2 6.2 mg/week, p<0.001, n=59). Out of 170 patients requiring a low-dose of acenocoumarol (70 years (OR=3.73, 95%CI=2.29-6.08, p<0.001), and the CYP2C9*3 allele (OR=4.75, 95%CI=2.36-9.55, p <0.001). Carriers of CYP2C9*3 spent less time within the therapeutic range (64.7 23.1%) than did patients with the CYP2C9*1/*1 genotype (75.1 22.0%, p<0.01), and more frequently had an INR >4.5 at the initiation of treatment (43.9% vs.11.6%, p<0.001), but did not show repeated bleeding more frequently (19.0% vs.15.5%, p=NS). INTERPRETATION AND CONCLUSIONS: CYP2C9*3 is related to lower acenocoumarol dose requirements, a higher frequency of over-anticoagulation at the initiation of therapy and an unstable anticoagulant response.