Variations of Prothrombin Time, Factor VII and Protein C with a Single Daily Dose of Acenocoumarol

Jn, Fiessinger; Vitoux, J F; Roncato, M; Dellinger, A.; Dizien, O.; Aiach, Martine

doi:10.1159/000215906

Cited by 4 publications

(2 citation statements)

References 5 publications

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“…They limit the action of mainly involving those factors with the shortest half-lives such as factor VII and protein c.l2 5,26) carboxylase by exhausting the active vitamin Khydroquinone, thus reducing the intrahepatic y-carboxylation ofGlu residues of the vitamin K-dependent clotting proteins. They limit the action of mainly involving those factors with the shortest half-lives such as factor VII and protein c.l2 5,26) carboxylase by exhausting the active vitamin Khydroquinone, thus reducing the intrahepatic y-carboxylation ofGlu residues of the vitamin K-dependent clotting proteins.…”

Section: Oral Anticoagulantsmentioning

confidence: 99%

Warfarin Withdrawal

Palareti

Legnani

1996

Clinical Pharmacokinetics

130

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Warfarin, like all the 4-hydroxycoumarin compounds, has an asymmetric carbon atom. The clinically available warfarin preparations consist of a racemic mixture of equal amounts of 2 distinct S and R isomers, the former being 4-times more potent as anticoagulant and more susceptible to drug interaction. Warfarin is highly water soluble and rapidly absorbed from the stomach and the upper gastrointestinal tract; its plasma concentrations peak 60 to 90 minutes after oral administration. Warfarin binds to the enzyme vitamin K 2,3-epoxide reductase in liver microsomes, stopping the cycle of vitamin K and reducing gamma-carboxylation of the precursors of vitamin D-dependent pro- and anticoagulant factors. A variable fraction of the binding with the target enzyme, albeit small, can be reversed by competitive displacers, such as dithiol-reducing agent activity. Differences in dithiol-reducing activity have been suggested as a contributing factor to the wide interindividual differences in sensitivity to oral anticoagulants. The anticoagulant effect is caused by a small fraction of the drug, since most (97 to 99%) is protein bound (mainly to albumin) and ineffective. Drugs that can displace the albumin binding will increase the action of warfarin, even though this effect is counteracted by a more rapid elimination of the drug. The elimination half-life of warfarin varies greatly among individuals, ranging from 35 to 45 hours; the S isomer has, however, an average half-life shorter than the R isomer. The plasma levels of vitamin K-dependent proteins are determined by a dynamic equilibrium between their synthesis and half-life times. The delay before warfarin takes effect reflects the half-life of the clotting proteins; the levels of factor VII and protein C (with shorter half-lives) are reduced earlier, reaching steady inhibited levels in about 1 day, whereas factor II takes more than 10 days. Oral anticoagulant therapy (OAT) with warfarin or other coumarin derivatives is increasingly administered to patients for primary or secondary prevention of various arterial or venous thromboembolic diseases. If in some clinical conditions OAT is given indefinitely, in others--such as venous thromboembolism or after tissue heart valve replacement--anticoagulants are usually given only for the high risk period of thrombotic complication. A recent large prospective study performed by the Italian Federation of Anticoagulation Clinics showed that about 30% of the patients who began OAT for various clinical indications stopped treatment at different times, confirming that withdrawal from OAT is an occurrence that affects a large number of patients. The expression 'rebound phenomenon' was adopted to indicate a hypercoagulant condition occurring after warfarin withdrawal. A possible more frequent recurrence of thromboembolism after cessation of anticoagulation became a matter of controversy and many clinical studies, mostly observational and noncontrolled, reported on the issue with inconsistent results. Most authoritative commentators agreed ...

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Section: Oral Anticoagulantsmentioning

confidence: 99%

Warfarin Withdrawal

Palareti

Legnani

1996

Clinical Pharmacokinetics

130

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“…In this modelhecould showthat the plasma leveloffactor VII fluctuated morethan the plasma leveloffactor II, especially in ashort-acting VKA,such as acenocoumarol. In other studies the variation of the INR values and some clotting factorsd uring 24 hw as determinedf or phenprocoumon (14),a cenocoumarol (14)(15)(16)(17) and warfarin (18). However, these studiesw ere carried outo nlyd uring one (14,(16)(17)(18) or twodays (15), mostly withasmall number of patients.…”

Section: Introductionmentioning

confidence: 99%

The influence on INRs and coagulation factors of the time span between blood sample collection and intake of phenprocoumon or acenocoumarol: Consequences for the assessment of the dose

Geest-Daalderop¹,

Hutten²,

Péquériaux³

et al. 2007

Thromb Haemost

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SummaryManaging treatment with vitamin K antagonists, the prothrombin time (PT),expressed as international normalized ratio (INR), may not represent the INR during the entire 24 hour (h) period, and this variation may be different between long-acting phenprocoumon and short-acting acenocoumarol. For both drugs we investigated the variation in 24 h of the PT/INR, the consequences for the assessment of the doses and which vitamin K-dependent factor causes the daily variation. Patients on self-management took their medication at 6 p.m. and determined their INRs for eight weeks, once a week and three times daily (8.30 a.m., 6 p.m. and 11 p.m., thus 14.5 h, 24 h and 29 h after taking the medication, respectively). Acenocoumarol showed a significant variation in INRs over the 24 h period, with 22 out of 80 INRs >20% lower at 11 p.m. versus 8.30 a.m. Phenprocoumon showed only few variations. Patients managed by the anticoagulation clinic took their medication at 6 p.m. for four weeks and then at 8 a.m. for four weeks, 15 h and 25 h, respectively, before the weekly blood collection. PT/INR and coagulation factorsVII, X and II were determined. With acenocoumarol, taken 25 h before blood collection, the INRs were significantly different compared to 15 h, especially attributed to plasma levels of factorVII. Those on phenprocoumon were equal. These variations of INRs during 24 h may have major effects on the prescribed dose of short-acting vitamin K antagonists, such as acenocoumarol, especially for INRs at the limits of the therapeutic ranges.

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