Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy.

BACKGROUND: Although prothrombin complex concentrate (PCC) is often used to counteract vitamin K antagonist (VKA) therapy, evidence regarding the optimal dose for this indication is lacking. In Dutch hospitals, either a variable dose, based on body weight, target INR (international normalised ratio) and initial INR, or a fixed dose is used. AIM/OBJECTIVES: In this observational, pilot study, the efficacy and feasibility of the fixed dose strategy compared to the variable dosing regimen, is investigated. MATERIALS AND METHODS: Consecutive patients receiving PCC (Cofact®, Sanquin, Amsterdam) for VKA reversal because of a major non-cranial bleed or an invasive procedure were enrolled in two cohorts. Data were collected prospectively in the fixed dose group, cohort 1, and retrospectively in the variable dose regimen, cohort 2. Study endpoints were proportion of patients reaching target INR and successful clinical outcome. RESULTS: Cohort 1 consisted of 35 and cohort 2 of 32 patients. Target INR was reached in 70% of patients in cohort 1 versus 81% in cohort 2 (P = 0·37). Successful clinical outcome was seen in 91% of patients in cohort 1 versus 94% in cohort 2 (P = 1·00). Median INR decreased from 4·7 to 1·8 with a median dosage of 1040 IU factor IX (F IX) in cohort 1 and from 4·7 to 1·6 with a median dosage of 1580 IU F IX in cohort 2. CONCLUSION: This study suggests that a fixed dose of 1040 IU of F IX may be an effective way to rapidly counteract VKA therapy in our patient population and provides a basis for future research.

[Reversal of acenocoumarol anticoagulation with activated factor VII in massive hemorrhage following rupture of a splenic artery pseudoaneurysm]. / Reversión del efecto del acenocumarol con factor VII activado en la hemorragia masiva tras rotura de aneurisma esplénico.

A 66-year-old man with a metallic valve and under treatment with acenocoumarol developed hypovolemic shock after rupture of a splenic artery pseudoaneurysm. We managed to reverse anticoagulation within 60 minutes by administering 20 mg of vitamin K and 4.8 mg of activated recombinant factor VII. No thromboembolic adverse events were observed. We discuss the pharmacologic effects of coumarin derivatives and their antagonists, as well as the use of activated factor VII in the reversal of anticoagulation by these drugs.

Impact of pre-treatment INR level on the effect of intravenous low dose vitamin K in patients with excessive anticoagulation.

Administration of vitamin K is the common mode of treatment in excessively anticoagulated patients. However, patient's response to vitamin K varies, depending on the vitamin K dose and the route of administration. Another potential source of variation is the pre-treatment INR which has not been accounted for in most previous studies. In the present study the effect of baseline INR on the response to a single dose of intravenous vitamin K (0.5 mg) was studied in 95 episodes of excessively anticoagulated patients (n = 76). In 67 episodes of moderately excessive baseline INR (6-10) mean INR declined from 8.0 +/- 1.2 to 2.6 +/- 0.9 at 24 hours, 59/67 (88%) responding within the first 12 hours and not requiring a second dose. In contrast, in 28 episodes with highly excessive baseline INR (> 10) response was slower; mean INR declining from 13.6 +/- 2.7 to 4.0 +/- 2.1 at 24 hours. In 14/28 of these episodes, patients failed to respond to vitamin K in the first 12 hours and required a second vitamin K dose. We conclude that INR at presentation affects the response to vitamin K and that this INR value should be considered in determining appropriate vitamin K doses.

Platelet aggregation in different antithrombotic regimens. Possible proaggregant effect of low level oral anticoagulation.

UNLABELLED: Few trials have studied platelet activity during oral anticoagulation and all show a tendency for platelet aggregation to increase. This adverse effect has also been shown in some patients treated with unfractionated heparin, the so-called white clot syndrome. We studied platelet aggregation in patients with atrial fibrillation enrolled in the NASPEAF study and receiving antiaggregant, anticoagulant and both treatments. METHODS: 15 healthy control subjects (group C) and 99 patients were enrolled, the latter receiving 4 different antithrombotic regimens for platelet aggregation: group 1, 600 mg of the antiplatelet drug triflusal; group 2, anticoagulation for an INR of 2-3; and both treatments with 2 different levels of anticoagulation, mean INR of 1.85 (group 3) and of 2.15 (group 4). The same amounts of the agonists ADP, arachidonic acid and collagen were used in all tests. For statistical analysis we used the interval in min, from the addition of the agonist to the beginning of aggregation and the % of aggregation at 5 and 8 min. RESULTS: After arachidonic acid was given, the interval to the beginning of aggregation was shorter in group 2 than in group C: 0.6 +/- 0.21 and 1.1 +/- 1.2, and in both was significantly shorter than in the other three receiving antiplatelet drugs alone: group 1 = 1.58 +/- 1.4 or combined with anticoagulants: group 3 = 1.7 +/- 1.7 and group 4 = 2.4 +/- 2.1. The % of aggregation at 5 min, in groups C, 2, 1, 3 and 4 was respectively 48 +/- 24, 43.2 +/- 19, 29.6 +/- 17, 34.8 +/- 22 and 23.2 +/- 22.5. The data showed significantly increased platelet activity in groups C and 2 compared to groups 1, 3 and 4. Group 3 with a low anticoagulation level (mean INR = 1.85) showed a tendency to greater platelet activity than group 1 and 4 with p value = 0.08. CONCLUSIONS: The antiplatelet drug triflusal alone or combined with a therapeutic level of anticoagulation effectively reduces platelet aggregation and is not influenced by anticoagulant treatment. A low level of anticoagulation (INR < 2) shows a tendency to increase platelet activity.

Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes.

The oral anticoagulant acenocoumarol is given as a racemic mixture. The (S)-enantiomer is rapidly cleared and is the reason why only (R)-acenocoumarol contributes to the pharmacological effect. The objective of the study was to establish the cytochrome P450 (CYP) enzymes catalyzing the hydroxylations of the acenocoumarol enantiomers. Of various cDNA-expressed human CYPs, only CYP2C9 hydroxylated (S)-acenocoumarol. Hydroxylation occurred at the 6-, 7-, and 8-position with equal K(m) values and a ratio of 0.9:1:0.1 for V(max). CYP2C9 also mediated the 6-, 7-, and 8-hydroxylations of (R)-acenocoumarol with K(m) values three to four times and V(max) values one-sixth times those of (S)-acenocoumarol. (R)-Acenocoumarol was also metabolized by CYP1A2 (6-hydroxylation) and CYP2C19 (6-, 7-, and 8-hydroxylation). In human liver microsomes one enzyme only catalyzed (S)-acenocoumarol hydroxylations with K(m) values < 1 microM. In most of the samples tested the 7-hydroxylation of (R)-acenocoumarol was also catalyzed by one enzyme only. The 6-hydroxylation was catalyzed by at least two enzymes. Sulfaphenazole could completely inhibit in a competitive way the hydroxylations of (S)-acenocoumarol and the 7-hydroxylation of (R)-acenocoumarol. The 6-hydroxylation of (R)-acenocoumarol could be partially inhibited by sulfaphenazole, 40 to 50%, and by furafylline, 20 to 30%. Significant mutual correlations were obtained between the hydroxylations of (S)-acenocoumarol, the 7-hydroxylation of (R)-acenocoumarol, the 7-hydroxylation of (S)-warfarin, and the methylhydroxylation of tolbutamide. The results demonstrate that (S)-acenocoumarol is hydroxylated by a single enzyme, namely CYP2C9. CYP2C9 is also the main enzyme in the 7-hydroxylation of (R)-acenocoumarol. Other enzymes involved in (R)-acenocoumarol hydroxylation reactions are CYP1A2 and CYP2C19. Drug interactions must be expected, particularly for drugs interfering with CYP2C9. Also, drugs interfering with CYP1A2 and CYP2C19 may potentiate acenocoumarol anticoagulant therapy.

Lack of effect of influenza vaccine on anticoagulation by acenocoumarol.

OBJECTIVE: To analyze the effects of influenza vaccine on patients receiving chronic anticoagulant therapy with acenocoumarol. DESIGN: A prospective trial. SETTING: Hospital de la Santa Creu i Sant Pau, Barcelona. PATIENTS: Forty-three patients who received acenocoumarol, had stable levels of International Normalized Ratio (INR), and did not need dosage modification for four months before entering the study. INTERVENTION: A study of anticoagulation levels measured by INR at 7, 15, and 30 days from administration of the trivalent vaccine from the 91-92 campaign was conducted. MAIN OUTCOME MEASURES: Comparison was made between basal values (day 0) and anticoagulation levels at 7, 15, and 30 days from vaccine administration by means of a repeated-measures ANOVA. RESULTS: Nine patients (21 percent) had INR levels out of the therapeutic range during the study period. INR increased in three of these patients and decreased in six. There were no significant intraindividual changes in INR values during the time period analyzed (p = 0.125). No hemorrhagic or thrombotic manifestations occurred and no significant changes in renal or hepatic biochemistry were observed. CONCLUSIONS: Influenza vaccine does not modify acenocoumarol activity in patients receiving long-term anticoagulant therapy.

Interaction between anticoagulants and contraceptives: an unsuspected finding.

To assess the effects of oral contraceptives on anticoagulant treatment the prothrombin times of 12 patients were measured while they were taking both drugs simultaneously and while they were taking only anticoagulants. The mean prothrombin time ratio was significantly higher when patients were taking both drugs than when they were taking only anticoagulants and their doses of anticoagulant were significantly lower. During both periods most of the prothrombin values remained in the therapeutic range. These findings suggest that, contrary to the common belief that oral contraceptives diminish the effects of anticoagulants, contraceptives in fact potentiate the action of the anticoagulants.

PIP: Of 197 patients with heart disease on oral anticoagulant treatment (nicoumalone) 12 were simultaneously taking an estroprogestogenic oral contraceptive. The patients were aged 27-44 years old and anticoagulation control was maintained by measuring prothrombin activity. For 230 months the women took anticoagulant only. The mean prothrombin time ratio was significantly higher when the women were taking both the anticoagulant and the pill than taking only the anticoagulant, but the prothrombin values were in the therapeutic range during both periods. The oral contraceptive seems to potentiate anticoagulation activity not diminish their effect. It is suggested that the estrogen in the pill may produce enzymatic inhibition in microsomes of hepatic cells which potentiate anticoagulant activity through retarded metabolic degradation.