Anticoagulation Parameters Research Articles

Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols

Purpose The potential association between vitamin K intake and coagulation instability has been explored primarily in case reports and small, retrospective, uncontrolled studies. We prospectively evaluated the effects of dietary vitamin K intake on anticoagulation parameters. Methods In an observational protocol, clinical characteristics and vitamin K intake, assessed semiquantitatively, were evaluated in 39 outpatients who made 230 visits to our anticoagulation clinic. In a randomized crossover protocol, 12 patients with stable anticoagulation underwent 4-day in-hospital dietary interventions, 1 to 2 weeks apart, providing a 500% increase and an 80% decrease in vitamin K intake relative to the baseline level. Results Univariate analysis of the observational data demonstrated a progressive, statistically significant inverse association between the vitamin K intake score and different levels of anticoagulation. Multivariate logistic regression analysis showed that vitamin K intake was independently associated with both overcoagulation and undercoagulation. In the randomized protocol, the international normalized ratio increased from 2.6 ± 0.5 at baseline to 3.3 ± 0.9 at day 7 ( P = 0.005) in subjects on the vitamin K–depleted diet and decreased from 3.1 ± 0.8 at baseline to 2.8 ± 0.6 at day 4 ( P = 0.04) in those on the vitamin K–enriched diet. Conclusion Our prospective data strengthen the concept that the interaction between vitamin K and coumarin is a clinically relevant, major independent factor that interferes with anticoagulation stability.

Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor VLeiden mutation: a randomized trial

AbstractA plausible mechanism to explain thrombotic risk differences associated with the use of second- and third-generation oral contraceptives (OCs), particularly in carriers of factor VLeiden, is still lacking. In a double-blind trial, 51 women without and 35 women with factor VLeiden were randomized to either a second- (30 μg ethinylestradiol/150 μg levonorgestrel) or third- (30 μg ethinylestradiol/150 μg desogestrel) generation OC. After 2 cycles of use and a wash-out of 2 cycles, the participants continued with the corresponding progestagen-only preparation. Hemostatic variables that probe the activity of the anticoagulant protein C system were determined. Compared with levonorgestrel, desogestrel-containing OCs significantly decreased protein S and increased activated protein C (APC) resistance in both groups. OCs with desogestrel had the most pronounced effects in carriers of factor VLeiden. Progestagen-only preparations caused changes of anticoagulant parameters opposite to those of combined OCs, which in a number of cases were more pronounced with levonorgestrel. Our data show that progestagens in combined OCs counteract the thrombotic effect of the estrogen component. The higher thrombotic risk associated with third-generation OCs compared with second-generation OCs may be explained by the fact that desogestrel appeared less antithrombotic than levonorgestrel, especially in women with factor VLeiden. (Blood. 2004;103:927-933)

The effect of nateglinide on the pharmacokinetics and pharmacodynamics of acenocoumarol

SUMMARYObjective: The potential for a drug interaction was investigated between nateglinide, an oral antidiabetic agent, and acenocoumarol, an oral anticoagulant, as these drugs are primarily metabolized via CYP2C9.Methods: A two-period, randomized, double-blind, two-way crossover study design was employed to evaluate the effect of nateglinide on the pharmacokinetics and pharmacodynamics of acenocoumarol in 11 healthy male or female subjects. All subjects received either nateglinide 120 mg t.i.d. or placebo for 5 days in a crossover fashion and a single 10-mg dose of acenocoumarol on day 3. Plasma concentrations of R- and S-acenocoumarol and the anticoagulation parameters [prothrombin time (PT) and international normalized ratio of PT (PTINR)] were determined for 72 h following acenocoumarol administration. The pharmacokinetic and pharmacodynamic parameters of acenocoumarol were determined by noncompartmental analysis.Results: The mean (coefficient of variation (CV%)) area under the concentration-time curve (AUC0 () of R-acenocoumarol in the presence and absence of nateglinide was 4217 (23%) and 3831(24%) ng.h/ml, respectively. The corresponding values for S-acenocoumarol were 397 (20%) and 382 (23%), respectively. The mean (CV%) Cmax of R-acenocoumarol in the presence and absence of nateglinide was 304 (16%) and 316 (16%), respectively and the corresponding values for S-acenocoumarol were 142 (36%) and 141 (34%), respectively. The 90% confidence intervals indicated that exposure parameters, AUC0 (and Cmax, of both R- and S-acenocoumarol were within the acceptable limits of 0.8–1.25. The mean (CV%) of area under the concentration-time curve of PT (AUCPT) following acenocoumarol administration in the presence and absence of nateglinide was 1170 (10%) and 1136 (8%), respectively. The corresponding AUCINR values were 104 (13%) and 99 (10%), respectively. Nateglinide co-administration has no influence on the PT or PTINR of acenocoumarol (p > 0.05).Conclusion: Co-administration of nateglinide does not influence either the pharmacokinetics or the anticoagulant activity of R- and S-acenocoumarol in healthy subjects. This suggests that no dosage adjustments will be required when nateglinide and acenocoumarol are co-administered in clinical practice.

Active site-inactivated factor VIIa prevents thrombosis without increased surgical bleeding: Topical and intravenous administration in a rat model of deep arterial injury

Purpose: The primary event in the procoagulant response after vascular interventions is the tissue factor (TF)f–factor VIIa complex formation, which occurs when TF is exposed to the circulating blood by the inflicted trauma. Human recombinant active site-inhibited coagulation factor VIIa (FFR-rFVIIa) binds well to TF but cannot initiate blood coagulation, and should thereby block thrombus formation. This hypothesis was tested with a rat model of arterial thrombosis. Methods: In a blinded randomized study, the antithrombotic and antihemostatic effects of FFR-rFVIIa and heparin were evaluated in a rat model of mechanical deep arterial injury. In one arm of the study, FFR-rFVIIa (0.2 mg in 150 μL) or vehicle alone was applied topically at the site of vascular injury. In the other arm, FFR-rFVIIa (4 mg/kg), heparin (1 mg/kg), or vehicle alone was injected intravenously. Results: FFR-rFVIIa produced a powerful antithrombotic effect after both topical and intravenous administrations (P =.02 and P =.005, respectively) without increasing the surgical bleeding. Heparin prevented thrombosis equally well as FFR-rFVIIa (P =.0007), but doubled the surgical bleeding compared with FFR-rFVIIa (P =.03) and controls (P =.008). In the topical study, the antithrombotic effect was achieved without altering parameters of plasma anticoagulation (prothrombin time and activated partial thromboplastin time) or producing detectable levels of FFR-rFVIIa in plasma. Conclusion: In this model FFR-rFVIIa effectively inhibits thrombus formation without the expense of increased surgical bleeding, which indicates the potential of FFR-rFVIIa as an effective and safe strategy for prevention of thrombosis in reconstructive vascular surgery and various forms of percutaneous revascularization.(J Vasc Surg 2001;33:1072-9.)

Intracranial Hemorrhage and Oral Anticoagulant Treatment

Objective: To detect risk factors for intracranial hemorrhage (ICH) in patients with long-term oral anticoagulant and to identify clinical or radiological data specific of anticoagulant-related ICH. Methods and Patients: Three groups of patients were included. Group 1 represents patients who were admitted because of anticoagulant-related ICH between January 1984 and February 1996. All patients underwent CT scan. Clinical data, anticoagulation parameters, location and volume of the ICH, treatment and the 30-days in-hospital mortality were analyzed. Group 2 consisted of patients selected at random among all patients with spontaneous ICH admitted to our department during the same period of time. Patients without ICH, but regularly taking oral anticoagulants constituted group 3. Results: Seventy-nine patients with anticoagulant-related ICH were compared to 127 patients with spontaneous ICH. The volume of supratentorial ICH was greater in group 1 of patients and was correlated with a worse prognosis. Comparison of group 1 with group 3 (212 controls) demonstrated that length of anticoagulation, prothrombin time or excessive anticoagulation, prior cerebral infarct and use of acénocoumarol, but not age or indication of anticoagulant, were significant risk factors for ICH in multivariate analysis. Conclusions: The results emphasize that anticoagulant-related ICH are not clinically different from spontaneous ICH except for volume of bleeding, and that frequent and careful coagulation monitoring is needed, especially during the first year in order to decrease the risk of ICH.

Argatroban.

Argatroban is a direct thrombin inhibitor synthesised to bind to the catalytic site of the thrombin molecule. It binds rapidly and reversibly to both clot-bound and soluble thrombin. The relatively short elimination half-life of argatroban (39 to 51 minutes) and its reversible binding allow rapid achievement of therapeutic effect on initiation of therapy and rapid restoration of normal haemostasis upon cessation of therapy. Argatroban produces a predictable dose response that is well correlated with changes in anticoagulant parameters. Argatroban, given to patients with heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombosis (HITTS) in a large scale, nonrandomised, prospective trial, reduced a combined end-point 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.

A Randomized Cross-over Study on the Effects of Levonorgestrel- and Desogestrel-containing Oral Contraceptives on the Anticoagulant Pathways

The use of oral contraceptives (OC) causes disturbances of the procoagulant, anticoagulant and fibrinolytic pathways of blood coagulation which may contribute to the increased risk of venous thrombosis associated with OC therapy. Here we report the results of a cycle-controlled randomized cross-over study, in which we determined the effects of so-called second and third generation OC's on a number of anticoagulant parameters. In this study, 28 non-OC using women were randomly prescribed either a second generation (150 microg levonorgestrel/30 microg ethinylestradiol) or a third generation OC (150 microg desogestrel/30 microg ethinylestradiol) and who switched to the other OC after a two month wash out period. The anticoagulant parameters determined were: antithrombin (AT), alpha2-macroglobulin (alpha2-M), alpha1-antitrypsin, protein C inhibitor (PCI), protein C, total and free protein S and activated protein C sensitivity ratios (APC-sr) measured with two functional APC resistance tests which quantify the effect of APC on either the activated partial thromboplastin time (aPTT) or on the endogenous thrombin potential (ETP). During the use of desogestrel-containing OC the plasma levels of alpha2-M, alpha1-antitrypsin, PCI and protein C significantly increased, whereas AT and protein S significantly decreased. Similar trends were observed with levonorgestrel-containing OC, although on this kind of OC the changes in AT, PCI and protein S (which was even slightly increased) did not reach significance. Compared with levonorgestrel, desogestrel-containing OC caused a significant decrease of total (p <0.005) as well as free protein S (p <0.0001) and more pronounced APC resistance in both the aPTT (p = 0.02) and ETP-based (p <0.0001) APC resistance tests. These observations indicate that the activity of the anticoagulant pathways in plasma from users of desogestrel-containing OC is more extensively impaired than in plasma from users of levonorgestrel-containing OC.

Hypercoagulability and secondary hyperfibrinolysis may be related to abnormal lipid metabolism in patients treated with continuous ambulatory peritoneal dialysis.

To investigate abnormalities in the hemostatic and fibrinolytic system in CAPD patients, parameters of coagulation, anticoagulation, fibrinolysis, and platelet function were measured in 21 CAPD patients and 20 healthy controls. The CAPD patients had significantly higher levels of factor (F) IX, FVII, FX, antithrombin III, thrombin/antithrombin III complex, protein C, protein S, thrombomodulin, fibrinogen, fibrinopeptide A, plasminogen, FXIII, alpha2-plasmin inhibitor, alpha2-plasmin inhibitor/plasmin complex, D-dimer, fibrinopeptide B beta 15-42, and beta-thromboglobin than the healthy controls. The CAPD patients also showed a shorter prothrombin time. However, tissue plasminogen activator, plasminogen activator inhibitor-1 and platelet factor-4 did not show any significant differences from the levels in healthy controls. There was a significant positive correlation between many of the blood parameters and serum lipids. These results demonstrate that hypercoagulability and secondary hyperfibrinolysis occur in CAPD patients, and suggest that these changes may be related to abnormalities in lipid metabolism.

The Successful Application of a Heparin Nomogram in a Community Hospital

Heparin administration by physicians can vary greatly, and this variance can result in ineffective anticoagulation and reduced effectiveness of treatment. To examine the use of a heparin nomogram in two community hospitals to validate its effect on anticoagulation parameters and to determine its influence on length of hospital stay. Prenomogram and postnomogram intervention in two community hospitals in Sudbury, Ontario. All patients who presented and were admitted to the hospitals between 1991 and 1994 with a confirmed primary diagnosis of deep vein thrombosis and/or pulmonary embolism were eligible for the study. A heparin nomogram was instituted in April 1993 for treatment of deep vein thrombophlebitis and pulmonary embolism in hospitalized patients. The study patients were designated as prenomogram or postnomogram. Anticoagulation parameters (time to therapeutic activated partial thromboplastin time), number of diagnostic tests, percentage of times within the therapeutic range, and length of hospital stay were recorded for both groups. A total of 326 patients were identified from the database; 163 (50%) met the inclusion criteria. Patients in both groups appeared to be similar. Adequate anticoagulation was achieved faster (17.9 hours postnomogram vs 48.8 hours prenomogram; P < .001) and remained subtherapeutic less frequently in the postnomogram group (number of activated partial thromboplastin time tests below the therapeutic window; 56% prenomogram vs 28% postnomogram; P < .001). There were no differences between the groups with respect to length of stay (11.3 days prenomogram vs 10.9 days postnomogram; P = .60). More activated partial thromboplastin time tests were ordered in the postnomogram group (15.6 postnomogram vs 12.7 prenomogram; P = .001); however, fewer prothrombin time tests were ordered in the postnomogram group. A heparin nomogram was successfully used in a community hospital without a structured hematology-thrombosis service. Therapeutic anticoagulation was achieved faster and maintained more frequently, with less logistical problems, with this protocol. However, additional measures may be required to reduce the length of hospital stay.

Use of a Standardized Heparin Nomogram to Achieve Therapeutic Anticoagulation After Thrombolytic Therapy in Myocardial Infarction

Background: The recently completed Thrombolysis in Myocardial Infarction (TIMI) 4 Study compared three thrombolytic treatment regimens for acute myocardial infarction. The treatment arms included frontloaded recombinant tissue plasminogen activator (rtPA), anistreplase (APSAC), or both, in conjunction with an intravenous bolus of 5000 U of heparin, followed by 1000 U/h. To facilitate anticoagulation, a heparin nomogram was developed to maintain the therapeutic activated partial thromboplastin time at 1 1/2 to 2 times the control value. Methods: A poll revealed that nine centers made use of the recommended heparin nomogram and six did not, adjusting the heparin dosage according to local practice. Anticoagulation parameters, major hemorrhagic events, and the frequency of heparin interruption were compared between centers that used and did not use the nomogram. Results: Subtherapeutic activated partial thromboplastin time values were noted in 4%, 14%, 29%, 46%, 37%, and 34% of patients 8, 12, 24, 48, 72, and 96 hours, respectively, after heparin treatment was begun. Patients with subtherapeutic values at 24 hours were younger (mean±SD, 55.2±10.6 vs 59.6±10.6 years, P =.02) and weighed more (86.4±13.5 vs 78.9±15.7 kg, P =.007) than patients with therapeutic values. Centers that used the nomogram had significantly fewer subtherapeutic values at 48 and 96 hours. In addition, heparin therapy was interrupted less frequently at centers that used the nomogram (38.1% vs 68.7%, P Conclusions: The use of a heparin nomogram provided improved anticoagulation in patients treated with thrombolytic therapy for myocardial infarction. Weight- and age-adjusted heparin dosing may provide further improvement in anticoagulation with heparin therapy. Our findings support the need for frequent monitoring of the activated partial thromboplastin time and for a standardized approach to adjusting the heparin dosage. (Arch Intern Med. 1994;154:1492-1496)

Use of a standardized heparin nomogram to achieve therapeutic anticoagulation after thrombolytic therapy in myocardial infarction. TIMI 4 investigators. Thrombolysis in Myocardial Infarction

The recently completed Thrombolysis in Myocardial Infarction (TIMI) 4 Study compared three thrombolytic treatment regimens for acute myocardial infarction. The treatment arms included front-loaded recombinant tissue plasminogen activator (rtPA), anistreplase (APSAC), or both, in conjunction with an intravenous bolus of 5000 U of heparin, followed by 1000 U/h. To facilitate anticoagulation, a heparin nomogram was developed to maintain the therapeutic activated partial thromboplastin time at 1 1/2 to 2 times the control value. A poll revealed that nine centers made use of the recommended heparin nomogram and six did not, adjusting the heparin dosage according to local practice. Anticoagulation parameters, major hemorrhagic events, and the frequency of heparin interruption were compared between centers that used and did not use the nomogram. Subtherapeutic activated partial thromboplastin time values were noted in 4%, 14%, 29%, 46%, 37%, and 34% of patients 8, 12, 24, 48, 72, and 96 hours, respectively, after heparin treatment was begun. Patients with subtherapeutic values at 24 hours were younger (mean +/- SD, 55.2 +/- 10.6 vs 59.6 +/- 10.6 years, P = .02) and weighed more (86.4 +/- 13.5 vs 78.9 +/- 15.7 kg, P = .007) than patients with therapeutic values. Centers that used the nomogram had significantly fewer subtherapeutic values at 48 and 96 hours. In addition, heparin therapy was interrupted less frequently at centers that used the nomogram (38.1% vs 68.7%, P < .001). Major spontaneous hemorrhage, reinfarction, and reocclusion rates were low and were about the same in the two groups. The use of a heparin nomogram provided improved anticoagulation in patients treated with thrombolytic therapy for myocardial infarction. Weight- and age-adjusted heparin dosing may provide further improvement in anticoagulation with heparin therapy. Our findings support the need for frequent monitoring of the activated partial thromboplastin time and for a standardized approach to adjusting the heparin dosage.

Recombinant hirudin in patients with chronic, stable coronary artery disease. Safety, half-life, and effect on coagulation parameters.

Because the specific antithrombin hirudin prevents platelet-rich arterial thrombus and accelerates thrombolysis in a variety of animal models, it has promise as antithrombotic therapy. We therefore studied the half-life, effect on anticoagulant parameters, and safety of hirudin in patients with coronary artery disease. Thirty-eight men and 1 woman (age [mean +/- SD], 60.4 +/- 6.9 years) with angiographic coronary disease were allocated in a single-blind ascending dosage study to a 6-hour i.v. infusion of recombinant hirudin (CGP 39,393) or matching placebo. The median terminal half-life for hirudin, measured by ELISA, was 2.7, 2.3, 2.9, 3.1, and 2.0 hours for the 0.02, 0.05, 0.1, 0.2, and 0.3 mg.kg-1 x h-1 groups, respectively. Activated partial thromboplastin times (aPTT) at 3, 4, and 6 hours were averaged into a plateau value. The aPTT plateau-to-baseline ratios were 1.5 +/- 0.1, 2.0 +/- 0.1, 2.3 +/- 0.1, 2.7 +/- 0.1, and 2.9 +/- 0.1, respectively, with hirudin infused at 0.02, 0.05, 0.1, 0.2, and 0.3 mg.kg-1 x h-1. From 62% to 77% of the aPTT plateau value was seen within 30 minutes of starting the infusions and was directly related to dose. The aPTT-to-baseline ratios correlated well with plasma hirudin levels (r = .88), whereas poor correlation and sensitivity were observed between plasma hirudin levels and activated coagulation time (ACT)-to-baseline ratios (r = .44). Plasma levels of hirudin and ACT in seconds correlated overall well (r = .80), but considerable overlap occurred between baseline ACT and ACT at plasma hirudin concentrations < 1000 ng/mL. Prothrombin times were significantly prolonged only at a dosage of > or = 0.05 mg.kg-1 x h-1 and were 11.8 +/- 0.5 (INR = 1.0), 12.3 +/- 0.7 (INR = 1.1), 13.3 +/- 1.2 (INR = 1.4), 14.2 +/- 0.4 (INR = 1.7), and 15.8 +/- 0.9 (INR = 2.3) seconds for each respective hirudin dosage. Thrombin times were beyond range (> 600 seconds) at 6 hours in all except 2 patients who received the lowest dosage. All parameters returned to baseline between 8 and 18 hours after the infusion. Bleeding times were not significantly prolonged. No side effects occurred. No antibodies to hirudin were detected 2 weeks after the infusion. Recombinant hirudin has a terminal half-life of 2 to 3 hours. The aPTT correlates well with plasma levels of hirudin and allows close titration over a wide range of anticoagulation, while ACT and prothrombin time are relatively insensitive for monitoring hirudin administration. At anticoagulant levels effective in experimental thrombosis, a 6-hour infusion of hirudin is well tolerated and safe in a predominantly male group of patients with stable coronary atherosclerosis.

Activated Clotting Time, Anticoagulation, Use of Heparin, and Thrombin Activation during Extra-corporeal Circulation: Changes under Aprotinin Therapy

In a prospective randomized double-blind study, the activated clotting time (ACT), heparin use, parameters of anticoagulation, and thrombin activation during extracorporeal circulation were studied in 20 patients who underwent aortocoronary bypass operations. The patients were divided into two groups: Group A was given a placebo, while Group B was given aprotinin according to the high-dosage Trasylol scheme. During ACT-controlled heparinization (ACT > 460 s) there was a significant heparin reduction in Group B (22,100 USP-E) in comparison to Group A (35,200 USP-E). Despite this lower quantity of total heparin, the ACT in Group B was significantly extended (Group B = 837 s, Group A = 492 s). The ACT did not correlate thereby with the heparin concentration or the total quantity of heparin in either group. In contrast to the control group, there was no increased thrombin generation in the aprotinin group. The thrombin-antithrombin III complexes (Group A = 143 micrograms/L, Group B = 102 micrograms/L) as well as the specific dimers (Group A = 2755 ng/ml, Group B = 448 ng/ml) were significantly lower under the use of aprotinin. The connection between the ACT, the heparin concentration, and the aprotinin concentration was further investigated in an ex-vivo model. The ACT samples were diluted with the aim of eliminating the influence of aprotinin. Under these conditions it was shown that for heparin concentrations between 2-4 U/ml there was a parallel shift of the ACT/heparinconcentration curve with the addition of aprotinin in a defined concentration range of 200-300 KIU.(ABSTRACT TRUNCATED AT 250 WORDS)