-
Yan Liang, Marilyn Johnston,
Jack Hirsh,
Guillaume Pare,
Chunjian Li,
Shamir Mehta,
Koon K Teo,
Debi Sloane,
Qilong Yi,
Jun Zhu,
John W Eikelboom
Journal of Thrombosis and Thrombolysis 10/2012; · 1.48 Impact Factor
-
Yan Liang, Marilyn Johnston,
Jack Hirsh,
Guillaume Pare,
Chunjian Li,
Shamir Mehta,
Koon K Teo,
Debi Sloane,
Qilong Yi,
Jun Zhu,
John W Eikelboom
[show abstract]
[hide abstract]
ABSTRACT: Clopidogrel is a prodrug that undergoes bioconversion via cytochrome P450 system to form an active metabolite (AM) that binds to the platelet ADP receptor. The antiplatelet effect of clopidogrel is commonly assessed by measuring the aggregatory response to 5 μM ADP by light transmission aggregation (LTA) or multiple electrode aggregometry (MEA) or by the vasodilator-stimulated phosphoprotein platelet reactivity index (VASP-PRI). To determine which of these three tests of platelet ADP receptor pathway inhibition most closely correlates with clopidogrel AM levels. We analyzed blood samples from 82 patients with coronary artery disease who were randomized to receive double-dose or standard dose clopidogrel for 2 weeks. We measured peak clopidogrel AM levels, platelet aggregation in response to ADP and VASP-PRI on days 1, and repeated all the measures on days 7 and 14. Linear regression analysis was used to examine the correlation between clopidogrel AM and LTA, MEA and VASP-PRI. Bland-Altman plots were used to explore the agreement between tests of the antiplatelet effects of clopidogrel. Clopidogrel AM on day 1 correlated most closely with VASP-PRI (r = -0.5767) and demonstrated weaker correlations with LTA (r = -0.4656) and MEA (r = -0.3384) (all p < 0.01). Intra-class correlation (ICC) between VASP-PRI and LTA was 0.6446; VASP-PRI and MEA was 0.4720; and LTA and MEA was 0.4693. Similar results were obtained on days 7 and 14. Commonly used pharmacodynamic measures of clopidogrel response are only moderately correlated with clopidogrel AM levels and may not be suitable to measure the adequacy of clopidogrel therapy.
Journal of Thrombosis and Thrombolysis 07/2012; 34(4):429-36. · 1.48 Impact Factor
-
Jim D Douketis,
Jim A Julian,
Mark A Crowther,
Clive Kearon,
Shannon M Bates,
Marisa Barone,
Franco Piovella,
Saskia Middeldorp,
Paolo Prandoni, Marilyn Johnston,
Lorrie Costantini,
Jeffrey S Ginsberg
[show abstract]
[hide abstract]
ABSTRACT: Few studies have assessed the effect of prothrombotic blood abnormalities on the risk of deep vein thrombosis (DVT) with hormone replacement therapy (HRT).
We studied postmenopausal women with suspected DVT in whom HRT use and prothrombotic blood abnormalities were sought. Cases had unprovoked DVT and controls had no DVT and without DVT risk factors. The risk of DVT was determined in women with and without prothrombotic abnormalities.
A total of 510 postmenopausal women with suspected DVT were assessed; 57 cases and 283 controls were identified. Compared to HRT, nonusers without the factor V Leiden mutation, the risk of DVT was increased in estrogen-progestin HRT users (odds ratio [OR], 3.2; 95% confidence interval [CI]: 1.2-8.6) and in nonusers with the factor V Leiden mutation (OR, 5.3; 1.9-15.4) and appears multiplied in users of estrogen-progestin HRT with the factor V Leiden mutation (OR, 17.1; 3.7-78). Compared to HRT, nonusers with normal factor VIII, the risk of DVT was increased in estrogen-progestin HRT users with normal factor VIII (OR, 2.8; 1.0-7.9) and in HRT nonusers with the highest factor VIII quartile (OR, 6.0; 2.1-17), and appears to be multiplied in women who are users of estrogen-progestin HRT with the highest factor VIII quartile (OR, 17.0; 3.6-80).
In postmenopausal women who are estrogen-progestin HRT users, the presence of the factor V Leiden mutation or an elevated factor VIII level appears to have a multiplicative effect on their overall risk of DVT, increasing it 17-fold compared to women without these blood abnormalities who are HRT nonusers.
Clinical and Applied Thrombosis/Hemostasis 11/2011; 17(6):E106-13. · 1.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Abnormalities of the Protein C (PC) pathway are found in the majority of patients with thrombophilia. ProC Global is a coagulation assay that reflects the net effect of the PC pathway by measuring the activated partial thromboplastin time (APTT) of patient and control plasma, before and after activation of endogenous PC by Protac, a snake venom. Previous studies have suggested that abnormalities in this test are associated with an increased risk of venous thromboembolism (VTE). A retrospective analysis was performed using frozen plasma samples from 140 patients with confirmed VTE to determine whether an abnormal ProC Global result (in the presence and in the absence of known abnormalities in the PC pathway) is a predictor of initial and recurrent VTE. Patients were tested for the presence of activated protein C resistance, Factor V Leiden, PC and protein S (PS) deficiency, and non-specific inhibitor positivity. Mean ProC Global results were significantly lower in patients with recurrent VTE than in patients without recurrent VTE. The association between abnormal ProC Global result and recurrent VTE showed a strong trend, before (odds ratio, OR 3.6) and after (OR 3.1) exclusion of known thrombophilic abnormalities. Patients with a first episode of idiopathic VTE also expressed significant lower ProC Global results than those with secondary VTE. After exclusion of known PC pathway abnormalities, there was a statistically significant association between abnormal ProC Global and initial idiopathic VTE (p=0.04). These results suggest that ProC Global may serve as a predictor of recurrent VTE and potentially for first episode of idiopathic VTE. ProC Global may help identify patients at increased risk of initial and recurrent VTE.
Thrombosis and Haemostasis 04/2005; 93(3):600-4. · 5.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Because clinical diagnosis is inaccurate, objective testing is usually considered necessary when patients present with suspected deep venous thrombosis (DVT).
To determine whether a negative result on a quantitative latex D dimer assay eliminates the need for further investigation in patients with a low or moderate pretest probability of DVT.
Prospective cohort study.
Three tertiary care hospitals in Canada.
556 consecutive outpatients with suspected first DVT.
Patients were categorized as having a low, moderate, or high pretest probability of DVT and then underwent D-dimer testing. Patients with low or moderate pretest probability and a negative D-dimer result had no further diagnostic testing and received no anticoagulant therapy. Serial compression ultrasonography was performed in all other patients. Patients who did not receive a diagnosis of DVT were followed for symptomatic venous thromboembolism.
Objectively confirmed symptomatic venous thromboembolic events during 3 months of follow-up.
283 patients (51%) had low or moderate pretest probability and a negative D-dimer result. One of these patients had DVT during follow-up (negative likelihood ratio, 0.05 [CI, 0.01 to 0.23]). The negative likelihood ratio of the d -dimer test in all patients was 0.03 (CI, 0.01 to 0.16).
A negative result on a quantitative latex d -dimer assay safely eliminates the need for further testing in patients with low or moderate pretest probability of DVT.
Annals of internal medicine 06/2003; 138(10):787-94. · 16.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We studied whether aspirin resistance, defined as failure of suppression of thromboxane generation, increases the risk of cardiovascular events in a high-risk population.
Baseline urine samples were obtained from 5529 Canadian patients enrolled in the Heart Outcomes Prevention Evaluation (HOPE) Study. Using a nested case-control design, we measured urinary 11-dehydro thromboxane B2 levels, a marker of in vivo thromboxane generation, in 488 cases treated with aspirin who had myocardial infarction, stroke, or cardiovascular death during 5 years of follow-up and in 488 sex- and age-matched control subjects also receiving aspirin who did not have an event. After adjustment for baseline differences, the odds for the composite outcome of myocardial infarction, stroke, or cardiovascular death increased with each increasing quartile of 11-dehydro thromboxane B2, with patients in the upper quartile having a 1.8-times-higher risk than those in the lower quartile (OR, 1.8; 95% CI, 1.2 to 2.7; P=0.009). Those in the upper quartile had a 2-times-higher risk of myocardial infarction (OR, 2.0; 95% CI, 1.2 to 3.4; P=0.006) and a 3.5-times-higher risk of cardiovascular death (OR, 3.5; 95% CI, 1.7 to 7.4; P<0.001) than those in the lower quartile.
In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B2 predict the future risk of myocardial infarction or cardiovascular death. These findings raise the possibility that elevated urinary 11-dehydro thromboxane B2 levels identify patients who are relatively resistant to aspirin and who may benefit from additional antiplatelet therapies or treatments that more effectively block in vivo thromboxane production or activity.
Circulation 04/2002; 105(14):1650-5. · 14.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Local ISI calibration has been proposed to improve INR accuracy and inter-laboratory precision. We evaluated the affect of local PT calibration on INR precision and accuracy using six levels of frozen plasma calibrants prepared and pooled from normal donors and patients stabilized on sodium warfarin (coumarin) based oral anticoagulant therapy (OAT). Reference prothrombin time (PT) and INR values were assigned to these calibrants in accordance with World Health Organization (WHO) procedure using rTF 95 international reference preparation (IRP) of thromboplastin (human recombinant). These calibrants, along with five similarly characterized individual OAT patient plasmas, were distributed to 127 laboratories in a multi-center study. Calibrant plasmas were evaluated and INR's subsequently determined on the 5 OAT test samples using: 1) the ISI and MNPT in place before the study (the local system), 2) the locally calibrated ISI value (local system with ISI calibration) and 3) a PT-INR calibration curve. Precision of INR results improved across the study group using the local system with ISI calibration and the PT-INR calibration curve methods, while accuracy of INR results improved using the PT-INR calibration curve approach only and not the local ISI calibration. The authors conclude that frozen plasma calibrants can be used locally to enhance precision and accuracy of PT results as reported in INR. These calibrants are effective over a range of reagents and instrument combinations. Furthermore, the PT-INR calibration curve appears to be the superior method for local calibration.
Thrombosis and Haemostasis 02/2002; 87(1):74-9. · 5.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The issue of whether long-term sodium warfarin therapy results in decreased bone density is controversial. To address this question, we randomized rats to once daily subcutaneous injections of either sodium warfarin (0.20 or 0.25 mg/kg) or saline for 28 days and monitored the effects on bone, both biomechanically and by histomorphometric analysis. In addition, the anticoagulant status of both saline- and warfarin-treated rats were monitored throughout the course of the experiment by measuring the prothrombin time, expressed as international normalized ratios (INRs). Rats treated with 0.25 mg/kg warfarin demonstrated INRs of approximately 2.6, while rats treated with either 0.20 mg/kg warfarin or saline were found to have INRs of 1.3 and 1.0, respectively. Biomechanical testing of the right femur of rats treated with 0.25 mg/kg warfarin demonstrated that warfarin caused an 8% reduction in bone strength as measured by maximum tolerated load. A similar reduction in the biomechanical parameters of energy to break (P<.0001) and force at break point (P<.005) was also observed. Histomorphometric analysis of the left femur of warfarin-treated rats revealed a 17% reduction in cancellous bone volume. This was accompanied by a 60% decrease in osteoblast surface, as well as an 80% reduction in osteoid surface. In contrast, warfarin treatment had the opposite effect on osteoclast surface, which was 35% higher following warfarin treatment. Based on these observations, we conclude that clinically relevant doses of warfarin decrease femoral bone strength and cancellous bone volume, both by decreasing the rate of bone formation and increasing the rate of bone resorption.
Thrombosis Research 02/2002; 105(4):353-8. · 2.44 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Anticoagulant therapy during pregnancy is problematic. Patients are frequently treated with long-term low-molecular weight heparin despite a lack of evidence for its effectiveness, and in the absence of validated dosing recommendations. The objectives of this investigation were to characterize the safety and pharmacokinetic behavior of a low-molecular weight heparin (reviparin) administered throughout pregnancy. Forty-two patients followed in a tertiary-care rheumatology clinic who received prophylactic doses of reviparin (4900 anti-Xa units subcutaneously once daily) were enrolled in this investigation. Anti-Xa heparin levels, weights, and gestational ages of the patients were obtained on up to four occasions distributed throughout their pregnancy. The achieved anti-Xa heparin levels were highly correlated with the patient's weight, irrespective of the gestational age. No toxicity other than injection site hematomas was observed. The achieved intensity of anticoagulation with reviparin varies during pregnancy in direct proportion to the patient's weight. This variability may mandate dose adjustment in response to changes in a patient's weight during pregnancy, particularly if low-molecular weight heparin is administered at therapeutic doses.
Thrombosis Research - THROMB RES. 01/2000; 98(2):133-138.
-
[show abstract]
[hide abstract]
ABSTRACT: Clinical and Laboratory Standards Institute document H54-A—Procedures for Validation of INR and Local Calibration of PT/INR Systems; Approved Guideline is one in a series of guidelines that addresses methodology in blood coagulation testing. It is intended to provide guidance for both manufacturers and clinical laboratory personnel responsible for reporting patient INR results. H54 describes the use of certified plasmas to enhance performance of the prothrombin time (PT)/International Normalized Ratio (INR) system test; reviews limitations of the PT/INR system that may occur when a manufacturer-determined ISI is used without local verification or calibration; and provides a rationale for performing local ISI verification with recommendations as to when PT calibration may be indicated. This guideline is published in two parts. Part I provides an expanded account of the subject and Part II is an abbreviated version that may be useful in the clinical laboratory. Methods of calculating local ISI are provided and the procedure for creating a calibration line for direct INR determination is included. In the expanded guideline, the method of certified plasma preparation and method of INR value assignments are also described in detail. This guideline includes a recommended INR range that certified plasmas should cover and recommended number of certified plasmas required for local ISI calibration. A protocol for performing calibration of PT systems is provided. The objective of this guideline is to improve precision and trueness (accuracy) of PT/INR systems and enhance both laboratory standardization and patient care.
