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Benjamin D Horne,
Petra A Lenzini,
Mia Wadelius,
Andrea L Jorgensen,
Stephen E Kimmel,
Paul M Ridker,
Niclas Eriksson,
Jeffrey L Anderson,
Munir Pirmohamed,
Nita A Limdi, [......],
Jae-Gook Shin,
Ho-Sook Kim,
Pantep Angchaisuksiri,
Robert J Glynn,
Kathryn E Kronquist,
John F Carlquist,
Gloria R Grice,
Robert L Barrack,
Juan Li,
Brian F Gage
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ABSTRACT: By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6-11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6-11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that "effective" dose constituted a treatment response index . Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R(2) was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R(2)= 69.1% (p<0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.
Thrombosis and Haemostasis 12/2011; 107(2):232-40. · 5.04 Impact Factor
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E J Do,
P Lenzini, C S Eby,
A R Bass,
G A McMillin,
S M Stevens,
S C Woller,
R C Pendleton,
J L Anderson,
P Proctor,
R M Nunley,
V Davila-Roman,
B F Gage
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ABSTRACT: The risk of venous thromboembolism (VTE) is higher after the total hip or knee replacement surgery than after almost any other surgical procedure; warfarin sodium is commonly prescribed to reduce this peri-operative risk. Warfarin has a narrow therapeutic window with high inter-individual dose variability and can cause hemorrhage. The genetics-informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT) is a 2 × 2 factorial-design, randomized controlled trial designed to compare the safety and effectiveness of warfarin-dosing strategies. GIFT will answer two questions: (1) does pharmacogenetic (PGx) dosing reduce the rate of adverse events in orthopedic patients; and (2) is a lower target international normalized ratio (INR) non-inferior to a higher target INR in orthopedic participants? The composite primary endpoint of the trial is symptomatic and asymptomatic VTE (identified on screening ultrasonography), major hemorrhage, INR4, and death.
The Pharmacogenomics Journal 05/2011; 12(5):417-24. · 4.54 Impact Factor
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D Voora,
D C Koboldt,
C R King,
P A Lenzini, C S Eby,
R Porche-Sorbet,
E Deych,
M Crankshaw,
P E Milligan,
H L McLeod,
S R Patel,
L H Cavallari,
P M Ridker,
G R Grice,
R D Miller,
B F Gage
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ABSTRACT: Warfarin demonstrates a wide interindividual variability in response that is mediated partly by variants in cytochrome P450 2C9 (CYP2C9) and vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1). It is not known whether variants in calumenin (CALU) (vitamin K reductase regulator) have an influence on warfarin dose requirements. We resequenced CALU regions in a discovery cohort of dose outliers: patients with high (>90th percentile, n = 55) or low (<10th percentile, n = 53) warfarin dose requirements (after accounting for known genetic and nongenetic variables). One CALU variant, rs339097, was associated with high doses (P = 0.01). We validated this variant as a predictor of higher warfarin doses in two replication cohorts: (i) 496 patients of mixed ethnicity and (ii) 194 African-American patients. The G allele of rs339097 (the allele frequency was 0.14 in African Americans and 0.002 in Caucasians) was associated with the requirement for a 14.5% (SD +/- 7%) higher therapeutic dose (P = 0.03) in the first replication cohort and a higher-than-predicted dose in the second replication cohort (allele frequency 0.14, one-sided P = 0.03). CALU rs339097 A>G is associated with higher warfarin dose requirements, independent of known genetic and nongenetic predictors of warfarin dose in African Americans.
Clinical Pharmacology & Therapeutics 03/2010; 87(4):445-51. · 6.04 Impact Factor
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N S Ferder, C S Eby,
E Deych,
J K Harris,
P M Ridker,
P E Milligan,
S Z Goldhaber,
C R King,
T Giri,
H L McLeod,
R J Glynn,
B F Gage
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ABSTRACT: CYP2C9 and VKORC1 genotypes predict therapeutic warfarin dose at initiation of therapy; however, the predictive ability of genetic information after a week or longer is unknown. Experts have hypothesized that genotype becomes irrelevant once international normalized ratio (INR) values are available because INR response reflects warfarin sensitivity.
We genotyped the participants in the Prevention of Recurrent Venous Thromboembolism (PREVENT) trial, who had idiopathic venous thromboemboli and began low-intensity warfarin (therapeutic INR 1.5-2.0) using a standard dosing protocol. To develop pharmacogenetic models, we quantified the effect of genotypes, clinical factors, previous doses and INR on therapeutic warfarin dose in the 223 PREVENT participants who were randomized to warfarin and achieved stable therapeutic INRs.
A pharmacogenetic model using data from day 0 (before therapy initiation) explained 54% of the variability in therapeutic dose (R(2)). The R(2) increased to 68% at day 7, 75% at day 14, and 77% at day 21, because of increasing contributions from prior doses and INR response. Although CYP2C9 and VKORC1 genotypes were significant independent predictors of therapeutic dose at each weekly interval, the magnitude of their predictive ability diminished over time: partial R(2) of genotype was 43% at day 0, 12% at day 7, 4% at day 14, and 1% at day 21.
Over the first weeks of warfarin therapy, INR and prior dose become increasingly predictive of therapeutic dose, and genotype becomes less relevant. However, at day 7, genotype remains clinically relevant, accounting for 12% of therapeutic dose variability.
Journal of Thrombosis and Haemostasis 10/2009; 8(1):95-100. · 5.73 Impact Factor
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P A Lenzini,
G R Grice,
P E Milligan,
M B Dowd,
S Subherwal,
E Deych, C S Eby,
C R King,
R M Porche-Sorbet,
C V Murphy,
R Marchand,
E A Millican,
R L Barrack,
J C Clohisy,
K Kronquist,
S K Gatchel,
B F Gage
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ABSTRACT: Warfarin is commonly prescribed for prophylaxis and treatment of thromboembolism after orthopedic surgery. During warfarin initiation, out-of-range International Normalized Ratio (INR) values and adverse events are common.
In orthopedic patients beginning warfarin therapy, we developed and prospectively validated pharmacogenetic and clinical dose refinement algorithms to revise the estimated therapeutic dose after 4 days of therapy.
The pharmacogenetic algorithm used the cytochrome P450 (CYP) 2C9 genotype, smoking status, peri-operative blood loss, liver disease, INR values and dose history to predict the therapeutic dose. The R(2) was 82% in a derivation cohort (n = 86) and 70% when used prospectively (n = 146). The R(2) of the clinical algorithm that used INR values and dose history to predict the therapeutic dose was 57% in a derivation cohort (n = 178) and 48% in a prospective validation cohort (n = 146). In 1 month of prospective follow-up, the percent time spent in the therapeutic range was 7% higher (95% CI: 2.7-11.7) in the pharmacogenetic cohort. The risk of a laboratory or clinical adverse event was also significantly reduced in the pharmacogenetic cohort (Hazard Ratio 0.54; 95% CI: 0.30-0.97).
Warfarin dose adjustments that incorporate genotype and clinical variables available after four warfarin doses are accurate. In this non-randomized, prospective study, pharmacogenetic dose refinements were associated with more time spent in the therapeutic range and fewer laboratory or clinical adverse events. To facilitate gene-guided warfarin dosing we created a non-profit website, http://www.WarfarinDosing.org.
Journal of Thrombosis and Haemostasis 08/2008; 6(10):1655-62. · 5.73 Impact Factor
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Journal of Thrombosis and Haemostasis 03/2006; 4(2):473-4. · 5.73 Impact Factor
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The Pharmacogenomics Journal 02/2004; 4(4):224-5. · 4.54 Impact Factor
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ABSTRACT: Formation of destructive haemorrhagic pseudocysts or pseudotumours thought to arise from unresolved, encapsulated haematomas is a well-recognized, rare complication of severe haemophilia A or B, and has been reported in a single patient with von Willebrand disease (vWD). We report a 41-year-old patient with type 3 vWD who underwent incomplete resection of a large retroperitoneal pseudocyst in 1995 and presented with a recurrent, extensive right abdominal and flank mass and signs and symptoms of large bowel obstruction. He required emergency partial colectomy for bowel ischaemia and removal of his right kidney, which was hydronephrotic due to prolonged ureteral obstruction by the pseudocyst. Following repeat partial resection of the pseudotumour, he developed persistent bleeding into the operative site despite aggressive administration of von Willebrand factor (vWF)-rich factor VIII concentrates, resulting in retroperitoneal haematomas and abscesses, which resolved after 13 months of percutaneous drainage, extended supplementation of vWF and antibiotic therapy.
Haemophilia 04/2002; 8(2):136-41. · 2.60 Impact Factor
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ABSTRACT: A 32-year-old woman presented with an acute anterior-lateral myocardial infarction 7 days postpartum. Coronary angiography revealed an occlusive left main coronary artery dissection. After coronary artery bypass surgery the patient's cardiac function improved and stabilized. Thrombocytopenia and a femoral artery thrombosis after 9 days of heparin exposure marked the development of heparin-induced thrombocytopenia and thrombosis that was successfully managed with argatroban, a direct thrombin inhibitor anticoagulant.
The Annals of Thoracic Surgery 04/2001; 71(3):1025-7. · 3.74 Impact Factor
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ABSTRACT: Several cold autoantibodies (usually IgG) with IT specificity have been reported previously, as have autoantibodies with joint I and P blood group specificities (IP1, ITP1, iP1, IP). A fatal outcome associated with an IgM cold autoantibody of ITP specificity is reported.
A 54-year-old man suffered from progressively severe cold autoimmune hemolytic anemia for 9 months. Hemoglobin concentration ranged from 6 to 7 g per dL (60-70 g/L) and reticulocytes from 3 to 5 percent (0.030-0.050). The direct antiglobulin test was weakly positive for IgM and strongly positive for C3d. The serum contained a cold agglutinin that reacted strongest with cord i red cells (RBCs) > adult I RBCs > adult i RBCs, which is consistent with IT specificity. The Donath-Landsteiner test was positive; the reaction was neutralized by globoside. The serum reacted weakly or was negative with RBCs from five group p blood donors, which suggests anti-ITP specificity. Dithiothreitol treatment of the serum abolished the cold agglutinin reactivity, which suggests that the anti-IT was IgM. The patient received > 40 RBC transfusions and failed to respond to oral steroids, oral cytoxan, high-dose pulse intravenous steroids, and plasma exchange at room temperature and at 35 degrees C. He died of sepsis following an unsuccessful trial of chlorambucil. Autopsy revealed unsuspected disseminated non-Hodgkin's lymphoma.
Serologic studies are consistent with our patient's having a single IgM cold autoantibody with IT and P specificities (anti-ITP) and requiring both specificities on the same RBC to permit maximal antibody expression.
Transfusion 05/1994; 34(5):427-31. · 3.22 Impact Factor
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C S Eby
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ABSTRACT: Warfarin-induced skin necrosis is a rare but potentially devastating complication of oral anticoagulation. In this article the historical, clinical, and pathophysiologic features of this hypercoagulable event are reviewed, and recommendations for prevention and treatment are discussed.
Hematology/Oncology Clinics of North America 01/1994; 7(6):1291-300. · 2.64 Impact Factor
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C S Eby
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ABSTRACT: The hypercoagulable state refers to those factors, both acquired and congenital, that predispose an individual to thromboembolic events. In this article, the major acquired and inherited conditions associated with an increased risk for venous thromboembolic events are critically reviewed.
Hematology/Oncology Clinics of North America 01/1994; 7(6):1121-42. · 2.64 Impact Factor
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ABSTRACT: A 54 y.o. woman presented with acute Coombs-negative hemolytic anemia at an outside hospital where she received 25 RBC transfusions and did not respond to prednisone or splenectomy. On transfer to our hospital, routine DAT and IAT were weakly positive, occasionally negative. When a modified "cold" antiglobulin test was employed, the result was strongly positive for IgG, weakly positive for C3d. Cold agglutinin titer was 32, and the Donath-Landsteiner test was negative. The autoantibody exhibited Pra specificity. The patient failed IV-IgG, high dose IV pulse steroids and cyclophosphamide, and continued to require daily transfusions. She responded 21 days after receiving daily plasma exchange (x3), with pulse cyclophosphamide on the third day, followed by escalating daily oral cyclophosphamide.
Autoimmunity 02/1992; 12(2):149-54. · 2.47 Impact Factor
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C S Eby
Clinical laboratory science: journal of the American Society for Medical Technology 12(6):365-9.
