Warfarin has well-proven benefit (stroke prevention) but an associated increase in harm (major bleeding) in patients with atrial fibrillation (AF). Current clinical prediction rules (CPRs) are limited in that stroke CPRs predict only the probabilities of “stroke” and “no stroke” and bleeding CPRs predict only “bleed” and “no bleed” despite the fact that outcomes actually include combinations of these four groups. The study objective was to evaluate methods to create a CPR that calculates individual patient probabilities of warfarin’s four combined benefit/harm outcome groups: i) no stroke/no bleed; ii) no stroke/bleed; iii) stroke/no bleed; iv) stroke/bleed. Methods: Patient-level data were analyzed from a randomized controlled trial database (n=9,155) and an observational anticoagulant clinic database (n=5,475) from start of trial or time of AF diagnosis respectively (baseline), until end of follow-up. Patients were stratified into the four groups based on their outcomes during follow-up. Due to high mortality in both datasets, death was included as an outcome. Decision tree modeling and polytomous logistic regression (PLR) were conducted to identify baseline patient factors predicting each outcome group. Results: Based on a literature review of recent high quality RCTs, benefit and harm are reported separately and not at a more individualized level than subgroup analysis. In this individualized combined benefit/harm analysis, both PLR and decision tree modeling identified predictors of no stroke/no bleed, no stroke/bleed, stroke/no bleed and death without a prior stroke or bleed. PLR results predicted probabilities of combined benefit/harm outcomes for every patient but required detailed computation. However, results could potentially be converted into automated form for ease of use. Decision trees provided a visual algorithm approach to risk assessment but did not i) predict the probability of warfarin’s combined benefit/harm outcomes based on all predictors simultaneously, ii) predict the probability of these outcomes for every patient or iii) provide statistical parameters of predictive value (odds ratios). Conclusions: The PLR technique could be used to predict patient probabilities of combined benefit/harm outcomes with warfarin. The study results require validation, preferably prospectively, in other cohorts. If validated, this approach should be tested to determine if it aids patient decision-making.

Warfarin has well-proven benefit (stroke prevention) but an associated increase in harm (major bleeding) in patients with atrial fibrillation (AF). Current clinical prediction rules (CPRs) are limited in that stroke CPRs predict only the probabilities of “stroke” and “no stroke” and bleeding CPRs predict only “bleed” and “no bleed” despite the fact that outcomes actually include combinations of these four groups. The study objective was to evaluate methods to create a CPR that calculates individual patient probabilities of warfarin’s four combined benefit/harm outcome groups: i) no stroke/no bleed; ii) no stroke/bleed; iii) stroke/no bleed; iv) stroke/bleed. Methods: Patient-level data were analyzed from a randomized controlled trial database (n=9,155) and an observational anticoagulant clinic database (n=5,475) from start of trial or time of AF diagnosis respectively (baseline), until end of follow-up. Patients were stratified into the four groups based on their outcomes during follow-up. Due to high mortality in both datasets, death was included as an outcome. Decision tree modeling and polytomous logistic regression (PLR) were conducted to identify baseline patient factors predicting each outcome group. Results: Based on a literature review of recent high quality RCTs, benefit and harm are reported separately and not at a more individualized level than subgroup analysis. In this individualized combined benefit/harm analysis, both PLR and decision tree modeling identified predictors of no stroke/no bleed, no stroke/bleed, stroke/no bleed and death without a prior stroke or bleed. PLR results predicted probabilities of combined benefit/harm outcomes for every patient but required detailed computation. However, results could potentially be converted into automated form for ease of use. Decision trees provided a visual algorithm approach to risk assessment but did not i) predict the probability of warfarin’s combined benefit/harm outcomes based on all predictors simultaneously, ii) predict the probability of these outcomes for every patient or iii) provide statistical parameters of predictive value (odds ratios). Conclusions: The PLR technique could be used to predict patient probabilities of combined benefit/harm outcomes with warfarin. The study results require validation, preferably prospectively, in other cohorts. If validated, this approach should be tested to determine if it aids patient decision-making.

A fundamental challenge in evolutionary biology and medical genetic research is to connect the phenotype (a disease in humans or an adaptive trait in animals or plants) with the genotype. Using a classical example of an adaptive trait with a strong Mendelian genetic basis - warfarin resistance in the Norway rat (Rattus norvegicus), my dissertation tests the main hypothesis that speculated ‘simple’ adaptive trait has a more complex genetic architecture. Warfarin is an anticoagulant rodenticide used since the 1950s, and also is a widely prescribed blood-thinning drug in human. As a rodenticide, warfarin has initially been very effective. However, resistant rodents have evolved quickly and Vkorc1 (vitamin K epoxide reductase complex subunit 1) is the known resistance gene. As a popular drug, warfarin has a narrow therapeutic window with several genes VKORC1, CYP2C9, CYP4F2 established as biomarkers predicting warfarin dose in humans, suggesting a complex genetic architecture of warfarin resistance in rodents. In my thesis I performed network-guided genomic association studies (NetGWAS) and gene expression analysis to identify candidate genes involved in warfarin resistance based on a sample of ~600 wild rats from 19 populations in Germany. My thesis work revealed that the resistance mutation in Vkorc1 likely is under balancing selection and was recently introduced to the rat population in our study area. A key innovation of my thesis is adopting a NetGWAS approach to prioritize true associations and conducting co-expression network analysis to detect expression changes related to warfarin. My work shows that additional candidate genes are connected to the vitamin K pathway of which Vkorc1 is an essential component. While the validation of identified genes remains a challenge, the value of my thesis for future investigation is shown: one candidate gene Calu (Calumenin) is associated with warfarin resistance in multiple populations and is an essential part of the vitamin K cycle. Finally, my thesis briefly examines the genetics underlying a newly postulated cost of resistance, arterial calcification. This dissertation provides us an innovative framework in which we learned the genetic architecture of an adaptive trait in multiple dimensions: nucleotide or expression variation, genomic distribution and gene-gene interactions.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1953. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 53-54).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1970. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliography.

Class of 2005 Abstract / Objective: To analyze the quantity of active ingredient as well as the content uniformity of lovastatin and warfarin manufactured in Mexico as compared to the lovastatin and warfarin manufactured in the United States. Methods: High-pressure liquid chromatography assays modified from the U.S. Pharmacopoeia will be used to evaluate the amount of active ingredient found in lovastatin and warfarin manufactured in Mexico and America. Area-under-the-curve analysis was done to evaluate relative quantities of the active ingredients. Results: The amount of lovastatin found in the Mexican manufactured product was found to be 64%, and content uniformity was found to be 73%, both values are outside of the acceptable range of 90%-110% set by the USP-NF guidelines. The amount of warfarin found in the Mexican manufactured product was found to be 84% with a content uniformity of 100%. The average content value is outside of the acceptable range of 90%-110% set by the USP-NF guidelines. Conclusion: The results of this study showed that the amounts of active ingredients found in Mexican manufactured lovastatin and warfarin were significantly different from the amounts found in the American manufactured products.

No description available.

Class of 2010 Abstract / OBJECTIVES: The purpose of this study was to demonstrate that an increase in INR is associated with a hemorrhagic event in patients taking the oral anticoagulant warfarin. METHODS: A retrospective review of data from 18 patients previously stable on warfarin therapy with an elevation in INR at the time of a hemorrhagic event. Patients were receiving warfarin treatment in the anticoagulation clinic at the Southern Arizona VA Healthcare system from April 2008 to December 2009. Primary outcome measures included a comparison of INR, warfarin dose, and hematocrit at baseline, within 7 days of the event, and during follow-­‐up. RESULTS: A significant increase in INR was observed from baseline to the event (2.5 +/-­‐ 0.36 vs 6.2 +/-­‐ 3.2; p = 0.0002) but differences in INR during all periods of follow-­‐up did not differ from baseline (p = 0.35 – 0.99). When compared with baseline, differences in warfarin dose reached statistical significance when all 12 weeks of follow-­‐up were included (34.4 +/-­‐ 13.8 mg vs 32.4+/-­‐ 15.5 mg; p = 0.01) but were not significant when only the last 8 weeks (p = 0.06) or 4 weeks (p = 0.16) were included. Hematocrit values decreased significantly following hemorrhage (39.8 +/-­‐ 3.63 vs 33.5 +/-­‐ 5.72; p = 0.0002) before trending toward baseline (39.85 +/-­‐ 3.63 vs 37.13 +/-­‐ 4.72; p = 0.007). CONCLUSIONS: Hemorrhagic events were associated with an increased INR in previously stable warfarin patients. The mean weekly warfarin dose required to maintain a therapeutic INR returned to baseline within 8 weeks of the hemorrhagic event.

Treament with oral anticoagulation is highly effective in reducing the burden of thromboembolic complications in several clinical conditions. The number of patients receiving oral anticoagulation is growing steadily. InSwedenabout 1.5 percent of the population receives treatment. Although the treatment is highly effective in preventing thromboembolic complications, it is also associated with a substantial increase in the risk of bleeding. In clinical practice every physician has to balance the potential benefit of treatment against the risk of bleeding complications in the individual patient. To aid in this decision making, risk scores addressing the likelihood of thromboembolic events, as well as the risk of bleeding complications, have been developed. These scores are imperfect and, to some degree limited by the fact that the risk factors predictive of thromboembolic events are also often associated with bleeding complications. The addition of biomarkers has the potential to increase the predictive ability of risk scores and further enhance the net benefit of oral anticoagulant treatment in the individual patient. In this thesis several potential biomarkers for thromoboembolic and haemorrhagic complications of anticoagulant therapy have been investigated in a longitudinal cohort study of 719 patients with a median follow-up time of 4.2 years. Thrombomodulin is a key component in the generation of activated protein C and hence, a coagulation inhibitor. Conversely, it is also a key component in the inhibition of fibrinolysis by activation of trombin-activated fibrinolysis inhibitor. In warfarin-treated patients we demonstrate that thrombomodulin predicts an increased risk of bleeding complications, but not cardiovascular events. Thus, thrombomodulin has potential as a biomarker specifically for bleeding complications. Von Willebrand factor plays a central and intricate role in the aggregation of platelets and low levels of VWF have been associated with bleeding as a manifestation of von Willebrand’s disease. In our study we noted that high levels of von Willebrand factor predict an increased risk of cardiovascular as well as all-cause mortality, possibly as an expression of endothelial dysfunction. We also noted that high levels of WVF seem to be associated with serious bleeding complications. Decreased renal function is usually measured by an increase in the levels of creatinine and cystatin C, or a decrease in the calculated glomerular filtration rate. A decrease in kidney function is regarded as a marker of an increased risk of bleeding complications. We investigated all the mentioned markers of kidney function and no association with bleeding complications became apparent. However, a clear association between a decrease in kidney function and mortality was noted. Our findings indicate that the emphasis on impaired kidney function as a risk marker needs to be shifted from bleeding complications toward thromboembolic events. Fibrinolysis is important in containing coagulation and several constituents of the fibrinolytic pathway have been shown to predict cardiovascular events and mortality. We found that fibrinolytic factors seem to predict cardiovascular events in patients with oral anticoagulation and that D-dimer also predicts bleeding complications. In conclusion, we have found several biomarkers which exhibit different predictive abilities in patients with oral anticoagulation. It is likely that biomarkers, either alone, in combination, or as ancillary components of risk scores, can contribute to improved risk stratification in patients with oral anticoagulation.

A problem with the widley usedanticoagulant medicine Warfarin hasalways been that the therapeutic dosevaries from person to person and thatthere has not been any methods toestimate individually-based dosingregimens. By using a new populationmodeldescribing the relationship betweenWarfarin dose and INR(internationalnormalized ratio) response fordifferent individuals based on their age,weight and genotypes, a user friendly,dose estimating program has beendeveloped in Java. The applicationestimates the INR given the individualparameters and dosing, but it's alsopossible to estimate the predicted dosegiven the desired INR. The applicationmakes it possible for others to take partof the model, and to give a moreindividualized Warfarin treatment inclinical practice.