Effect Of Warfarin Treatment Research Articles

Effect of Warfarin Treatment on Memory Function in Mice

Effect of Warfarin Treatment on Memory Function in Mice

Chronic oral anticoagluation and risk of prostate cancer: Evidence of detection bias.

Warfarin treatment has been associated with lower risks of prostate cancer, without a specified biological mechanism. Our study tested the hypothesis that reluctance to perform prostate biopsies in men who are anticoagulated results in lower rates of diagnosed prostate cancer, leading to an apparent protective effect. Rates of prostate biopsies have decreased from 2000 to 2015, allowing calendar time to be used as the intervention. In a national population-based sample of elderly men, our study compared trends in prostate cancer incidence between 17,815 men treated with chronic oral anticoagulation for prosthetic heart valve thromboprophylaxis and a general population comparison group of 356,300 men. Cancer events were based on administrative claims. Among men enrolled in 2000-2001 and followed through 2015, prostate cancer incidence was substantially lower in the anticoagulation group (adjusted incidence rate ratio [IRR] 0.70; 95% confidence interval [CI] 0.62-0.80). Incidence decreased over time in the general population group to approach that of the anticoagulation group among men enrolled in 2008-2010 (IRR 0.86; 95% CI 0.71-1.04). Rates of prostate biopsies also decreased over time in the general population group to match the rate in the anticoagulation group. These results indicate that the apparent protective effect of warfarin treatment on the risk of prostate cancer is likely the result of detection bias from lower rates of biopsies among men who are anticoagulated.

Stroke : Highlights of Selected Articles

<i>Stroke</i> : Highlights of Selected Articles

Warfarin Treatment and All‐Cause Mortality in Community‐Dwelling Older Adults with Atrial Fibrillation: A Retrospective Observational Study

To investigate the relationship between warfarin treatment and different strata of all-cause mortality risk assessed using the Multidimensional Prognostic Index (MPI) based on information collected using the Standardized Multidimensional Assessment Schedule for Adults and Aged Persons (SVaMA) in community-dwelling older adults with atrial fibrillation (AF). Retrospective observational study. Older community-dwelling adults who underwent a SVaMA evaluation establishing accessibility to homecare services and nursing home admission from 2005 to 2013 in the Padova Health District, Italy. Community-dwelling individuals with AF aged 65 and older (N = 1,827). Participants were classified as being at mild (MPI-SVaMA-1), moderate (MPI-SVaMA-2), or severe (MPI-SVaMA-3) risk of mortality using the MPI-SVaMA, a validated prognostic tool based on age, sex, comorbidity, cognitive status, mobility and functional disability, pressure sore risk, and social support. The association between warfarin treatment and mortality was tested using multivariate- and propensity score-adjusted Cox regression models, controlling for age, sex, all SVaMA domains, concomitant diseases, and drug treatments. Higher MPI-SVaMA scores were associated with lower rates of warfarin treatment and higher 3-year mortality. After adjustment for propensity score quintiles, warfarin treatment was significantly associated with lower 2-year mortality in individuals with MPI-SVaMA-1 (hazard ratio (HR) = 0.64, 95% confidence interval (CI) = 0.50-0.82), MPI-SVaMA-2 (HR = 0.68, 95% CI = 0.55-0.85), and MPI-SVaMA-3 (HR = 0.55, 95% CI = 0.44-0.67). Heterogeneity analyses confirmed that the effect of warfarin treatment was not different between MPI-SVaMA groups (P for heterogeneity = .48). Community-dwelling older adults with AF benefitted from anticoagulation in terms of lower all-cause mortality over a mean follow-up of 2 years, regardless of poor health and functional condition. Although this benefit can be ascribed to the treatment, it may also reflect better overall care.

Letter by Nikpour et al Regarding Article, “Effect of Warfarin Treatment on Survival of Patients With Pulmonary Arterial Hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL)”

We thank Nikpour et al for highlighting their observational, retrospective study, which suggested, in a multivariate analysis, that anticoagulation of at least 6 months was associated with improved survival in connective disease–associated pulmonary arterial hypertension (PAH).1 Their results, indeed, are contrary to our US-based (Registry to Evaluate Early and Long-Term PAH Disease Management [REVEAL]) and the EU-based (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension [COMPERA]) databases,2,3 both of which suggested lack of (or even possible harm with) anticoagulation in this high-risk population. Acknowledging that these analyses are limited by the lack of randomization, the study by Ngian et al also suffers from several flaws: lack of definition of survival analysis (start at entry in the …

Understanding the mechanism of warfarin-mediated PC prevention.

e635 Background: Multi-institution retrospective trials have shown that prolonged use of warfarin reduces the risk of prostate cancer (PC), an effect that is not observed for other cancers. The anti-coagulant warfarin prevents the gamma-carboxylation (gla) of target proteins by interfering with the vitamin K cycle through its inhibition of the vitamin K epoxide reductase (VKOR). Most known gla proteins are found in the clotting cascade, but here we investigate the role of gla of the androgen receptor (AR) and other warfarin-mediated effects in the prevention of PC by warfarin. Methods: We treated mice with warfarin and performed RNA-seq on prostate tissues. We used immunoprecipitation (IP) followed by mass spec sequencing to identify gla sites on AR. We used cell culture models to investigate the role of AR-gla and other pathways identified by RNA-seq data in the mechanism of action of warfarin. Finally, we sequenced a SNP in VKOR and performed IHC to detect VKOR expression in prostatectomy tissues in an institutional series. Results: RNA-seq data show alteration of several pathways in warfarin-treated mouse prostates, including AR signaling, hormone and lipid synthesis, and genes known to affect PC (e.g. SPINK1). Mass spec shows that AR is gla’d at amino acid 2E, which is known to be mutated in partial androgen insensitivity syndrome patients. Warfarin inhibits AR conformation change and transcriptional activity in benign (non-cancerous) prostate cells. VKOR knock-down recapitulates effects of warfarin treatment, suggesting an on target effect of the drug. Mutation of the AR-gla site has modest effects in benign prostate cells. In a small series of patients, we found that one allele of a VKOR SNP is found at a significantly higher rate in PC patients than expected. We also found that VKOR is highly expressed in normal human prostate epithelia but is lost in cancerous tissue, a pattern of expression that is unique to PC. Conclusions: Warfarin, likely through its ability to control AR-gla, inhibits AR transcriptional activity. The relative contribution of modest AR inhibition and the effect on other pathways must be investigated to determine how warfarin reduces the risk of PC and to identify optimal drug targets for development of chemopreventative therapeutics.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Elderly Disabled Patients in Oral Anticoagulation Treatment: An Evaluation of a Bioanalyst-Led Management Program Reaching an Average of 72% of Time in Therapeutic Range

Introduction: The need for anticoagulation therapy increases with age, mainly due to the increased prevalence of atrial fibrillation. Time in therapeutic range (TTR) is a marker of the quality of the therapy as TTR is inversely correlated with adverse reactions. We developed a bioanalyst-led management program for control of warfarin treatment in elderly disabled patients in their own home and maintain a high TTR. Material and Methods: Residents in nursing home settings were included. Visiting nurses measured INR with a point of care testing device. If INR was within Therapeutic Range (TR), the nurse dosed warfarin unaltered. If INR was out of TR, the visiting nurse contacted a specially trained bioanalyst by phone. An explanation was sought, and a new dosage plan was made. Results: A total of 579 patients were included; 356 females (61%). Mean age was 79.6 years. Approximately 10% were residents in nursing home settings and the rest in domiciliary care. TTR was 72%. The subtherapeutic values were 15% and supratherapeutic values 13%. In total, 139 patients died during the study period. Ten deaths could be related to possible side effects of warfarin treatment. Conclusions: Our results indicate that a bioanalyst-led program is able to simplify anticoagulation monitoring, while maintaining INR control similar to a specialized clinic. Furthermore, we avoided hospitalizations when INR was unacceptably high by treating the patient with oral vitamin-K at home. Our findings could be helpful when planning warfarin treatment in elderly, fragile patients.

Relationship between platelet indices and international normalized ratio in patients with non-valvular atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia and associated with adverse outcomes and increased risk for thromboembolic events. Warfarin is still the most extensively prescribed oral anticoagulant in AF to prevent ischemic complications. We aimed to determine the differences at platelet indices with warfarin usage layered by International Normalized Ratio (INR). A total of 250 patients with permanent non-valvular AF (mean age 70.2 ± 9.1; 153 female) were divided into two groups. Group 1 included 125 patients whose INR is between 2.0 and 3.0 (called as “effective”) and Group 2 included 125 patients whose INR is <2.0 (called as “ineffective”). Also 123 age- and sex-matched individuals in sinus rhythm enrolled as control group (Group 3). After physical and echocardiographic examination, complete blood counts and INR were studied. There was no statistically significant difference in age, sex, co-morbidities and medications, also hemoglobin, white blood cell and platelet counts among the groups. The CHA2DS2-VASc scores were similar between Groups 1 and 2. The mean platelet volume (MPV), platelet distribution width (PDW) and plateletcrit (PCT) were significantly higher in Group 2 than Groups 1 and 3 and similar between Groups 1 and 3. MPV was positively correlated with PDW and PCT and also inversely correlated with INR value and platelet count. On multivariate logistic regression analysis, MPV, PDW and PCT were independent predictors of ineffectiveness of INR. The results of this study showed that MPV, PDW and PCT are increased in patients with non-valvular AF without effective warfarin treatment. Warfarin usage adjusted by INR is associated with lower values of these platelet indices, even lower as the values of subjects in sinus rhythm. MPV, PDW and PCT are independent predictors of INR ineffectiveness and seem to be useful parameters for monitoring the effectiveness of warfarin treatment.

Effect of warfarin treatment on thrombin activatable fibrinolysis inhibitor (TAFI) activation and TAFI‐mediated inhibition of fibrinolysis

Severe clotting deficiencies are associated with enhanced in vitro fibrinolysis due to insufficient thrombin activatable fibrinolysis inhibitor (TAFI) activation. Because oral anticoagulant therapy (OAT) with warfarin causes a partial deficiency of vitamin K-dependent factors, its effect on clot lysability remains unclear. To evaluate plasma and blood fibrinolytic capacity in patients under stable OAT (n = 221) as compared with controls (n = 132). Fibrinolysis resistance of plasma (turbidimetry) and blood (thromboelastography) clots was calculated as the lysis time of tissue factor-induced clots exposed to 30 and 100 ng mL(-1) t-PA, respectively. Plasma PAI-1 was similar in the two groups, whereas TAFI was slightly lower in patients. OAT plasma clots lysed faster than controls (P = 0.001). The addition of the TAFIa inhibitor PTCI reduced lysis time by 14% in OAT and 34% in controls, and the difference between the groups disappeared. Similar data were obtained with blood clots. Thrombin and TAFIa generation in OAT plasma amounted to roughly 50% of controls, supporting a reduced thrombin-dependent TAFI activation. Clot resistance of OAT plasma was normalized by Ba-citrate plasma eluate or prothrombin but not by BaSO(4) serum eluate, rFVIIa or FX. Surprisingly, circulating levels of TAFIa and its inactive derivative TAFIai were higher in warfarin patients (P < 0.0001) and correlated with plasmin-antiplasmin (P = 0.0001) but not with prothrombin F(1) (+) (2) . OAT enhances both plasma and blood fibrinolysis by reducing thrombin-dependent TAFI activation, a phenomenon largely determined by low prothrombin levels. At variance with in vitro data, 'basal' in vivo TAFIa/ai levels seem related to plasmin rather than thrombin generation.

The effect of warfarin therapy on the charge properties of urinary prothrombin fragment 1 and crystallization of calcium oxalate in undiluted human urine.

Urinary prothrombin fragment 1 (UPTF1) is the principal protein in calcium oxalate (CaOx) crystals precipitated from human urine and is a potent inhibitor of CaOx crystallization, a property that should depend, at least in part, upon the extent of gamma-carboxylation of the 10 glutamic residues in its N-terminal region. Warfarin therapy limits full gamma-carboxylation of vitamin K-dependent proteins, including UPTF1. The aims of this study were to determine the effect of warfarin therapy on UPTF1, its occlusion into CaOx urinary crystals, and its influence on the crystallization of CaOx in undiluted human urine. In the first part of the study, urines were collected from six men prior to cardiac surgery and after stabilization on long-term warfarin treatment. Proteins in the urines and in the matrix of CaOx crystals precipitated from them were analyzed by two-dimensional SDS-PAGE and Western blotting. In urine, at least two charge variants of UPTF1 with low isoelectric point (pI) values were detected before and during warfarin therapy, but additional higher pI forms of the protein were also seen during anticoagulation. Nonetheless, the majority of UPTF1 was present in the more fully gamma-carboxylated state. CaOx crystals precipitated from the same urine samples contained only low pI forms of UPTF1. The effect of warfarin treatment on CaOx crystallization in urine was tested by collecting two consecutive 24-h urine samples from 16 men prior to cardiac surgery and during subsequent warfarin treatment. CaOx crystallization was induced in each sample by the addition of sodium oxalate. The size and volume of the particles deposited were determined using a Coulter counter, and the crystals were examined by scanning electron microscopy (SEM). There were no significant differences between the urinary metastable limits before or during warfarin treatment or in the total volume of crystals precipitated. A slight increase in the mean diameter of the crystalline particles precipitated from the urines during anticoagulant therapy was not significant. SEM showed little evidence of changes in overall particle size, although individual crystals of CaOx tended to be larger during warfarin treatment. It was concluded from these studies that the binding of UPTF1 to CaOx crystal surfaces is related to the degree of gamma-carboxylation of its Gla domain, which would also influence the protein's inhibitory effects on CaOx crystallization. However, during warfarin therapy the majority of UPTF1 exists in a highly charged state, indicating that it is completely, or almost completely, gamma-carboxylated, which would explain the lack of any difference between CaOx crystallization parameters in the urine of subjects before and during warfarin administration. We conclude that physiologically significant reductions in the inhibitory potency of UPTF1 would be likely to occur only as a result of proscription of gamma-carboxylation more extensive than that induced by warfarin.

Localization of endogenous osteocalcin in neonatal rat bone and its absence in articular cartilage: Effect of warfarin treatment

Immunocytochemistry after cryoultramicrotomy was used to localize endogenous osteocalcin in bone (calvaria, femoral diaphysis) and epiphyseal femoral cartilage from 8-day-old rats treated (or mot) for 7 days with warfarin. Ultrathin frozen sections were incubated with goat antiserum against rat osteocalcin at high dilutions (2 x 10(-4) to 2 x 10(-6). In calvaria and femur of untreated rats, endogenous osteocalcin was observed in osteoblasts (cytoplasm and nucleus) and in the collagenous matrix. Osteocalcin appeared progressively in osteoblasts and bone matrix in the mineralization front, then increased in the regions of extended calcification. Osteocalcin was also detected in osteocytes but was not as abundant as in osteoblasts. In bone samples of warfarin-treated rats, endogenous osteocalcin was only detected in bone matrix but not in osteoblasts. Furthermore, osteocalcin was only observed if antiserum was not very dilute (2 x 10(-2). In cartilage (hypertrophied and degenerative zones), osteocalcin was not observed in matrix and chondrocytes. However, it was found in the vicinity of matrix vesicles at the initial loci of calcification. Osteocalcin was never detected in the cartilage of warfarin-treated rats. Our results provide ultrastructural immunocytological evidence for the localization of endogenous osteocalcin in osteoblasts, the presence of osteocalcin in bone matrix and a direct gradient between the presence of osteocalcin and the calcification process. Osteocalcin is absent from cartilage, except possibly close to calcifying matrix vesicles. Warfarin inhibits the formation of osteocalcin.

Effect of warfarin on the induction and course of experimental Staphylococcus epidermidis endocarditis.

The effect of warfarin treatment on an experimental Staphylococcus epidermidis endocarditis was studied. Warfarin was found to affect both the induction and course of the infection of catheter-induced endocardial vegetations. In warfarin-treated rabbits, larger bacterial inocula were needed to induce an infection, and the degree of infection of the vegetations was also significantly lower, eventually resulting in the total elimination of the bacteria from the vegetations. Thus, warfarin treatment seems to have an inhibitory effect on the induction and development of an S. epidermidis infection of the endocardium. The results differ from previous findings in studies done with Streptococcus anguis, where warfarin was found to have no effect on the induction or course of the infection of endocardial vegetations, which suggests that different mechanisms are involved in the pathogenesis of endocarditis caused by these two species of bacteria.

Effect of warfarin on the induction and course of experimental endocarditis.

The effect of warfarin treatment on an experimental endocarditis was studied in rabbits. Warfarin had no effect on the induction of a Streptococcus sanguis infection in catheter-induced endocardial vegetations, and the course of this infection was also unaltered. However, warfarin treatment resulted in rapidly progressive bacteremia, probably due to impaired circulation in clearing organs such as the lungs, liver, and spleen. Warfarin also reduced the survival time of the infected rabbits, in which pulmonary edema and extensive lung hemorrhages may have been a contributory factor.