warfarin and Inflammation

To administer optimal and safe pharmacotherapy, development of stratified and personalized therapy is imperative. Pharmacogenomics (PGx) is useful in elucidating factors causing individual differences in drug efficacy and the emergence of adverse effects. It also helps design accurate drug administration methods by evaluating the effects of patient-related factors, such as genetic factors, that influence pharmacokinetics (PK) and pharmacodynamics (PD). In addition, selection of appropriate therapeutic agents requires the implementation of precision medicine allowing accurate disease diagnosis. To establish precision medicine, it is necessary to uncover the association of pathophysiological factors, which are represented as endotype or genotype, with the pathology of several phenotypes. This review describes two aspects related to realization of individualized medicine, namely the effectiveness of PK/PD/PGx studies and the stratification of pathological conditions. First, we conducted a PK/PD/PGx study with the aim to individualize warfarin treatment. In this study, we elucidated the effect of CYP4F2 polymorphisms associated with vitamin K metabolism by measuring the blood concentrations of warfarin and vitamin K. Then, to develop precision medicine for asthma and chronic obstructive pulmonary disease (COPD), we analyzed not only clinical symptoms but also pathological biomarkers and genes associated with inflammation. The findings may contribute toward better understanding of the pathological conditions of asthma, COPD, and asthma-COPD overlap.

Topics: Asthma; Cytochrome P450 Family 4; Drug Therapy; Humans; Inflammation; Pharmacogenomic Testing; Pharmacokinetics; Polymorphism, Genetic; Precision Medicine; Pulmonary Disease, Chronic Obstructive; Vitamin K; Warfarin

Coagulopathies and inflammatory diseases, ostensibly, have distinct underlying molecular bases. Notwithstanding, both are host defense mechanisms to physical injury. In invertebrates, clotting can function directly in anti-pathogen defense. Molecules of the vertebrate clotting cascade have also been directly linked to the regulation of inflammation. We posit that thrombophilia may provide resistance against pathogens in vertebrates. The selective pressure of improved anti-pathogen defense may have retained mutations associated with a thrombophilic state in the human population and directly contributed to enhanced inflammation. Indeed, in some inflammatory diseases, at least a subset of patients can be identified as hypercoagulable. Therefore, anticoagulants such as warfarin or apixaban may have a therapeutic role in some inflammatory diseases.

Topics: Animals; Anticoagulants; Humans; Inflammation; Pyrazoles; Pyridones; Thrombophilia; Warfarin

The role of thrombin in vascular physiology and pathophysiology continues to impact our understanding of many cellular processes and systems including the function of platelets, endothelial cells, smooth muscle cells, leukocytes and the regulation of the coagulation cascade. Recent acute coronary syndrome clinical trial results that have compared the use of parenteral or oral anticoagulants versus or in combination with anti-platelet agents have forced a reexamination of the importance of thrombin activity in influencing patient outcomes, particularly in the area of secondary prevention. The debate of the need to include oral anticoagulation as a concomitant or replacement therapy to an antiplatelet regimen as a means to improve patient outcomes requires further examination and larger prospective clinical trials.

Topics: Acute Coronary Syndrome; Administration, Oral; Animals; Anticoagulants; Atherosclerosis; Blood Coagulation; Blood Platelets; Cardiovascular Diseases; Clinical Trials as Topic; Fibrinolytic Agents; Humans; Inflammation; Mice; Platelet Aggregation Inhibitors; Receptor, PAR-1; Receptors, Thrombin; Risk Factors; Secondary Prevention; Thrombin; Warfarin

Pancreas graft thrombosis remains one of the most common reasons for pancreas transplant loss. Patients with a history of thrombotic events should be identified and evaluated for thrombophilia to identify transplant candidates at highest risk.. Early after transplant, vascular thrombosis is multifactorial, but beyond 2 weeks, inflammation or acute rejection predominate as the cause of thrombosis. Most pancreas transplant centers utilize some form of anticoagulation following transplantation. Aspirin is highly recommended. Unfractionated or low-molecular-weight heparin is often administered, but some centers use heparin selectively and typically at low dose to avoid postoperative bleeding. Warfarin is less frequently given and its use should probably be limited to patients with thrombophilia.. Thrombectomy, either surgical or percutaneous, may salvage the pancreas graft if performed early after the occurrence of thrombosis.

Topics: Acute Disease; Anticoagulants; Aspirin; Fibrinolytic Agents; Graft Rejection; Heparin; Humans; Incidence; Inflammation; Pancreas Transplantation; Postoperative Hemorrhage; Risk Factors; Thrombectomy; Thrombosis; Warfarin

Topics: Anti-Inflammatory Agents; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Inflammation; International Normalized Ratio; Stroke; Thrombin; Warfarin

From the preceding exposition it is now clear that the regulation of monocyte/macrophage PCA is dependent upon a complex network of interacting pathways, some of which amplify the response of the monocyte/macrophage, while others inhibit. In all probability many more will emerge. The construct illustrated in Figure 3, therefore, is a simplified view of the two major stimulatory pathways: the T cell-dependent pathway, activated by immune recognition and mediated by lymphokine(s); and the T cell-independent pathway, activated by direct perturbation of monocytes by such stimuli as LPS. At least 2 or 3 different PCAs can be expressed by monocyte/macrophages from different species, depending upon the anatomic site of the origin of the cell and the types of stimuli imposed. Inhibition of PCA expression is accomplished by at least one set of regulatory lipoproteins, and other inhibitory loops may be found. The result of these multiple interactions is the deposition of fibrin on the cell surface or in the surrounding milieu. It is our belief that this close relationship between coagulation reactions and inflammatory reactions, resulting in fibrin deposition, represents a fundamental host defense designed to delimit the inflammatory response. Nevertheless, the precise role of monocyte procoagulants in vivo remains unclear. A number of potential mechanisms exist for activation of coagulation in both inflammatory and neoplastic disorders, and the finding of enhanced monocyte procoagulant activity by no means establishes its importance in physiologic or, pathosphysiologic responses in vivo. Further studies, possibly with agents capable of specific inhibition of monocyte procoagulants in vivo, will be necessary to define the precise importance of these procoagulants in clinical disorders.

Topics: Animals; Anti-Inflammatory Agents; Antigens; Blood Coagulation; Blood Coagulation Factors; Cell Line; Factor V; Factor VII; Factor X; Factor Xa; Fibrin; Fibrin Fibrinogen Degradation Products; Guinea Pigs; Humans; Hypersensitivity, Delayed; Immunologic Deficiency Syndromes; Infections; Inflammation; Lipopolysaccharides; Macrophages; Mice; Monocytes; Neoplasms; Neutrophils; Rabbits; Rats; T-Lymphocytes; Thromboembolism; Thromboplastin; Warfarin

Atrial fibrillation (AF) is a risk factor for stroke and mortality and the prothrombotic state has been linked to inflammation. In this study we evaluated the relationship between inflammatory biomarkers at baseline and future risk of cardiovascular events in the Apixaban for Reduction In Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.. The ARISTOTLE trial randomised 18,201 patients with AF to apixaban or warfarin. Interleukin 6 (IL-6) and C reactive protein (CRP) were analysed in plasma obtained at randomisation from 14,954 participants, and median follow-up was 1.9 years. Association between quartile groups of IL-6 and CRP and outcomes were analysed by Cox regression adjusted for clinical risk factors and other cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C).. The IL-6 median level was 2.3 ng/L (IQR 1.5-3.9), median CRP level was 2.2 mg/L (1.0-4.8). IL-6 and CRP were significantly associated with all-cause mortality independent of clinical risk factors and other biomarkers (HR (95% CI) 1.93 (1.57 to 2.37) and 1.49 (1.24 to 1.79), respectively, Q4 vs Q1). IL-6 was associated with myocardial infarction, cardiovascular mortality, and major bleeding beyond clinical risk factors but not in the presence of cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C). Neither inflammatory biomarker was associated with stroke/systemic embolism. Risk prediction for stroke, death and major bleeding was not improved by IL-6 or CRP when added to clinical risk factors and the other cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C).. In patients with AF on anticoagulation, after accounting for clinical risk factors and other biomarkers, biomarkers of inflammation were significantly associated with an increased risk of mortality. However, there were no associations with the risk of stroke or major bleeding.. ClinicalTrials.gov identifier: NCT00412984 post-results.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Biomarkers; C-Reactive Protein; Female; Follow-Up Studies; Hemorrhage; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Predictive Value of Tests; Prognosis; Pyrazoles; Pyridones; Risk Assessment; Thromboembolism; Warfarin

The aim of this study was to assess the influence of aspirin on selected inflammatory markers in patients recovering from acute myocardial infarction (AMI). Patients participating in the Warfarin Aspirin Re-Infarction Study-II were randomized to either aspirin 160 mg/day or aspirin 75 mg/day + warfarin, or warfarin alone after AMI. After AMI, aspirin 160 mg/day was associated with significantly lower levels of high-sensitivity C-reactive protein and tumor necrosis factor-alpha than warfarin alone over 4 years. However, the same levels were not predictors for clinical end points.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Aspirin; Biomarkers; C-Reactive Protein; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Inflammation; Interleukin-10; Interleukin-6; Male; Middle Aged; Myocardial Infarction; Time; Tumor Necrosis Factor-alpha; Warfarin

Acute pancreatitis (AP) is a severe disease with high morbidity and mortality in which inflammation and coagulation play crucial roles. The development of inflammation leads to vascular injury, endothelium and leukocytes stimulation, and an increased level of tissue factor, which results in the activation of the coagulation process. For this reason, anticoagulants may be considered as a therapeutic option in AP. Previous studies have shown that pretreatment with heparin, low-molecular-weight heparin (LMWH), or acenocoumarol inhibits the development of AP. The aim of the present study was to check if pretreatment with warfarin affects the development of edematous pancreatitis evoked by cerulein. Warfarin (90, 180, or 270 µg/kg/dose) or saline were administered intragastrically once a day for 7 days consecutively before the induction of AP. AP was evoked by the intraperitoneal administration of cerulein. The pre-administration of warfarin at doses of 90 or 180 µg/kg/dose reduced the histological signs of pancreatic damage in animals with the induction of AP. Additionally, other parameters of AP, such as an increase in the serum activity of lipase and amylase, the plasma concentration of D-dimer, and interleukin-1β, were decreased. In addition, pretreatment with warfarin administered at doses of 90 or 180 µg/kg/dose reversed the limitation of pancreatic blood flow evoked by AP development. Warfarin administered at a dose of 270 µg/kg/dose did not exhibit a preventive effect in cerulein-induced AP. Conclusion: Pretreatment with low doses of warfarin inhibits the development of AP evoked by the intraperitoneal administration of cerulein.

Topics: Acute Disease; Animals; Ceruletide; Heparin, Low-Molecular-Weight; Inflammation; Pancreatitis; Rats; Rats, Wistar; Warfarin

Rivaroxaban is a direct inhibitor of activated Factor X (FXa), an anti-inflammatory protein exerting a protective effect on the cardiac valve and vascular endothelium. We compare the effect of Warfarin and Rivaroxaban on inflammation biomarkers and their contribution to heart valve calcification progression and renal preservation in a population of atrial fibrillation (AF) patients with chronic kidney disease (CKD) stage 3b - 4.. This was an observational, multicenter, prospective study enrolling 347 consecutive CKD stage 3b - 4 patients newly diagnosed with AF: 247 were treated with Rivaroxaban and 100 with Warfarin. Every 12 months, we measured creatinine levels and cardiac valve calcification via standard trans-thoracic echocardiogram, while plasma levels of inflammatory mediators were quantified by ELISA at baseline and after 24 months.. Over a follow-up of 24 months, long-term treatment with Rivaroxaban was associated with a significative reduction of cytokines. Patients treated with Rivaroxaban experienced a more frequent stabilization/regression of valve calcifications comparing with patients treated with Warfarin. Rivaroxaban use was related with an improvement in kidney function in 87.4% of patients, while in those treated with Warfarin was reported a worsening of renal clearance in 98% of cases. Patients taking Rivaroxaban experienced lower adverse events (3.2% vs 49%, p-value <0.001).. Our findings suggest that Rivaroxaban compared to Warfarin is associated with lower levels of serum markers of inflammation. The inhibition of FXa may exert an anti-inflammatory effect contributing to reduce the risk of cardiac valve calcification progression and worsening of renal function.

Topics: Anticoagulants; Atrial Fibrillation; Calcinosis; Factor Xa Inhibitors; Heart Valves; Humans; Inflammation; Kidney; Prospective Studies; Rivaroxaban; Stroke; Treatment Outcome; Warfarin

Thromboangiitis obliterans (TAO) is a chronic, non-atherosclerotic, progressive inflammatory vascular disease affecting the small- and medium-size arteries and veins of the extremities.. To evaluate whether long-term anticoagulation with low-molecular-weight heparin (LMWH) and warfarin is beneficial for treating the inflammation and symptoms associated with TAO.. Patients with TAO who underwent anticoagulation as the mainstay of treatment were included in this prospective study. Rest pain relief and healing of trophic lesions (as the primary and secondary endpoint) were investigated at Day 14 and after 6 months of follow-up. High sensitivity C-reactive protein (hsCRP), monocyte count, and ankle-brachial index (ABI) were recorded, and the difference was compared before and after 2-week anticoagulation. The Chi-square test was used to compare the difference between anticoagulant and aspirin groups (based on the literature).. From 2014 to 2019, 18 patients were included. Only 1 patient with wet gangrene received endo-therapy for a failing stent at the start of treatment. After ~14 days, 12 of 13 (92%) patients showed complete ulcer healing, and 17 of 18 (94%) patients showed complete relief from rest pain. Monocyte-counts and hsCRP levels decreased significantly (p<0.001) after a 2-week period of anticoagulation with LMWH. The mean follow-up was 2.6 years (range 0.5-5 years). At 6 months, all patients showed relief of rest pain and complete healing of trophic lesions. All endpoints were significantly improved compared with the aspirin group (p<0.01), and no rest pain or ulcer/gangrene recurred during follow-up.. Anticoagulant therapy may alleviate the inflammation and symptoms of TAO.

Topics: Anticoagulants; Aspirin; C-Reactive Protein; Gangrene; Heparin, Low-Molecular-Weight; Humans; Inflammation; Pain; Prospective Studies; Thromboangiitis Obliterans; Treatment Outcome; Ulcer; Warfarin

Activated factor X (FXa), which contributes to chronic inflammation via protease-activated receptor 2 (PAR2), might play an important role in atrial fibrillation (AF) arrhythmogenesis. This study aimed to assess whether PAR2 signaling contributes to AF arrhythmogenesis and whether rivaroxaban ameliorates atrial inflammation and prevents AF.Methods and Results:In Study 1, PAR2 deficient (PAR2-/-) and wild-type mice were infused with angiotensin II (Ang II) or a vehicle via an osmotic minipump for 2 weeks. In Study 2, spontaneously hypertensive rats (SHRs) were treated with rivaroxaban, warfarin, or vehicle for 2 weeks after 8 h of right atrial rapid pacing. The AF inducibility and atrial remodeling in both studies were examined. Ang II-treated PAR2-/- mice had a lower incidence of AF and less mRNA expression of collagen1 and collagen3 in the atrium compared to wild-type mice treated with Ang II. Rivaroxaban significantly reduced AF inducibility compared with warfarin or vehicle. In SHRs treated with a vehicle, rapid atrial pacing promoted gene expression of inflammatory and fibrosis-related biomarkers in the atrium. Rivaroxaban, but not warfarin, significantly reduced expression levels of these genes.. The FXa-PAR2 signaling pathway might contribute to AF arrhythmogenesis associated with atrial inflammation. A direct FXa inhibitor, rivaroxaban, could prevent atrial inflammation and reduce AF inducibility, probably by inhibiting the pro-inflammatory activation.

Topics: Angiotensin II; Animals; Atrial Fibrillation; Factor Xa; Inflammation; Mice; Rats; Receptor, PAR-2; Rivaroxaban; Signal Transduction; Warfarin

Topics: Fasting; Fluorine Radioisotopes; Glucose; Heparin, Low-Molecular-Weight; Humans; Inflammation; Positron-Emission Tomography; Tomography, X-Ray Computed; Warfarin

Warfarin (WF) is an anticoagulant which also affects physiological processes other than hemostasis. Our previous investigations showed the effect of WF which gained access to the organism via skin on resting peripheral blood granulocytes. Based on these data, the aim of the present study was to examine whether WF could modulate the inflammatory processes as well. To this aim the effect of WF on the inflammatory response induced by subcutaneous sponge implantation in rats was examined.. Warfarin-soaked polyvinyl sponges (WF-sponges) were implanted subcutaneously and cell infiltration into sponges, the levels of nitric oxide (NO) and inflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6) production by sponge cells were measured as parameters of inflammation. T cell infiltration and cytokine interferon-γ (IFN-γ), interleukin-17 (IL-17) and interleukin-10 (IL-10) were measured at day 7 post implantation.. Warfarin exerted both stimulatory and suppressive effects depending on the parameter examined. Flow cytometry of cells recovered from sponges showed higher numbers of granulocytes (HIS48. Warfarin affects some of the parameters of inflammatory reaction induced by subcutaneous polyvinyl sponge implantation. Differential (both stimulatory as well as inhibitory) effects of WF on inflammatory response to sponge implants might affect the course and/or duration of this reaction.

Topics: Animals; Anticoagulants; Cell Survival; Cytokines; Inflammation; Leukocyte Count; Male; Nitric Oxide; Peroxidase; Polyvinyls; Rats; Skin; Warfarin

Essentials Complement activation has a pathogenic role in thrombotic antiphospholipid syndrome (APS). Coagulation proteases such as factor Xa can activate complement proteins. Complement activation markers were elevated in anticoagulated thrombotic APS patients. Complement activation decreased in APS patients switching from warfarin to rivaroxaban.. Background Complement activation may play a major role in the pathogenesis of thrombotic antiphospholipid syndrome (APS). Coagulation proteases such as factor Xa can activate complement proteins. Aims To establish whether rivaroxaban, a direct factor Xa inhibitor, limits complement activation compared with warfarin in APS patients with previous venous thromboembolism (VTE). Methods A total of 111 APS patients with previous VTE, on warfarin target INR 2.5, had blood samples taken at baseline and at day 42 after randomization in the RAPS (Rivaroxaban in Antiphospholipid Syndrome) trial. Fifty-six patients remained on warfarin and 55 switched to rivaroxaban. Fifty-five normal controls (NC) were also studied. Markers of complement activation (C3a, C5a, terminal complement complex [SC5b-9] and Bb fragment) were assessed. Results APS patients had significantly higher complement activation markers compared with NC at both time-points irrespective of the anticoagulant. There were no differences between the two patient groups at baseline, or patients remaining on warfarin at day 42. In 55 patients randomized to rivaroxaban, C3a, C5a and SC5b-9 were lower at day 42 (median (ng mL

Topics: Adult; Anticoagulants; Antiphospholipid Syndrome; Blood Coagulation; Complement Activation; Factor Xa; Factor Xa Inhibitors; Female; Humans; Inflammation; International Normalized Ratio; Male; Middle Aged; Rivaroxaban; Thrombosis; Venous Thromboembolism; Warfarin

Influenza A virus infection is a common respiratory tract infection. Alveolar hemorrhage has been reported in patients with influenza pneumonia and in mice infected with influenza A. In this study, we investigated the effect of two anticoagulants on alveolar hemorrhage after influenza A virus (IAV) infection of wild-type mice. Wild-type mice were anticoagulated with either warfarin or the direct thrombin inhibitor dabigatran etexilate and then infected with a mouse-adapted influenza virus (A/Puerto Rico/8/34 H1N1). Alveolar hemorrhage was assessed by measuring hemoglobin levels in the bronchoalveolar lavage fluid (BALF). We also measured vascular permeability and viral genomes in the lung, as well as white blood cells, inflammatory mediators, and protein in BALF Survival and body weight were monitored for 14 days after influenza A infection. In infected mice receiving either warfarin or dabigatran etexilate we observed decreased activation of coagulation in the BALF and increased alveolar hemorrhage. Warfarin but not dabigatran etexilate increased vascular permeability and mortality of influenza A-infected mice. Anticoagulation did not affect levels of influenza A genomes, white blood cells, inflammatory mediators, or protein in the BALF Our study indicates that systemic anticoagulation increases alveolar hemorrhage in influenza A-infected mice.

Topics: Animals; Anticoagulants; Capillary Permeability; Dabigatran; Hemorrhage; Inflammation; Influenza A Virus, H1N1 Subtype; Male; Mice; Mice, Inbred C57BL; Orthomyxoviridae Infections; Pulmonary Alveoli; Survival Analysis; Warfarin

Topics: Aged; Angiotensin Amide; Anticoagulants; Atrial Fibrillation; Cardiovascular Diseases; Endothelium, Vascular; Female; Glomerular Filtration Rate; Humans; Inflammation; Kidney; Male; Middle Aged; Risk Factors; Severity of Illness Index; Smoking; Treatment Outcome; von Willebrand Factor; Warfarin

Immune responses to therapeutic factor VIII remain a major problem, affecting 30% of patients with severe hemophilia A. The primary factors that drive immune responses in these patients remain elusive. There have been conflicting reports on a role of coagulation (or thrombin) in anti-FVIII immune responses.. To assess the importance of coagulation-associated processes for the onset of the anti-FVIII immune response.. Using FVIII-deficient mice, we compared the immunogenicity of recombinant FVIII or the inactive FVIII(V) (634M) mutant. In parallel, the involvement of tissue factor (TF) activity in the anti-FVIII immune response was investigated upon injection of a neutralizing anti-TF antibody or by the use of chimeric mice that lack TF expression in myeloid cells. The development of the anti-FVIII immune response was also monitored after treatment with warfarin.. The kinetics of the development of antibody responses to FVIII(V) (634M) were indistinguishable from those of wild-type FVIII. Inhibition of TF activity did not modulate immune responses to exogenous FVIII. Additionally, global inhibition of coagulation with warfarin failed to reduce the anti-FVIII immune response.. Thrombin generation or coagulation-associated processes do not modulate the anti-FVIII antibody response in mouse model of severe hemophilia A.

Topics: Animals; Antibodies, Neutralizing; Blood Coagulation; Disease Models, Animal; Factor VIII; Hemophilia A; Immunity, Humoral; Inflammation; Mice; Mutation; Plasmids; Protein Structure, Tertiary; Recombinant Proteins; Thrombin; Thromboplastin; Warfarin

We investigated incidence and risk factors for postextraction bleeding in patients receiving warfarin and those not receiving anticoagulation therapy.. Cross-sectional, multicentre, observational study.. 26 hospitals where an oral surgeon is available.. Data on 2817 teeth (from 496 patients receiving warfarin, 2321 patients not receiving warfarin; mean age (SD): 62.2 (17.6)) extracted between 1 November 2008 and 31 March 2010, were collected. Warfarin-receiving patients were eligible when prothrombin time-international normalised ratio (PT-INR) measured within 7 days prior to the extraction was less than 3.0.. Simple dental extraction was performed, and incidence of postextraction bleeding and comorbidities were recorded.. Postextraction bleeding not controlled by basic haemostasis procedure was clinically significant.. Bleeding events were reported for 35 (7.1%) and 49 (2.1%) teeth, of which 18 (3.6%) and 9 (0.4%) teeth were considered clinically significant, in warfarin and non-warfarin groups, respectively, the difference between which was 3.24% (CI 1.58% to 4.90%). The incidence rates by patients were 2.77% and 0.39%, in warfarin and non-warfarin groups, respectively (incidence difference 2.38%, CI 0.65% to 4/10%). Univariate analyses showed that age (OR 0.197, p=0.001), PT-INR (OR 3.635, p=0.003), mandibular foramen conduction anaesthesia (OR 4.854, p=0.050) and formation of abnormal granulation tissue in extraction socket (OR 2.900, p=0.031) significantly correlate with bleeding incidence. Multivariate analysis revealed that age (OR 0.126, p=0.001), antiplatelet drugs (OR 0.100, p=0.049), PT-INR (OR 7.797, p=0.001) and history of acute inflammation at extraction site (OR 3.722, p=0.037) were significant risk factors for postextraction bleeding.. Our results suggest that there is slight but significant increase in the incidences of postextraction bleeding in patients receiving warfarin. Although absolute incidence was low in both groups, the bleeding risk is not negligible.

Topics: Age Factors; Aged; Anesthesia; Anticoagulants; Blood Coagulation; Cross-Sectional Studies; Female; Humans; Incidence; Inflammation; International Normalized Ratio; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Platelet Aggregation Inhibitors; Postoperative Hemorrhage; Prothrombin Time; Thromboembolism; Tooth; Tooth Extraction; Tooth Socket; Warfarin

Thromboembolic events are well recognised in patients with inflammatory bowel disease (IBD). We present three cases which highlight the need for vigilance with respect to this complication. We also propose that consideration be given to re-evaluating disease activity in those patients who develop thromboembolic complications.

Topics: Adult; Anticoagulants; Female; Heparin, Low-Molecular-Weight; Humans; Inflammation; Inflammatory Bowel Diseases; Leg; Male; Middle Aged; Risk Factors; Smoking; Thrombectomy; Thromboembolism; Tinzaparin; Treatment Outcome; Warfarin

To evaluate the effects of epicutaneous application of anticoagulant warfarin, by examining the presence of tissue injury and immune/inflammatory activity in exposed skin.. Rats were exposed to warfarin by applying 10 μg of warfarin-sodium to 10-12 cm(2) skin (range 0.8-1 μg per 1 cm(2)) for 3 consecutive days. Tissue injury was evaluated by lipid peroxidation, histomorphological changes and signs of reparative activity in skin. T cell infiltration and selected aspects of epidermal cell activity were examined as indicators of immune/inflammatory skin response to warfarin application.. Repeated warfarin application exerted no effect on skin metabolic viability, but resulted in tissue injury (increased malondialdehyde, MDA, production, evident histo-morphological changes in epidermis and dermis depicting cell injury and death). Increased numbers of proliferating cell nuclear antigen (PCNA(+)) cells indicated reparative processes in injured skin. Infiltration of CD3(+) cells (T lymphocytes) along with the increased production of tumor necrosis factor-a (TNF-a) by epidermal cells from warfarin-treated skin and their co-stimulatory effect in an in vitro T-cell activation assay demonstrated immunomodulatory effects of epicutaneous warfarin.. Presented data have documented tissue damage associated with immune/inflammatory activity in skin exposed to warfarin. Observed effects are relevant to immunotoxic potential of this anticoagulant in settings of external exposure.

Topics: Animals; CD3 Complex; Dermatitis, Contact; Epidermal Cells; Gene Expression Regulation; Inflammation; Lipid Peroxidation; Male; Proliferating Cell Nuclear Antigen; Rats; Rodenticides; Skin; T-Lymphocytes; Warfarin

This protocol describes microsphere-based protease assays for use in flow cytometry and high-throughput screening. This platform measures a loss of fluorescence from the surface of a microsphere due to the cleavage of an attached fluorescent protease substrate by a suitable protease enzyme. The assay format can be adapted to any site or protein-specific protease of interest and results can be measured in both real time and as endpoint fluorescence assays on a flow cytometer. Endpoint assays are easily adapted to microplate format for flow cytometry high-throughput analysis and inhibitor screening.

Topics: Animals; Biotinylation; Flow Cytometry; Fluorescence Resonance Energy Transfer; Green Fluorescent Proteins; High-Throughput Screening Assays; Humans; Inflammation; Kinetics; Microspheres; Peptide Hydrolases; Peptides; Reproducibility of Results; Temperature

Many hemodialysis patients receive antiplatelet therapy or warfarin; however, little is known about the effect of this on iron requirements. Given the association of antiplatelet therapy with bleeding we hypothesized that there should be a greater need for iron in such patients, which we tested in this study.. Retrospective 1-year cohort study of 205 chronic hemodialysis patients. The primary outcome variable was total iron dose, which was analyzed according to antiplatelet/warfarin use. Data were also collected on potential confounders, allowing for both unadjusted and adjusted (multiple regression) analysis.. 97/205 patients received antiplatelet/warfarin therapy. This group was older, with a higher incidence of macrovascular disease and diabetes and a higher median C-reactive protein (6.0 vs. 3.75 mg/l). Overall, median iron requirement was 1,300 mg/year. In a multiple regression analysis, antiplatelet/warfarin use was associated with an additional iron requirement of 703 mg (95% confidence interval 188-1,220 mg), with the strongest effect observed in patients with normal inflammatory markers.. We found a high requirement for iron in patients receiving antiplatelet agents/warfarin. We argue that the most likely mechanism for this association is chronic, low-grade blood loss, although further study is required before causality can be established.

Topics: Age Factors; Aged; Anemia, Iron-Deficiency; C-Reactive Protein; Comorbidity; Diabetic Nephropathies; Female; Ferric Compounds; Ferritins; Hemorrhage; Humans; Inflammation; Iron; Iron Deficiencies; Kidney Failure, Chronic; Male; Middle Aged; Nutritional Requirements; Platelet Aggregation Inhibitors; Renal Dialysis; Retrospective Studies; Thrombophilia; Transferrin; Vascular Diseases; Warfarin

Topics: Adenoviridae; Animals; Blood Proteins; Brain; Capsid; Factor X; Hepatocytes; Humans; Inflammation; Liver; Mice; Models, Biological; Muscles; Mutation; Warfarin

The synthesis of several novel coumarin derivatives with a 7-azomethine linkage was carried out starting from 7-formyl-coumarin. The compounds were tested in vivo for their anti-inflammatory activity and in vitro for their antioxidant ability. Compounds 3a and 3e possess significant protection against carrageenin induced rat paw edema.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Azo Compounds; Carrageenan; Coumarins; Edema; Hindlimb; Inflammation; Molecular Structure; Rats; Structure-Activity Relationship

Topics: Administration, Oral; Aged; Anticoagulants; Dimerization; Down-Regulation; Female; Humans; Inflammation; Male; Middle Aged; Stroke; Time Factors; Warfarin

Warfarin, a widely prescribed drug for preventing thrombosis, is thought to act solely through inhibition of vitamin K-dependent coagulation factors. Low concentrations of warfarin inhibit interleukin-6 production and phosphorylation of I-kappa B but not activation of p38 mitogen-activated protein kinase. Thus, warfarin inhibits inflammatory signal transduction, and this may contribute to clinical effects of warfarin.

Topics: Animals; Dose-Response Relationship, Drug; I-kappa B Kinase; Inflammation; Interleukin-6; Mice; Phosphorylation; Protein Serine-Threonine Kinases; Receptors, Tumor Necrosis Factor; Signal Transduction; Tumor Necrosis Factor-alpha; Warfarin

Material with leuckocyte migration inhibition (LMI) activity has been demonstrated in various types of nonimmunologically induced acute pleural inflammatory exudates. This activity is present in inflammatory cell-free exudate and appears to involved the deposition of fibrin around the migrating leukocyte, resulting in "cell-trapping." This is supported by the fact that removal or inhibition of fibrin formation leads to loss of exudate LMI activity. Both fibrinogen and complement as well as vitamin K-dependent clotting factors appear to be required for LMI activity. The mechanism involved in the LMI reaction and its significance in nonimmune and cell-mediated immune inflammation are discussed.

Topics: Animals; Cell Migration Inhibition; Fibrin; Heparin; Hot Temperature; Hydroxyapatites; Inflammation; Irritants; Leukocytes; Male; Pleural Effusion; Rats; Thrombin; Warfarin; Zymosan

1. Sodium warfarin, given by oral or by parenteral route, displays a pronounced anti-inflammatory effect in the formaldehyde and carrageenan induced rat paw edema. This effect becomes patent not only when the warfarin application precedes the local injection of the irritant substance (prophylactic effect), but also when it is given to animals with already developed inflammatory reactions (therapeutic effect). 2. The active doses of Na warfarin lie between 0.5 and 5.0 mg/kg. Smaller as well as higher doses show a reduced anti-inflammatory effect. 3. A marked anti-inflammatory effect can be noted already 90 min after drug injection at a still normal prothrombin level. 4. Vitamin K1 (phylloquinone), given by oral or parenteral route, in doses from 1.6 mg/kg upwards, shows a marked anti-inflammatory effect both in the prophylactic and the therapeutic rat paw test. Vitamin K3 is devoid of any anti-inflammatory activity. 5. The anti-inflammatory effect of both sodium warfarin and of vitamin K1 in rats, is not interfered with by previous adrenalectomy.

Topics: Adrenalectomy; Animals; Anti-Inflammatory Agents; Formaldehyde; Inflammation; Male; Prothrombin; Rats; Time Factors; Vitamin K 1; Warfarin

The i.p. inoculation of C3H mice with 5 times 10-6 cells of a transplantable ovarian carcinoma invariably evokes accumulation of large amounts of ascitic fluid. Histological and pharmacotherapeutic studies indicate that obstruction to peritoneal lymphatic drainage is a key factor in the formation of carcinomatous ascites in this model. In the early stages of ascites formation, an intense inflammatory reaction appears to occlude the condusts that connect the peritoneal cavity to the subdiaphragmatic lymphatic plexus. This inflammatory reaction, elicited by the presence of tumor cells within the peritoneal cavity, can be inhibited with high-dose systemic corticosteroid therapy. Ascitic fluid accumulation in animals so treated is markedly retarded. Tumor cells do not gain access to lymphatic capillaries draining the peritoneal cavity until ascitic fluid accumulation is massive. Systemic anticoagulation with heparin or sodium warfarin does not prevent lodgment of tumor cells within these lymphatic capillaries, nor does it alter the pattern of ascitic fluid accumulation. Various considerations suggest that excess production of ascitic fluid is not a likely pathogenetic factor in murine carcinomatous ascites.

Topics: Animals; Ascites; Female; Heparin; Hydrocortisone; Inflammation; Injections, Intraperitoneal; Lymph Nodes; Male; Mice; Mice, Inbred C3H; Neoplasms, Experimental; Ovarian Neoplasms; Peritoneum; Warfarin