warfarin and Fibrosis

Portal vein thrombosis (PVT) and acute variceal bleeding (AVB) are frequent complications of cirrhosis. The efficacy, safety, and timing of anticoagulant treatment in cirrhotic patients with PVT and AVB are contentious issues. We aimed to establish the safety and efficacy of initiating nadroparin calcium-warfarin sequential (NWS) anticoagulation therapy early after esophageal variceal band ligation within PVT patients having cirrhosis and AVB. Cirrhotic patients having AVB and PVT who underwent EVL were included and randomly allocated to either the NWS therapy group (1-month nadroparin calcium by subcutaneous injection following 5-month warfarin through oral administration, n = 43) or the control group (without any anticoagulation therapy, n = 43). The primary endpoint was the rate of PVT recanalization. Secondary endpoints included major bleeding events mainly referring to variceal rebleeding (5-day failure, 14-day, 4-week, 6-week, and 6-month rebleeding rates) and mortality after EVL. The overall recanalization (complete and partial) rate in the NWS therapy group was significantly higher than that in the control group (67.4% vs. 39.5%, P = 0.009). Low Child-Pugh score (P = 0.039, OR: 0.692, 95% CI 0.488-0.982), D-dimer < 2.00 ug/mL (P = 0.030, OR: 3.600, 95% CI 1.134-11.430), and NWS anticoagulation therapy (P = 0.002, OR: 4.189, 95% CI 1.660-10.568) were the predictors of PVT recanalization through univariate analysis of binary logistic regression. NWS anticoagulation therapy (P = 0.003, OR: 4.506, 95% CI 1.687-12.037) was the independent factor of recanalization through multivariate analysis. Nobody bled except for variceal rebleeding. Five-day failure and 14-day rebleeding were zero. There were no significantly different in 4-week (2.3% vs. 4.7%, P = 1.000), 6-week (4.7% vs. 9.3%, P = 0.672) and 6-month rebleeding (18.6% vs. 20.9%, P = 0.787) between the two groups. There was no mortality during six months follow-up. Low serum albumin (P = 0.011, OR: 0.844, 95% CI 0.741-0.962), high MELD score (P = 0.003, OR: 1.564, 95% CI 1.167-2.097) and Child-Pugh score (P = 0.006, OR: 1.950, 95% CI 1.206-3.155) were predictors of rebleeding by univariate analysis of binary logistic regression analysis. The Child-Pugh score (7 [6-8] vs. 6 [5-7], P = 0.003) and albumin levels (33.93 ± 5.30 vs. 37.28 ± 4.32, P = 0.002) were improved in the NWS therapy group at six months. In PVT patients with cirrhosis and AVB, starting NWS anticoagulation therapy early after EVL wa

Topics: Albumins; Anticoagulants; Esophageal and Gastric Varices; Fibrosis; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Nadroparin; Portal Vein; Treatment Outcome; Venous Thrombosis; Warfarin

Chronic kidney disease (CKD) is characterized by increased interstitial fibrosis and tubular atrophy (IFTA) in the kidney. Chronic hematuria is a hallmark of several human kidney diseases and often is seen in patients on anticoagulation therapy. We had previously demonstrated that chronic hematuria associated with warfarin increases IFTA in 5/6 nephrectomy (5/6NE) rats, and such treatment increases reactive oxygen species (ROS) in the kidney. The goal of this study was to evaluate the effects of the antioxidant N-acetylcysteine (NAC) on the progression of IFTA in 5/6NE mice. 5/6NE C57BL/6 and 5/6NE 129S1/SvImJ mice were treated with warfarin alone or with warfarin and NAC for 23 weeks. Serum creatinine (SCr), hematuria, blood pressure (BP), and ROSs in the kidney were measured; kidney morphology was evaluated. Warfarin doses were titrated to achieve prothrombin time (PT) increase to the levels seen with therapeutic human doses. Warfarin treatment resulted in an increased SCr, systolic BP, hematuria, expression of TGF-ß and ROS in the kidney in both mouse strains. Tumor necrosis factor alpha (TNF-ɑ) levels in the serum were increased in 5/6NE mice treated with warfarin. IFTA was increased as compared with control 5/6NE mice, and this increase in IFTA was more prominent in 129S1/SvImJ than in C57BL/6 mice. NAC ameliorated the warfarin-associated increase in SCr and BP but not hematuria. IFTA, TGF-ß, and ROS in the kidney as well as TNF-ɑ levels in the serum were reduced in mice treated with NAC and warfarin as compared to mice treated with warfarin alone. NAC mitigates the increase in SCr and IFTA in mice with chronic hematuria by reducing oxidative stress in the kidney. This data open novel possibilities for treatments in CKD patients.

Topics: Acetylcysteine; Animals; Fibrosis; Hematuria; Humans; Kidney; Mice; Mice, Inbred C57BL; Nephrectomy; Rats; Reactive Oxygen Species; Renal Insufficiency, Chronic; Tumor Necrosis Factor-alpha; Warfarin

Diabetic cardiomyopathy (DCM) is accompanied by microvascular complications that lead to myocardial dysfunction and heart failure. Most conventional therapies cannot ameliorate the microvascular insufficiency in DCM. In this study, we tested the hypothesis that undercarboxylated osteocalcin (ucOC) may be a new adjuvant therapy against the progression of DCM and its underlying microvascular pathology.. Diabetes was induced in Wistar rats with a high-fat diet combined with streptozotocin injections, and ucOC was upregulated after warfarin administration in the treated group. After 8 weeks, cardiac functions were assessed using a Langendorff apparatus. Cardiac tissue samples were also extracted to assess the ucOC receptor and vascular endothelial growth factor (VEGF) for histopathological studies.. Both the systolic and the diastolic dysfunction observed in the DCM group were significantly improved after the increase in ucOC blood levels. Significant improvement in VEGF and CD31 expression after warfarin injection was associated with increased capillary density, neovascularization, and decreased myocardial fibrosis together with the reestablishment of myocardial structural and ultrastructural patterns.. Undercarboxylated osteocalcin may have a promising effect in improving microvascular insufficiency and myocardial dysfunction in DCM.

Topics: Animals; Carboxylic Acids; Coronary Circulation; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Fibrosis; Isolated Heart Preparation; Male; Microcirculation; Myocardium; Osteocalcin; Platelet Endothelial Cell Adhesion Molecule-1; Protein Processing, Post-Translational; Rats, Wistar; Signal Transduction; Up-Regulation; Vascular Endothelial Growth Factor A; Ventricular Remodeling; Warfarin

Oral anticoagulation prevents thromboembolism in atrial fibrillation. Factor Xa inhibitors, like edoxaban, are known to reduce inflammation and proliferation of smooth muscle cells, while vitamin K antagonism can cause vascular calcific damage. The influence of edoxaban compared to warfarin on vascular remodeling, atherosclerosis and arteriogenesis is unknown.. Apolipoprotein E knockout (ApoE. There was no difference in hind-limb perfusion restoration between the three groups after 14 days (Co 0.36 ± 0.05 vs. Warf 0.39 ± 0.09 (p = .39), Co vs. Edo 0.51 ± 0.06 (p = .089), Warf vs. Edo (p = .83)) after ligation. Immuno-histologically, there was no difference in smooth muscle cell count in both hindlimbs between the three groups or in the amount of perivascular macrophages in collateral-bearing hindlimb tissue. Edoxaban showed the lowest amount of plaque tissue in the aortic sinus tissue (Co 74 ± 11% vs. Edo 62 ± 12% (p = .024), Co vs. Warf 69 ± 14% (p = .30), Edo vs. Warf (p = .14)) as well as the least amount of fibrosis (Co 3.1 ± 0.9% vs. Edo 1.7 ± 0.6% (p = .027), Co vs. Warf 4.1 ± 0.7% (p = .081), Edo vs. Warf (p < .001)). No difference in mRNA content of inflammatory cytokines in muscle tissue or spleen was detected between the three groups.. These data suggest that treatment with edoxaban unlike warfarin prevents vascular maladaptive remodeling, which may be clinically important.

Topics: Animals; Anticoagulants; Atherosclerosis; Collateral Circulation; Disease Models, Animal; Factor Xa Inhibitors; Fibrosis; Hindlimb; Ischemia; Mice, Inbred C57BL; Mice, Knockout, ApoE; Muscle, Skeletal; Neovascularization, Physiologic; Plaque, Atherosclerotic; Pyridines; Thiazoles; Vascular Remodeling; Warfarin

BACKGROUND Worldwide, the treatment of patients with chronic kidney disease (CKD) remains a challenge as warfarin treatment can be associated with severe adverse events related to bleeding. Alternative anticoagulants that can be used in CKD remain to be identified. This study aimed to compare the effects of indobufen, a new antiplatelet agent, with warfarin in a rat model of adenine-induced CKD. MATERIAL AND METHODS Forty-eight male Wistar rats were treated with intragastric adenine to create the rat model of CKD and were divided into four groups: an untreated control group (N=12), a group treated with dimethyl sulfoxide (DMSO) (N=12), a group treated with indobufen, (N=12) and a group treated with warfarin (N-12). Treatment was given for 4 weeks and 8 weeks. Kidney histology was performed, and the degree of fibrosis was quantified using Masson trichrome staining. RESULTS In the rat model of adenine-induced CKD, Masson trichrome staining showed that the degree of kidney fibrosis in the indobufen group (26%) was significantly reduced (p<0.05) when compared the DMSO group (58%) and the warfarin group (49%). Kidney fibrosis was associated with upregulation of 6-keto-PGI2/TXB2 in the rat kidney tissue. CONCLUSIONS In a rat model of adenine-induced CKD, preliminary findings showed that indobufen was associated with reduced kidney fibrosis when compared with warfarin.

Topics: Adenine; Animals; Anticoagulants; China; Disease Models, Animal; Fibrosis; Isoindoles; Kidney; Kidney Failure, Chronic; Male; Phenylbutyrates; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Warfarin

Here, we describe the identification and synthesis of novel indole sulfonamide derivatives that activate the three peroxisome proliferator activated receptor (PPAR) isoforms. Starting with a PPARα activator, compound 4, identified during a high throughput screening (HTS) of our proprietary screening library, a systematic optimization led to the discovery of lanifibranor (IVA337) 5, a moderately potent and well balanced pan PPAR agonist with an excellent safety profile. In vitro and in vivo, compound 5 demonstrated strong activity in models that are relevant to nonalcoholic steatohepatitis (NASH) pathophysiology suggesting therapeutic potential for NASH patients.

Topics: Animals; Benzothiazoles; Carbon Tetrachloride Poisoning; Cell Line; Drug Discovery; Fibrosis; Hepatocytes; High-Throughput Screening Assays; Humans; Hypoglycemic Agents; Indoles; Mice; Mice, Inbred C57BL; Models, Molecular; Molecular Structure; Non-alcoholic Fatty Liver Disease; Peroxisome Proliferator-Activated Receptors; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Sulfonamides

Portal vein thrombosis (PVT) is a common complication in cirrhosis. The aim of this study was to determine risk factors for PVT, assess the efficacy of anticoagulant therapy, and evaluate the effects of PVT on patients with cirrhosis undergoing elective transjugular intrahepatic portosystemic shunt (TIPSS). A total of 101 patients with cirrhosis undergoing elective TIPSS were prospectively studied. After TIPSS, all patients received preventive therapy for PVT and were followed up at 3, 6, 12, and 24 months. Clinical outcomes were compared between patients who developed PVT after TIPSS and those who did not. Multivariate analysis showed that white blood cell count (relative risk [RR]: 0.377; 95% confidence interval [CI]: 0.132-0.579; P = .001), Child-Turcotte-Pugh score (RR: 1.547; 95% CI: 1.029-2.365; P = .032), and ascites (RR: 1.264; 95% CI: 1.019-1.742; P = .040) were independent predictors for PVT. Warfarin treatment within 12 months achieved significantly higher rates of complete recanalization than aspirin or clopidogrel in patients with PVT (54.5% vs 31.3%; P = .013), although adverse events were similar between the 2 groups ( P > .05). Patients without PVT had significantly lower 2-year cumulative rates of variceal rebleeding (15.9% vs 36.6%; P = .023), shunt dysfunction (27.0% vs 46.8%; P = .039), hepatic encephalopathy (24.1% vs 42.6%; P = .045), and hepatocellular carcinoma (11.4% vs 31.2%; P = .024) and markedly higher 2-year cumulative survival rates (89.8% vs 72.9%; P = .041) than those with PVT. The PVT is associated with poorer clinical outcomes in TIPSS-treated patients, and warfarin is both safe and more effective in recanalizing PVT than aspirin or clopidogrel.

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Clopidogrel; Elective Surgical Procedures; Female; Fibrosis; Humans; Male; Middle Aged; Portal Vein; Portasystemic Shunt, Transjugular Intrahepatic; Risk Factors; Ticlopidine; Treatment Outcome; Venous Thrombosis; Warfarin

Anticoagulation may in the future become a therapeutic option for the prevention of liver fibrosis, such as due to recurrent hepatitis C virus infection after liver transplantation. Currently, there are other indications for anticoagulation after liver transplantation but no data regarding its safety. The objective of the study was to audit the safety of anticoagulation after liver transplantation. Liver transplant recipients receiving anticoagulation postoperatively were compared with a matched control group with respect to bleeding complications and postoperative course. Anticoagulation did not increase the risk of bleeding complications after liver transplantation. On the basis of safety, it appears feasible to use anticoagulation in trials to assess prevention of liver fibrosis.

Topics: Adolescent; Adult; Anticoagulants; Data Collection; Drug-Related Side Effects and Adverse Reactions; Female; Fibrosis; Hemorrhage; Humans; Incidence; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Warfarin; Young Adult

Arthrofibrosis following total knee replacement (TKR) is a relatively common complication which results in a reduction in knee range of movement and patient dissatisfaction. A retrospective study examined the relationship between anticoagulation with therapeutic warfarin and rates of arthrofibrosis following TKR. Arthrofibrosis was defined as less than 80 degrees of knee flexion 6-8 weeks post-TKR. Patients were warfarinised if they had a history of thrombophilic tendencies or medical conditions necessitating anti-coagulation, rather than as routine thromboprophylaxis. All other patients received thromboprophylaxis using low molecular weight heparin. A total of 728 patients underwent 874 primary TKR between 1993 and 2002 in one centre, performed by four surgeons. Mean age was 68 years (range 48-89 years) and there were 483 female and 391 male knees. Eighty cases were warfarinised post-operatively (53 female, 27 male). Overall, 83 of 874 TKRs (9%) had arthrofibrosis (57 female, 26 male) requiring manipulation under anaesthetic (MUA). In the warfarinised group, 21 knees (26%) had an MUA (15 female, 6 male). This compared to 62 cases (8%) requiring MUA in the non-warfarinised group (42 female, 20 male). There was a statistically significant difference on Fisher's exact testing (P<0.0001) between groups. Following MUA, knee flexion improved in 95% cases to a minimum 95 degrees but 8 cases had a fixed flexion deformity of 5-10 degrees . In conclusion, therapeutic warfarinisation post-TKR leads to a statistically greater chance of the patient developing arthrofibrosis compared to prophylactic low molecular weight heparin and that patients should be counseled appropriately.

Topics: Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Knee; Cohort Studies; Female; Fibrosis; Heparin, Low-Molecular-Weight; Humans; Joint Diseases; Knee Joint; Male; Middle Aged; Musculoskeletal Manipulations; Pliability; Postoperative Complications; Retrospective Studies; Warfarin

Topics: Adult; Bone and Bones; Bone Marrow; Fibrosis; Foot; Heparin; Humans; Intracranial Thrombosis; Ischemia; Male; Megakaryocytes; Peripheral Vascular Diseases; Reticulin; Tomography, X-Ray Computed; Warfarin

We report the case o a 40-year-old male patient with "primary antiphospholipid syndrome" who developed ischemic cerebral infarctions and renal microangiopathy with infarction. A review of the literature on renal involvement in the primary antiphospholipid syndrome disclosed the differences from the antiphospholipid syndrome in the systemic lupus erythematosus. We describe the evolution of the patient at eight years, and we emphasize the importance of the treatment with warfarin. Also, we review the pathophysiology of severe secondary arterial hypertension.

Topics: Adult; Anticoagulants; Antiphospholipid Syndrome; Arterioles; Brain Ischemia; Cerebral Infarction; Dysarthria; Fibrosis; Humans; Hypertension; Infarction; Kidney; Magnetic Resonance Imaging; Male; Smoking; Thrombophilia; Warfarin

Riedel's invasive fibrous thyroiditis (IFT) is a rare disease of unknown etiology characterized by a dense fibrosis involving the thyroid gland and its surrounding tissues. Clinically, patients present with a stony hard goiter frequently associated with compressive symptoms. Involvement of the surrounding neck structures by IFT can lead to various clinical sequelae. We report the case of a 55-year-old woman with known IFT who developed thrombosis in the right internal jugular vein that progressed to the right sigmoid, transverse, and superior sagittal sinuses. IFT could have predisposed to cerebral venous sinus thrombosis by causing venous stasis, vascular damage and possibly a hypercoagulable state. To our knowledge, this is the first report of cerebral venous sinus thrombosis that developed as a complication of IFT.

Topics: Cerebral Veins; Female; Fibrosis; Heparin; Humans; Jugular Veins; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Middle Aged; Thyroiditis; Thyroxine; Venous Thrombosis; Warfarin