warfarin and Liver-Diseases

Direct oral anticoagulants (DOACs), such as apixaban, edoxaban, rivaroxaban, or dabigatran, are an effective treatment for atrial fibrillation (AF) and deep venous thromboembolism. We hope to evaluate the safety of DOACs versus warfarin/low molecular weight heparin (LMWH) in improving bleeding events in patients with different severity of the liver disease.. We systematically searched the Cochrane Library, PubMed, and Embase databases for studies reporting the effects of DOACs in patients with liver cirrhosis. A random-effects model or fixed-effects model was selected to pool risk ratios (RR) and 95% confidence intervals (CI).. A total of 18 studies involving 41,447 participants was included in this meta-analysis. Compare with warfarin/ LMWH, the use of DOACs significantly reduced the incidence of all bleeding (RR: 0.76; 95%CI: 0.66 to 0.87), major bleeding (RR: 0.51; 95%CI: 0.28 to 0.91), intracranial hemorrhage (RR: 0.50; 95%CI: 0.31 to 0.81), and gastrointestinal bleeding (RR: 0.76, 95% CI: 0.60 to 0.97), and all-cause death in patients with liver disease (RR: 0.77; 95%CI: 0.62 to 0.95). Similar results were observed in atrial fibrillation patients with liver disease and cirrhosis subgroups. Furthermore, the pooled estimates of the Child-Turcotte-Pugh (CTP) class indicated that DOACs reduced the incidence of all bleeding (RR: 0.61; 95%CI: 0.45 to 0.82), gastrointestinal bleeding (RR 0.55; 95%CI: 0.37 to 0.83), and all-cause death (RR: 0.62; 95%CI: 0.49 to 0.79) in patients with mild to moderate cirrhosis.. Our study demonstrates that DOACs significantly reduce the risk of bleeding in patients with liver disease compared with warfarin/LMWH.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Gastrointestinal Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Liver Diseases; Venous Thromboembolism; Warfarin

Many concerns were raised about the outcome of non-vitamin K antagonist oral anticoagulants compared with warfarin in subjects with atrial fibrillation and liver disease. However, the reported relationship between their efficacy and safety was variable. This meta-analysis was performed to evaluate this relationship.. A systematic literature search up to July 2020 was performed and six studies included 50 074 subjects with atrial fibrillation and liver disease at the baseline with 32 229 non-vitamin K antagonist oral anticoagulant consumers and 18 920 warfarin consumers. They were reporting relationships between non-vitamin K antagonist oral anticoagulants and warfarin in subjects with atrial fibrillation and liver disease. Odds ratio (OR) with 95% confidence intervals (CIs) was calculated to evaluate the prognostic role of the efficacy and safety of non-vitamin K antagonist oral anticoagulants compared with warfarin in subjects with atrial fibrillation and liver disease subjects using the dichotomous method with a random or fixed-effect model.. Non-vitamin K antagonist oral anticoagulants consumption was significantly related to lower all-cause mortality in subjects with atrial fibrillation and liver disease (OR, 0.90; 95% CI, 0.81-0.99, P = .03); lower intracranial haemorrhage (OR, 0.67; 95% CI, 0.55- 0.82, P < .001) and low stroke and system embolism (OR, 0.76; 95% CI, 0.68-0.86, P < .001) compared with warfarin consumption. However, non-vitamin K antagonist oral anticoagulants consumption was not significantly related to lower major bleeding in subjects with atrial fibrillation and liver disease (OR, 0.73; 95% CI, 0.52-1.02, P = .06); and gastrointestinal bleeding (OR, 0.93; 95% CI, 0.58-1.49, P = .77) compared with warfarin consumption.. Based on this meta-analysis, non-vitamin K antagonist oral anticoagulant consumption may have an independent lower risk relationship with all-cause mortality, intracranial haemorrhage, and stroke and system embolism compared with warfarin consumption in subjects with atrial fibrillation and liver disease. This relationship forces us to recommend non-vitamin K antagonist oral anticoagulant use in subjects with atrial fibrillation and liver disease for better outcomes and to avoid any possible complications. Further studies are required.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Gastrointestinal Hemorrhage; Humans; Liver Diseases; Stroke; Warfarin

The effect of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) and liver disease remains largely unresolved. Therefore, we performed a meta-analysis to compare the efficacy and safety of NOACs with warfarin in this population.. We systematically searched the Cochrane Library, PubMed, and Embase databases for studies reporting the comparisons of NOACs with warfarin in patients with AF and liver disease. A random-effects model was selected to pool the risk ratios (RRs) and 95% confidence intervals (CIs).. A total of six studies with 41,954 participants were included in this meta-analysis. In AF patients with liver disease, compared with warfarin use, the use of NOACs was associated with reduced risks of all-cause death (RR 0.78, 95% CI 0.66-0.93), major bleeding (RR 0.68, 95% CI 0.53-0.88), and intracranial hemorrhage (RR 0.49, 95% CI 0.41-0.59), but had comparable risks of stroke or system embolism (RR 0.80, 95% CI 0.57-1.12) and gastrointestinal bleeding (RR 0.90, 95% CI 0.61-1.34). In AF patients with cirrhosis, NOACs significantly reduced the risks of major bleeding (RR 0.53, 95% CI 0.37-0.76), gastrointestinal bleeding (RR 0.57, 95% CI 0.38-0.84), and intracranial hemorrhage (RR 0.55, 95% CI 0.31-0.97) compared with warfarin.. Based on current publications, the use of NOACs is at least non-inferior to warfarin in patients with AF and liver disease.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Embolism; Hemorrhage; Humans; Liver Diseases; Stroke; Vitamin K; Warfarin

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Liver Diseases; Stroke; Thromboembolism; Warfarin

The purpose of this review article is to summarize the literature on diseases that are documented to have an effect on response to warfarin and other VKAs.. We searched the English literature from 1946 to September 2015 via PubMed, EMBASE, and Scopus for the effect of diseases on response vitamin K antagonists including warfarin, acenocoumarol, phenprocoumon, and fluindione.. Among many factors modifying response to VKAs, several disease states are clinically relevant. Liver disease, hyperthyroidism, and CKD are well documented to increase response to VKAs. Decompensated heart failure, fever, and diarrhea may also elevate response to VKAs, but more study is needed. Hypothyroidism is associated with decreased effect of VKAs, and obese patients will likely require higher initial doses of VKAs.. In order to minimize risks with VKAs while ensuring efficacy, clinicians must be aware of the effect of disease states when prescribing these oral anticoagulants.

Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Cardiovascular Diseases; Diarrhea; Fibrinolytic Agents; Heart Failure; Humans; Hyperthyroidism; Kidney Failure, Chronic; Liver Diseases; Obesity; Phenindione; Phenprocoumon; Vitamin K; Warfarin

Direct oral anticoagulants have recently emerged as an attractive choice for patients requiring anticoagulation treatment. They have a rapid onset of action and can be administered at fixed doses without the need for routine anticoagulation monitoring. They may present fewer interactions than warfarin but further experience is needed to assess the clinical significance of the interactions with cytochrome CYP3A and P-gp inhibitors/inducers. A higher rate of bleeding has been observed in association with antiplatelet agents or non-steroidal anti-inflammatory drugs. Their safety profile has not been sufficiently studied in the elderly, and in patients with liver disease or severe renal impairment. Dose adjustment is necessary in patients with moderate renal impairment and a higher bleeding rate has been observed in this subgroup, although not higher than with warfarin. The clinical settings that require monitoring of coagulation assays have not yet been specified. Reversal of their anticoagulant effect may be problematic in case of severe bleeding. Therefore, despite the obvious advantages of the direct oral anticoagulants, experience is still lacking for many patient subgroups in which they should be withheld awaiting more data.

Topics: Administration, Oral; Age Factors; Anticoagulants; Blood Coagulation; Food-Drug Interactions; Hemorrhage; Humans; Liver Diseases; Platelet Aggregation Inhibitors; Renal Insufficiency, Chronic; Warfarin

Although highly effective, warfarin use is complicated by its unpredictable narrow therapeutic window, genetic heterogeneity in pharmacokinetic response, numerous food and drug interactions, and the need for regular international normalized ratio (INR) monitoring. Currently, several novel oral anticoagulant (NOAC) drugs (dabigatran, rivaroxaban, apixaban) are available on the market as alternatives to warfarin. These agents all feature more predictable pharmacodynamic and pharmacokinetic properties than warfarin. Additionally, the NOACs do not require routine monitoring of coagulation parameters, and have a relatively lower potential for interactions with drug, herb, and dietary constituents, which enhances the convenience of management for both patients and health professionals alike. However, there are other considerations regarding the use of NOACs that must be taken into account during management of therapy. In contrast to warfarin, most NOACs need dosage adjustments in renal impairment and are contraindicated in severe liver impairment, and there are no specific antidotes for treating NOAC-related over-anticoagulation. The more frequent dosing needed for NOACs may reduce adherence, especially in elderly patients with polypharmacy. Furthermore, NOACs, especially dabigatran, are not as well tolerated as warfarin in patients with gastrointestinal diseases. Overall, the availability of the NOACs has expanded the treatment armamentarium, but they are not without risk. Given the limited experience with the NOACs, their limited range of indications, and their cost, the characteristics of each anticoagulant must be carefully considered to carefully select the agent that will provide the optimal risk/benefit profile in the individual patient.

Topics: Administration, Oral; Aging; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Complementary Therapies; Dabigatran; Drug Interactions; Drug Monitoring; Humans; International Normalized Ratio; Kidney Diseases; Liver Diseases; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Sex Factors; Stroke; Thiophenes; Warfarin

Adoption of international normalized ratio (INR) to harmonize prothrombin time has greatly improved the safety and effectiveness of vitamin K antagonists (VKA) oral anticoagulant therapy. INR is also a major laboratory variable in calculating the widely used Model for End-Stage Liver Disease (MELD) score for liver transplant organ prioritization. However, since the conventional INR (INRVKA) is calibrated specifically for VKA patients, its interlaboratory variation has a significant impact on the accuracy of MELD score. Though still requiring further clinical validation in large numbers of waitlisted patients, the alternative liver INR calibrated by using plasma from liver disease patients instead of VKA patients may harmonize the differences and thus more suitable for MELD score calculation. The objective of this article is to review the history of INR, MELD score, and liver INR, and discuss the challenges and solutions of liver INR implementation.

Topics: Animals; Anticoagulants; History, 20th Century; History, 21st Century; Humans; International Normalized Ratio; Liver Diseases; Prothrombin Time; Vitamin K; Warfarin

Oral vitamin K antagonists are highly efficacious in the prevention and treatment of thromboembolic disease. Optimal use of these agents in clinical practice is challenged by their narrow therapeutic window. The proportion of time spent in the International Normalized Ratio (INR) range of 2.0-3.0 [time in the therapeutic range (TTR)] has been closely associated with adverse outcomes, i.e., stroke, hemorrhage, mortality. Although TTR is a validated marker, it has several limitations. TTR does not capture short-term risks associated with highly variable periods or periods characterized by extreme deviations in INR. Because TTR measurement is limited to consecutive periods of warfarin exposure, it does not inform the risks associated with gap periods of 56 days or greater as these time intervals are excluded from end-point rate calculations. Because individuals with gaps in monitoring represent a different patient population than those without gaps, e.g., less adherent, more acutely ill, more frequent transitions in health status, TTR analyses are likely most valid and informative for individuals with uninterrupted monitoring of the INR. Duration of warfarin therapy and patient-specific factors have also been shown to influence TTR. Younger age, female sex, lower income, black race, frequent hospitalizations, polypharmacy, active cancer, decompensated heart failure, substance abuse, psychiatric disorders, dementia, and chronic liver disease have all been associated with lower TTR. Targeted strategies to improve TTR are urgently needed.

Topics: Age Factors; Anticoagulants; Chronic Disease; Female; Heart Failure; Hemorrhage; Humans; International Normalized Ratio; Liver Diseases; Male; Neoplasms; Sex Factors; Stroke; Substance-Related Disorders; Thromboembolism; Vitamin K; Warfarin

Warfarin significantly reduces thromboembolic risk, but perceptions of associated bleeding risk limit its use. The evidence supporting the association between bleeding and individual patient risks factors is unclear. This systematic review aims to determine the strength of evidence supporting an accentuated bleeding risk when patients with risk factors listed in the warfarin prescribing information are prescribed the drug. A systematic literature search of MEDLINE and Cochrane CENTRAL was conducted to identify studies reporting multivariate relationships between prespecified covariates and the risk of bleeding in patients receiving warfarin. The prespecified covariates were identified based on patient characteristics for bleeding listed in the warfarin package insert. Each covariate was evaluated for its association with specific types of bleeding. The quality of individual evaluations was rated as 'good', 'fair' or 'poor' using methods consistent with those recommended by the Agency for Healthcare Research and Quality (AHRQ). Overall strength of evidence was determined using the Grading of Recommendations Assessment, Development (GRADE) criteria and categorised as 'insufficient', 'very low', 'low', 'moderate' or 'high'. Thirty-four studies, reporting 134 multivariate evaluations of the association between a covariate and bleeding risk were identified. The majority of evaluations had a low strength of evidence for the association between covariates and bleeding and none had a high strength of evidence. Malignancy and renal insufficiency were the only two covariates that had a moderate strength of evidence for their association with major and minor bleeding respectively. The associations between covariates listed in the warfarin prescribing information and increased bleeding risk are not well supported by the medical literature.

Topics: Alcohol Drinking; Anemia; Anticoagulants; Drug Labeling; Heart Diseases; Hemorrhage; Humans; Liver Diseases; Medication Adherence; Mental Disorders; Neoplasms; Prescription Drugs; Renal Insufficiency; Risk Factors; Warfarin

Topics: Anticoagulants; Blood Coagulation Tests; Coagulation Protein Disorders; Disseminated Intravascular Coagulation; Drug Monitoring; Humans; Liver Diseases; Reference Values; Specimen Handling; Vitamin K Deficiency; Warfarin

To elucidate predisposing factors for enlargement of intracerebral hematoma (ICH) during warfarin therapy, we reviewed 47 patients on warfarin who developed acute ICH and determined relationships among ICH enlargement, INR reversal and clinical data. Among 36 patients treated to counteract the effects of warfarin within 24 h of onset, ICH increased in 10 patients (enlarged group), but remained unchanged in the remaining 26 (unchanged group), while ICH remained unchanged in another 11 patients in whom the effect of warfarin was reversed after 24 h. The international normalized ratio (INR) was counteracted immediately in 11 patients treated with prothrombin complex concentrate (PCC) but gradually in the other 36 treated by reducing the dose of warfarin, or by administering vitamin K or fresh frozen plasma. Multivariate analysis with a logistic regression model showed an INR value <2.0 at admission or for 24 h after immediate INR correction with PCC prevented ICH enlargement (OR 0.069, 95%CI 0.006-0.789, p = 0.031). An INR value of >2.0 within 24 h of ICH seems an important predisposing factor for ICH enlargement.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Comorbidity; Diabetes Mellitus; Disease Progression; Female; Humans; Hypercholesterolemia; Hypertension; International Normalized Ratio; Liver Diseases; Male; Middle Aged; Platelet Aggregation Inhibitors; Postoperative Complications; Retrospective Studies; Risk Factors; Tomography, X-Ray Computed; Vitamin K; Warfarin

Warfarin is associated with numerous drug and food interactions, and much attention has been appropriately focused on this subject. Because several disease states may also affect response to oral anticoagulants, we present a summary of the literature.. We searched MEDLINE for original articles on the effect of disease states on response to warfarin.. Liver disease and thyroid dysfunction are well-documented as affecting warfarin response. Further study is needed to establish whether febrile illness, congestive heart failure, and other disease states enhance the effect of warfarin in some patients.. Careful monitoring of anticoagulant therapy in patients with diseases that have the potential to affect warfarin response could increase safety and efficacy of this important agent.

Topics: Administration, Oral; Anticoagulants; Disease; Drug Interactions; Drug Monitoring; Fever; Food-Drug Interactions; Heart Failure; Humans; Liver Diseases; Safety; Thyroid Diseases; Warfarin

We report on a case of massive bleeding into the liver parenchyma during treatment with a combination of warfarin sodium and trimethoprim-sulfamethoxazole. A fifty-five-year-old woman was put on long-term anticoagulant therapy with warfarin sodium. Two years later a course of trimethoprim-sulfamethoxazole was given to treat bronchitis. Following a bout of severe epigastric pain, ultrasonography and computed tomography (CT) then showed an enlarged liver containing several large hematomas. Subsequent CT scans, after tentative treatment only, showed regression of the liver hematomas, with almost complete disappearance after eight months. Bleeding complications and drug interactions related to this case are discussed, together with a review of the only six previous reports in the world literature of liver hematomas following anticoagulant therapy. Also mentioned are five patients in whom thrombolytic therapy gave rise to the same adverse reaction.

Topics: Chemical and Drug Induced Liver Injury; Drug Interactions; Drug Therapy, Combination; Female; Hematoma; Humans; Liver; Liver Diseases; Middle Aged; Tomography, X-Ray Computed; Trimethoprim, Sulfamethoxazole Drug Combination; Warfarin

Topics: Biological Assay; Blood Coagulation; Blood Coagulation Factors; Blood Proteins; Colorimetry; Enzyme-Linked Immunosorbent Assay; Glycoproteins; Humans; Liver Diseases; Protein C; Radioimmunoassay; Warfarin

Topics: Anticoagulants; Biopsy; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Drug Resistance; Drug Synergism; Factor IX; Factor VII; Factor X; Fibrinolysis; Humans; Liver; Liver Diseases; Prothrombin; Vitamin K; Vitamin K Deficiency; Warfarin

The INR system was developed to standardize PT reporting in patients on oral anticoagulants. We prospectively collected blood samples from 29 patients with liver impairment (INR 1.5-3.5). Control patients were on warfarin (n = 31). PT's were measured on an ACL-300 with three thromboplastin reagents. INR's were calculated using instrument specific ISI's. Other tests performed were FDP's, fibrinogen, aPTT, factors II, V, VII and X. The INR's for each patient in the study population using the three thromboplastin reagents were significantly different (p = 0.0001). Those for the control population were not (p = 0.0658). Fibrinogen, factors V, II and X were different at the 5% level of significance between the populations. FDP's were detected in 17 study subjects. The INR system is not valid for comparison of patients with liver impairment because different reagents do not give the same INR for the same sample. It is, however, no less valid than the use of PT with different thromboplastin reagents. Further study is recommended.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Indicators and Reagents; Liver Diseases; Male; Middle Aged; Prospective Studies; Prothrombin Time; Reference Standards; Reproducibility of Results; Thromboplastin; Warfarin; World Health Organization

Prothrombinex-VF is being increasingly used as an off-label therapy to correct non-warfarin-related elevations in international normalised ratio (INR) in the critically ill. Currently there are no dosing guidelines for such use.. To validate a prediction equation, embedded in a smartphone application (app), to guide dosing of Prothrombinex-VF in critically ill patients.. A prospective pilot cohort study of critically ill adult patients with elevated INRs who were treated with Prothrombinex-VF. The main outcome measured was INR following Prothrombinex-VF administration.. Of the 31 patients included, five (16%) were taking warfarin prior to admission and 14 (45%) had chronic liver disease. There was a significant decrease in INR after Prothrombinex-VF treatment (P < 0.001) and a significant correlation between the app's predicted INRs and the measured INRs (r = 0.63 and P < 0.001). The app's predicted INRs were less accurate for patients with chronic liver disease than for those without. Overall, the app's recommendations achieved an INR either similar to (29.6%) or better than (55.6%) what would have been achieved had the warfarin reversal guidelines been applied to dose the Prothrombinex-VF.. The app appeared to be reasonably accurate at predicting normalisation of elevated INRs after administration of Prothrombinex-VF, especially among patients without liver disease. Its dosing recommendations were similar to or possibly better than preexisting warfarin reversal guidelines in over 85% of the situations analysed, if we assume a higher dose of Prothrombinex-VF would achieve a greater reduction in INR than a lower dose.

Topics: Adult; Anticoagulants; Critical Illness; Hemorrhage; Humans; International Normalized Ratio; Liver Diseases; Pilot Projects; Prospective Studies; Warfarin

The benefit-risk profile of direct oral anticoagulants (DOACs) compared with warfarin, and between DOACs in patients with atrial fibrillation (AF) and chronic liver disease is unclear.. We conducted a new-user, retrospective cohort study of patients with AF and chronic liver disease who were enrolled in a large, US-based administrative database between January 1, 2011, and December 31, 2017. We assessed the effectiveness and safety of DOACs (as a class and individually) compared with warfarin, and between DOACs in patients with AF and chronic liver disease. The primary outcomes were hospitalization for ischemic stroke/systemic embolism and hospitalization for major bleeding. Inverse probability treatment weights were used to balance the treatment groups on measured confounders.. Overall, 10 209 participants were included, with 4421 (43.2%) on warfarin, 2721 (26.7%) apixaban, 2211 (21.7%) rivaroxaban, and 851 (8.3%) dabigatran. The incidence rates per 100 person-years for ischemic stroke/systemic embolism were 2.2, 1.4, 2.6, and 4.4 for DOACs as a class, apixaban, rivaroxaban, and warfarin, respectively. The incidence rates per 100 person-years for major bleeding were 7.9, 6.5, 9.1, and 15.0 for DOACs as a class, apixaban, rivaroxaban, and warfarin, respectively. After inverse probability treatment weights, the risk of hospitalization for ischemic stroke/systemic embolism was significantly lower between DOACs as a class (hazard ratio [HR], 0.64 [95% CI, 0.46-0.90]) or apixaban (HR, 0.40 [95% CI, 0.19-0.82]) compared with warfarin, but not significantly different between rivaroxaban versus warfarin (HR, 0.76 [95% CI, 0.47-1.21]) or rivaroxaban versus apixaban (HR, 1.73 [95% CI, 0.91-3.29]). Compared with warfarin, the risk of hospitalization for major bleeding was lower with DOACs as a class (HR, 0.69 [95% CI, 0.58-0.82]), apixaban (HR, 0.60 [95% CI, 0.46-0.78]), and rivaroxaban (HR, 0.79 [95% CI, 0.62-1.0]). However, the risk of hospitalization for major bleeding was higher for rivaroxaban versus apixaban (HR, 1.59 [95% CI, 1.18-2.14]).. Among patients with AF and chronic liver disease, DOACs as a class were associated with lower risks of hospitalization for ischemic stroke/systemic embolism and major bleeding versus warfarin. However, the incidence of clinical outcomes among patients with AF and chronic liver disease varied between individual DOACs and warfarin, and in head-to-head DOAC comparisons.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cohort Studies; Dabigatran; Embolism; Hemorrhage; Humans; Ischemic Stroke; Liver Diseases; Retrospective Studies; Rivaroxaban; Stroke; Warfarin

Patients with chronic liver disease (CLD) often present with an elevated international normalized ratio (INR). Although elevated INR reflects a higher risk of hemorrhage among warfarin users, its clinical significance in CLD patients is less clear.. We used Veterans Health Administration data to quantify the association between INR and (non-variceal) hemorrhage in patients with CLD compared to warfarin users.. We performed a multivariate competing risk analysis to study the association between INR and hemorrhage in the two cohorts. We used an interaction term between INR and cohort (CLD/warfarin users) to test if INR had different effects on hemorrhage in the two cohorts.. Data from 80 134 patients (14, 412 with CLD and 65, 722 taking warfarin) were analyzed. The effect of INR on the risk of hemorrhage differed between CLD patients and warfarin users (interaction P < .001). As INR increased above 1.5, the adjusted hazard ratio (aHR) for hemorrhage in CLD patients increased to 2.25 but remained fairly constant with further elevation of INR values. In contrast, the risk of hemorrhage in patients taking warfarin remained low with INR in the subtherapeutic (INR <2.0) and therapeutic ranges (INR 2.0-3.0), and increased exponentially with INR in the supratherapeutic range (aHR 1.64 with INR >3.0-3.5, and 4.70 with INR >3.5).. The relationship between INR and risk of hemorrhage in CLD patients is different from that in warfarin users. Caution should be exercised extrapolating data from warfarin users to make clinical decisions in CLD patients.

Topics: Anticoagulants; Cohort Studies; Hemorrhage; Humans; International Normalized Ratio; Liver Diseases; Retrospective Studies; Warfarin

Topics: Anticoagulants; Blood Coagulation Factors; Humans; International Normalized Ratio; Liver Diseases; Prothrombin; Retrospective Studies; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Humans; Liver Diseases; Stroke; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Humans; Liver Diseases; Stroke; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Humans; Liver Diseases; Stroke; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Humans; Liver Diseases; Stroke; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Humans; Liver Diseases; Pyridines; Thiazoles; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Humans; Liver Diseases; Thromboembolism; Warfarin

Topics: Administration, Oral; Anticoagulants; Chronic Disease; Female; Hemorrhage; Humans; Liver Diseases; Male; Middle Aged; Retrospective Studies; Venous Thromboembolism; Warfarin

Advanced liver disease is known to increase the risk for bleeding and affects the hepatic clearance and metabolism of drugs. Subjects with active liver disease were excluded from pivotal clinical trials of direct oral anticoagulants (DOACs), so the evidence regarding the efficacy and safety of DOACs in patients with liver disease is lacking.. The aim of this study was to compare DOACs with warfarin in patients with nonvalvular atrial fibrillation and liver disease.. Using the Korean National Health Insurance Service database, subjects with atrial fibrillation and active liver disease treated with oral anticoagulation were included (12,778 with warfarin and 24,575 with DOACs), and analyzed ischemic stroke, intracranial hemorrhage, gastrointestinal bleeding, major bleeding, all-cause death, and the composite outcome. Propensity score weighting was used to balance covariates between the 2 groups.. DOACs were associated with lower risks for ischemic stroke (hazard ratio [HR]: 0.548; 95% confidence interval [CI]: 0.485 to 0.618), intracranial hemorrhage (HR: 0.479; 95% CI 0.394 to 0.581), gastrointestinal bleeding (HR: 0.819; 95% CI: 0.619 to 0.949), major bleeding (HR: 0.650; 95% CI: 0.575 to 0.736), all-cause death (HR: 0.698; 95% CI: 0.636 to 0.765), and the composite outcome (HR: 0.610; 95% CI: 0.567 to 0.656) than warfarin. Among the total study population, 13% of patients (n = 4,942) were identified as having significant active liver disease. A consistent benefit was observed in patients with significant active liver disease (HR for the composite outcome: 0.691; 95% CI: 0.577 to 0.827).. In this large Asian population with atrial fibrillation and liver disease, DOACs showed better effectiveness and safety than warfarin, which was consistent in those with significant active liver disease.

Topics: Aged; Atrial Fibrillation; Factor Xa Inhibitors; Female; Humans; Liver Diseases; Male; Middle Aged; Retrospective Studies; Stroke; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Humans; Liver Diseases; Warfarin

Topics: Atrial Fibrillation; Humans; Liver Diseases; Pyridines; Thiazoles; Warfarin

The incidence of warfarin-induced skin necrosis (WISN) is rare. The majority of WISN cases usually appear between 3 and 6 days after the initiation of warfarin therapy. Here we report a late-onset case of WISN that occurred in a 52-year-old man 4 years after the initiation of therapy. The skin lesions in the patient were associated with acquired deficiency of protein C and protein S and abnormal liver function.

Topics: Anticoagulants; Drug Eruptions; Humans; Liver Diseases; Male; Middle Aged; Necrosis; Protein C Deficiency; Protein S Deficiency; Time Factors; Warfarin

A complication of chronic liver disease (CLD) is the abnormality of coagulation. In clinical practice, this increased risk of bleeding has not been identified as a protective factor against stroke or systemic embolism associated with atrial fibrillation (AF). The objective of this study was to assess the safety of direct oral anticoagulant (DOAC) agents vs warfarin in CLD patients with AF.. This was a retrospective cohort study of patients with CLD and AF initiated on oral anticoagulants. Rates of all-cause bleeding were compared between warfarin and DOAC agents. Secondary endpoints included rates of major bleeding and other risk factors for bleeding on anticoagulant therapy.. The all-cause bleeding rates were similar between the groups, with 8.4% per year in the DOAC (n = 75) group and 8.8% in warfarin (n = 158) group (HR 0.9, 95% CI 0.4-1.8). No significant difference was noted in the rate of major bleeding. In the multivariable model, higher MELD-XI score and previous bleed were risk factors associated with increased bleeding.. No significant differences in bleeding rates were noted in patients treated with warfarin and DOAC agents. Further studies evaluating DOAC agents are needed to better understand the optimal anticoagulation strategy in setting of CLD.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Biomarkers; Blood Coagulation; Blood Coagulation Tests; Endoscopy, Gastrointestinal; Female; Hemorrhage; Humans; Liver Diseases; Male; Middle Aged; Proportional Hazards Models; Retrospective Studies; Risk Factors; Stroke; Treatment Outcome; Warfarin

Patients with liver disease are at an increased risk of both embolism and bleeding. The optimal anticoagulation strategy remains unclear when associated with venous thromboembolic disease. Moreover, currently approved oral anticoagulant drugs undergo metabolism and elimination in the liver with varying degrees of hepatic dysfunction. Thus, impaired liver function may lead to increased risk of bleeding, making anticoagulant therapy more intricate. This article summarizes the risk of bleeding and thrombosis in patients with liver disease, and the clinical research progress of oral anticoagulants in patients with liver disease to facilitate evidence for choosing oral anticoagulants therapy when required.. 肝病患者栓塞和出血风险均增加，当合并静脉血栓栓塞疾病时，尚不明确最佳的抗凝方案。而目前批准的口服抗凝药物都不同程度经肝脏代谢和消除，肝功能受损可能导致出血风险增加，使得抗凝治疗更加复杂。现对肝病患者的出血与血栓风险，以及口服抗凝药在肝病患者应用的临床研究进展进行总结，以期为需要抗凝治疗的肝病患者选用口服抗凝药提供证据。.

Topics: Administration, Oral; Anticoagulants; Hemorrhage; Humans; Liver Diseases; Thromboembolism; Warfarin

Spontaneous hepatic rupture without underlying liver diseases is uncommon entity. We report a rare case of spontaneous rupture of liver hematoma in patient treated with warfarin end enoxaparin sodium because of pulmonary embolism. Two day after admission the patient complained generalized abdominal pain and hemodynamic instability. The abdominal US and TC scan revealed free fluid and lesion at right liver lobe. The patient, despite intravenous fluid support and blood transfusion, was hemodinamically instable and urgent laparotomy was needed. At laparotomy, it was found that a subcapsular haematoma, involving the diaphragmatic face of the right liver, had ruptured into peritoneum. Hepatic bleeding was stopped using a conservative approach by Pringle manoeuvre, parenchymal suture and fibrin sealant. There was no complication related to hepatic surgery but the patient died because of new massive pulmonary embolism 10 days after surgery. The absence of underlying liver pathology was confirmed by autopsy examination. This case report suggests that the possibility of spontaneous liver rupture should be considered in patients being treated with oral anticoagulants. Early diagnosis are critically important given the high morbidity and mortality. Aggressive resuscitation and immediate exploratory laparotomy is needed when hemodynamic instability occurs. In our case a quick, safe and effective control of bleeding was provided by partial vascular occlusion, parenchymal suture and topical haemostatic agent.. Anticoagulant therapy, Araumatic hemoperitoneum, Liver hematoma.. La rottura spontanea di fegato in assenza di malattie epatiche concomitanti è un evento abbastanza raro. Nel nostro lavoro illustriamo un raro caso di rottura spontanea di fegato in un paziente in trattamento con warfarin ed enoxaparina sodica a causa di una embolia polmonare. Due giorni dopo la dimissione il paziente lamentava dolori addominali generalizzati e presentava instabilità emodinamica. L’ecografia addominale e la TC addome mostravano versamento libero in addome ed una lesione a carico del fegato destro. Nonostante la terapia infusionale di supporto e le trasfusioni, il paziente continuava ad essere instabile da un punto di vista emodinamico; si decideva pertanto di eseguire una laparotomia d’urgenza. Alla apertura della cavità addominale vi è stato il riscontro di un ematoma sotto-glissoniano che coinvolgeva la faccia diaframmatica del fegato di destra e che si era aperto in addome. Il sanguinamento è stato controllato con approccio conservativo utilizzando la manovra di Pringle, sutura del parenchima ed uso di emostatici. Non si sono osservate complicanze correlate all’intervento ma il paziente è deceduto a causa di un nuovo episodio di embolia polmonare massiva, in decima giornata postoperatoria. L’esame autoptico ha confermato l’assenza di patologie epatiche concomitanti. La possibilità di una rottura spontanea di fegato andrebbe sempre considerata in pazienti in trattamento con anticoagulanti. La diagnosi precoce è fondamentale date l’alta morbilità e mortalità. Una terapia rianimatoria aggressiva ed una laparotomia esplorativa d’urgenza sono indicate in caso di instabilità emodinamica. Nel nostro caso, un rapido e sicuro controllo dell’emostasi sono stati possibili grazie ad una emostasi compressiva, sutura diretta del parenchima ed uso di emostatici.

Topics: Anticoagulants; Drug Therapy, Combination; Enoxaparin; Fatal Outcome; Hematoma; Hepatectomy; Humans; Liver Diseases; Pulmonary Embolism; Recurrence; Rupture, Spontaneous; Warfarin

The aim of this study was to review and describe the use of Prothrombinex by a physician-led retrieval service based remote from a hospital blood bank.. This is a retrospective observational study. Patients to whom Prothrombinex was administered by the retrieval team were identified from the retrieval service patient database. The paper case cards of the identified patients were then manually reviewed and the data matched to patients in the state-wide electronic laboratory record.. Between 1 January 2010 and 30 November 2013 38 cases were identified. For 28 the indication was warfarinisation associated with life-threatening bleeding (most commonly intracranial or gastrointestinal tract). In the remaining 10 cases, Prothrombinex was used to treat coagulopathy associated with liver disease or massive haemorrhage. The median time saved by the retrieval team administering PTX-VF, rather than waiting to the receiving centre, was 120 min (interquartile range: 85-195 min). The median dose of PTX-VF administered was 23.25 IU/kg (interquartile range: 20-33 IU/kg). Paired international normalised ratios (INRs) were available for 33 of the 38 patients. In the warfarin group, all patients had an improvement in their INR and 21 of 25 had correction of their INR. In the non-warfarin group, the effect on INR was more variable.. Prothrombinex is a clinically useful product that can be relatively easily stored and used by retrieval services, even if they are based in isolation from a hospital blood bank. More research is required to look at the utility of Prothrombinex for non-warfarin-related bleeding in the pre-hospital and retrieval environment.

Topics: Adult; Aged; Anticoagulants; Blood Banks; Blood Coagulation Disorders; Blood Coagulation Factors; Emergency Service, Hospital; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Intracranial Hemorrhages; Liver Diseases; Male; Middle Aged; Retrospective Studies; Statistics, Nonparametric; Time-to-Treatment; Warfarin

Our aim was to identify risk factors for acute gastrointestinal (GI) bleeding in patients with myocardial infarction (MI) who were prescribed clopidogrel following hospital discharge.. Data were collected retrospectively from patients treated in Veteran Affairs hospitals in Ohio, USA, from 2001 to 2008 with a primary diagnosis of MI (International Classification of Diseases, 9th Revision) and a prescription for clopidogrel filled within 48 h of discharge. Primary outcome was acute GI bleeding after discharge.. Acute GI bleeding occurred in 107 of 3218 patients. Bleeding occurred in those who were elder (66.2 vs. 62.4 years, P = 0.0002), had lower glomerular filtration rate (74 vs. 81 mL/min, P = 0.024), had filled prescription for warfarin (15.9% vs. 6.9%, P = 0.0004), diagnosed as atrial fibrillation (20.6% vs. 11.1%, P = 0.003), chronic liver (5.6% vs. 2.2%, P = 0.018) or kidney disease (29.0% vs. 19.4%, P = 0.016). A risk model and GI bleed risk score were developed and showed that patients with age >65 years, use of warfarin, the presence of chronic liver or kidney disease were at increased risk for GI bleeding.. Veterans patients of advanced age, using warfarin and with chronic liver and kidney disease may be at increased risk of GI bleeding when prescribed clopidogrel following MI. A scoring system may help to identify patients at high risk for GI bleeding.

Topics: Acute Disease; Age Factors; Aged; Anticoagulants; Chronic Disease; Clopidogrel; Female; Gastrointestinal Hemorrhage; Humans; Kaplan-Meier Estimate; Kidney Diseases; Liver Diseases; Male; Middle Aged; Myocardial Infarction; Ohio; Platelet Aggregation Inhibitors; Retrospective Studies; Risk Assessment; Risk Factors; Ticlopidine; Veterans; Warfarin

Chronic liver disease presents a relative contraindication to warfarin therapy, but some patients with liver disease nevertheless require long-term anticoagulation. The goal is to identify which patients with liver disease might safely receive warfarin.. Among 102 134 patients who received warfarin from the Veterans Affairs from 2007 to 2008, International Classification of Diseases-Ninth Revision codes identified 1763 patients with chronic liver disease. Specific diagnoses and laboratory values (albumin, aspartate aminotransferase, alanine aminotransferase, creatinine, and cholesterol) were examined to identify risk of adverse outcomes, while controlling for available bleeding risk factors. Outcomes included percent time in therapeutic range, a measure of anticoagulation control, and major hemorrhagic events, by International Classification of Diseases-Ninth Revision codes. Patients with liver disease had lower mean time in therapeutic range (53.5%) when compared with patients without (61.7%; P<0.001) and more hemorrhages (hazard ratio, 2.02; P<0.001). Among patients with liver disease, serum albumin and creatinine levels were the strongest predictors of both outcomes. We created a 4-point score system: patients received 1 point each for albumin (2.5-3.49 g/dL) or creatinine (1.01-1.99 mg/dL), and 2 points each for albumin (<2.5 g/dL) or creatinine (≥2 mg/dL). This score predicted both anticoagulation control and hemorrhage. When compared with patients without liver disease, those with a score of zero had modestly lower time in therapeutic range (56.7%) and no increase in hemorrhages (hazard ratio, 1.16; P=0.59), whereas those with the worst score (4) had poor control (29.4%) and high hazard of hemorrhage (hazard ratio, 8.53; P<0.001).. Patients with liver disease receiving warfarin have poorer anticoagulation control and more hemorrhages. A simple 4-point scoring system using albumin and creatinine identifies those at risk for poor outcomes.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation; Chronic Disease; Creatinine; Female; Hemorrhage; Humans; Liver Diseases; Male; Middle Aged; Prognosis; Risk Assessment; Risk Factors; Serum Albumin; Treatment Outcome; Warfarin

The model for end-stage liver disease score (MELD = 3.8*LN[total bilirubin] + 9.6*LN[creatinine] + 11.2*[PT-INR] + 6.4) predicts mortality for tricuspid valve surgery. However, the MELD is problematic in patients undergoing warfarin therapy, as warfarin affects the international normalized ratio (INR). This study aimed to determine whether a simplified MELD score that does not require the INR for calculation could predict mortality for patients undergoing tricuspid valve surgery. Simplified MELD score = 3.8*LN[total bilirubin] + 9.6*LN[creatinine] + 6.4.. A total of 172 patients (male: 66, female: 106; mean age, 63.8 ± 10.3 years) who underwent tricuspid replacement (n = 18) or repair (n = 154) from January 1991 to July 2011 at a single centre were included. Of them, 168 patients in whom the simplified MELD score could be calculated were retrospectively analysed. The relationship between in-hospital mortality and perioperative variables was assessed by univariate and multivariate analysis.. The rate of in-hospital mortality was 6.4%. The mean admission simplified MELD score for the patients who died was significantly higher than for those surviving beyond discharge (11.3 ± 4.1 vs 5.8 ± 4.0; P = 0.001). By multivariate analysis, independent risk factors for in-hospital mortality included higher simplified MELD score (P = 0.001) and tricuspid valve replacement (P = 0.023). In-hospital mortality and morbidity increased along with increasing simplified MELD score. Scores <0, 0-6.9, 7-13.9 and >14 were associated with mortalities of 0, 2.0, 8.3 and 66.7%, respectively. The incidence of serious complications (multiple organ failure, P = 0.005; prolonged ventilation, P = 0.01; need for haemodialysis; P = 0.002) was also significantly higher in patients with simplified MELD score ≥ 7.. The simplified MELD score predicts mortality in patients undergoing tricuspid valve surgery. This model requires only total bilirubin and creatinine and is therefore applicable in patients undergoing warfarin therapy.

Topics: Aged; Bilirubin; Biomarkers; Blood Coagulation; Comorbidity; Creatinine; Female; Heart Valve Diseases; Heart Valve Prosthesis Implantation; Hospital Mortality; Humans; International Normalized Ratio; Japan; Liver Diseases; Logistic Models; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Retrospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Time Factors; Treatment Outcome; Tricuspid Valve; Warfarin

Topics: Aged, 80 and over; Anti-Bacterial Agents; Anticoagulants; Cholangiopancreatography, Endoscopic Retrograde; Enterococcus faecium; Gram-Positive Bacterial Infections; Hematoma; Humans; Liver Diseases; Male; Pulmonary Embolism; Warfarin

Neonatal chondrodysplasia punctata (CDP) is characterized by epiphyseal stippling and midfacial hypoplasia. CDP is usually inherited, but can be acquired because of maternal vitamin K deficiency. We describe an infant with CDP born to a teenager with sickle cell anemia and transfusional iron overload. The mother had severe liver fibrosis, elevated liver iron concentration (34 mg Fe/g), and coagulopathy, but no gestational use of warfarin. Fetal abnormalities were attributed to vitamin K deficiency secondary to liver dysfunction from iron toxicity. Treatment of iron overload among women with sickle cell anemia of childbearing potential is important to avoid possible CDP in newborns.

Topics: Abnormalities, Drug-Induced; Adolescent; Anemia, Sickle Cell; Chondrodysplasia Punctata; Female; Humans; Infant, Newborn; Iron Overload; Liver Diseases; Male; Nasal Bone; Pregnancy; Pregnancy Complications; Transfusion Reaction; Vitamin K Deficiency; Warfarin

Topics: Adult; Anticoagulants; Antiphospholipid Syndrome; Constriction, Pathologic; Female; Hepatic Artery; Humans; Liver Diseases; Lupus Erythematosus, Systemic; Radiography; Warfarin

Topics: Aged; Anticoagulants; Budd-Chiari Syndrome; Female; Granuloma, Plasma Cell; Humans; Hypertrophy; Liver Diseases; Tomography, X-Ray Computed; Warfarin

The International Normalised Ratio (INR)/International Sensitivity Index (ISI) system was developed as a way to standardise the prothrombin time during the monitoring of patients undergoing oral anti-coagulant therapy with vitamin K antagonists. The wide acceptance of the INR has led to its use as one of three parameters used in the Model for End stage Liver disease (MELD) scoring system to aid the prioritisation of patients for liver transplant. Literature published recently has highlighted the potential inadequacy of the INR system in this context. Our aim was to investigate the degree of difference between INR values calculated using an ISI derived from warfarinised patients and those calculated using an ISI derived from patients with liver disease. Prothrombin times from 60 patients with liver disease were determined using three working thromboplastin reagents; Innovin, Thromborel S and Thromboplastin C and two reference thromboplastins; rTF/95 and RBT/05. All thromboplastin reagents tested had standard international sensitivity indices (ISIs) assigned following calibration with patients on oral anticoagulant therapy (ISIvka). As a result of the new calibration each of the working thromboplastin reagents was assigned a specific "liver patient" ISI. Two INR values were calculated for each thromboplastin patient involved in the calibration. A comparison of the mean INRliver with INRvka showed a statistically significant difference between the two values (p<0.0001). A similar relationship existed for INRs on a further 20 patients with liver disease whose plasmas were not used to derive the ISIliver. This difference led to a change in the final MELD score and could therefore affect the prioritisation and management of these patients.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Blood Coagulation; Calibration; Chronic Disease; Humans; International Normalized Ratio; Liver; Liver Diseases; Liver Transplantation; Predictive Value of Tests; Prothrombin Time; Recombinant Proteins; Severity of Illness Index; Thromboplastin; Warfarin

Coagulopathy occurs frequently in critically ill patients, but its epidemiology, current treatment, and relation to patient outcome are poorly understood. We described the prevalence, risk factors, and treatment of prolongation of the prothrombin time in critically ill patients using the international normalized ratio to standardize data and explored its association with intensive care unit survival.. Prospective multiple center observational cohort study.. Twenty-nine adult intensive care units in the United Kingdom.. All sequentially admitted patients over an 8-wk period.. None.. Prospective daily data were collected concerning prevalence, predefined risk factors, and treatment of coagulopathy throughout intensive care unit admission. Of 1923 intensive care unit admissions, 30% developed abnormal international normalized ratio values (defined as an international normalized ratio > 1.5). Most international normalized ratio abnormalities were minor and short-lived (73% of worst international normalized ratio values 1.6-2.5). Male sex, chronic liver disease, sepsis, warfarin therapy, increments in Acute Physiology and Chronic Health Evaluation II score, severity of renal and hepatic dysfunction, and red cell transfusions were all independent risk factors for international normalized ratio abnormalities (all p < .001). In all regression models, there was a strong independent association between abnormal international normalized ratio values and greater intensive care unit mortality (p < .0001), particularly when international normalized ratio increased after intensive care unit admission. Among patients with abnormal international normalized ratios, 33% received fresh-frozen plasma transfusions during their intensive care unit stay, but the pretransfusion international normalized ratio value varied widely. Fifty-one percent of fresh-frozen plasma treatments were to nonbleeding patients and 40% to nonbleeding patients whose international normalized ratio was normal or only modestly deranged (≤ 2.5). The dose of fresh-frozen plasma administered was highly variable (median dose 10.8 mL/kg (first, third quartile 7.2, 14.4; range, 2.4-41.1 mL/kg).. Prothrombin time prolongation is prevalent in critically ill patients and is independently associated with greater intensive care unit mortality. Wide variation in fresh-frozen plasma treatment exists suggesting clinical uncertainty regarding best practice, particularly as a prophylactic treatment.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Child; Critical Care; Erythrocyte Transfusion; Female; Hospital Mortality; Humans; Intensive Care Units; Liver Diseases; Logistic Models; Male; Middle Aged; Plasma; Prevalence; Prospective Studies; Prothrombin Time; Risk Factors; Sepsis; Severity of Illness Index; Sex Factors; Time Factors; United Kingdom; Warfarin; Young Adult

The authors aimed to evaluate the utility of an in-office international normalized ratio (INR) testing device in identifying patients with INR test values considered out of the normal range for dental procedures.. This prospective cohort study involved use of an INR testing device to obtain INR test values in the dental office for patients thought to be at risk of experiencing bleeding complications after undergoing invasive dental procedures. The authors recorded demographic, social and medical history data, as well as clinical signs and symptoms of liver disease. The authors considered an INR out of range if it was greater than or equal to 1.4 for patients with potential liver disease and greater than 3.5 for patients receiving warfarin.. The authors completed an in-office INR test for 66 patients receiving warfarin whose INR had not been tested within the preceding 48 hours and 34 patients suspected of having liver disease. Eleven (17 percent) patients receiving warfarin and seven (21 percent) patients suspected of having liver disease had INR values considered out of range. Dental treatment was deferred for eight of 11 patients in the warfarin group who had INR values in the range of 3.6 to 7.4, while three others had dental procedures without bleeding complications. Six of seven patients who had documented or suspected liver disease and an out-of-range INR (range 1.5-2.5) underwent their dental procedures without experiencing bleeding complications.. Use of an in-office INR test indicated a high incidence of elevated INR values. The results of this study point to the importance of obtaining current INR values before performing invasive dental procedures for patients receiving warfarin therapy whose INR values have not been tested recently, and for patients thought to be at risk of developing or having liver disease.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Cohort Studies; Dental Care for Chronically Ill; Dental Prophylaxis; Dental Service, Hospital; Female; Humans; International Normalized Ratio; Liver Diseases; Male; Middle Aged; Oral Hemorrhage; Prospective Studies; Reference Values; Risk Factors; Tooth Extraction; Warfarin

Thromboelastography can be performed with native or citrated blood (a surrogate to native blood in healthy controls, surgical and cirrhotic patients). Activators such as kaolin are increasingly used to reduce the time to trace generation. To compare kaolin-activated thromboelastography with nonkaolin-activated thromboelastography of native and citrated blood in patients with liver disease, patients undergoing treatment with warfarin or low-molecular weight heparin and healthy volunteers. We studied thromboelastography parameters in 21 healthy volunteers (group 1) and 50 patients, including 20 patients with liver cirrhosis with a nonbiliary aetiology (group 2), 10 patients with primary biliary cirrhosis or primary sclerosing cholangitis (group 3), 10 patients on warfarin treatment (group 4) and 10 patients with enoxaparin prophylaxis (group 5). Thromboelastography was performed using four methods: native blood (kaolin-activated and nonkaolin-activated) and citrated blood (kaolin-activated and nonkaolin-activated). For all thromboelastography parameters, correlation was poor (Spearman correlation coefficient < 0.70) between nonkaolin-activated and kaolin-activated thromboelastography, for both citrated and native blood. In healthy volunteers, in patients with liver disease and in those receiving anticoagulant treatment, there was a poor correlation between nonkaolin-activated and kaolin-activated thromboelastography. Kaolin-activated thromboelastography needs further validation before routine clinical use in these settings, and the specific methodology must be considered in comparing published studies.

Topics: Adult; Aged; Anticoagulants; Artifacts; Blood Specimen Collection; Cholangitis, Sclerosing; Citrates; Enoxaparin; False Positive Reactions; Female; Hepatitis, Viral, Human; Humans; International Normalized Ratio; Kaolin; Liver Cirrhosis; Liver Cirrhosis, Biliary; Liver Diseases; Male; Middle Aged; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Sodium Citrate; Thrombelastography; Warfarin

Porto-caval hemitransposition (PCH) in liver transplantation allows revascularization of the liver when the porto-mesenteric axis is thrombosed. We, here, review our experience over an 11-year period. A total of 23 patients underwent liver transplantation using PCH. Immunosuppression was based on tacrolimus, with sirolimus used in case of renal insufficiency. Most common diagnoses were hepatitis C, Laennec's, Budd-Chiari and cryptogenic cirrhosis. Six patients needed splenectomy prior to transplant, 5 during transplant, 1 post-transplant, 11 had no splenectomy. Overall survival was 60% at 1 year and 38% at 3 years, with 10 of 23 patients currently alive and the longest survivor at 9.3 years. Most common cause of death was sepsis/multisystem organ failure, followed by pulmonary embolism. A total of 7/23 patients experienced post-operative gastrointestinal bleeding episodes, 6/23 patients developed thrombosis of the vena cava (median 162 days post-op). Post-operative ascites was noted in almost all patients. Renal dysfunction was commonly seen even after the first month post-transplant. PCH offers a feasible option for liver transplantation in those patients with complex thrombosis of the mesenteric and portal circulation.

Topics: Adult; Anticoagulants; Budd-Chiari Syndrome; Female; Follow-Up Studies; Humans; Immunosuppression Therapy; Kidney; Liver Diseases; Liver Transplantation; Longitudinal Studies; Male; Middle Aged; Portacaval Shunt, Surgical; Portal Vein; Survival Rate; Warfarin

Topics: Biopsy; Blood Platelets; Child; Female; Hematopoiesis, Extramedullary; Hematopoietic Stem Cell Transplantation; Hepatocytes; Humans; Liver Diseases; Magnetic Resonance Imaging; Portal Vein; Primary Myelofibrosis; Transplantation, Homologous; Venous Thrombosis; Warfarin

Low molecular weight heparins (LMWHs) are a rapidly growing class of anticoagulant drug. Their efficacy has been demonstrated in several clinical settings where they are rapidly becoming the anticoagulant of choice. Controlled clinical studies in patients with deep vein thrombosis, pulmonary embolism, and unstable angina have documented that the frequency of major hemorrhage is 0.5-4%. The purpose of the study was to determine the frequency of minor and major hemorrhage occurring in patients receiving anticoagulant doses of an LMWH (enoxaparin) during routine clinical practice. A prospective, observational study of consecutive patients receiving enoxaparin 1 mg/kg twice daily for at least 24 hours in five internal medicine wards of a university teaching hospital was performed. Five hundred forty-nine patients were studied. The mean age was 67.5+/-15.5 years and the mean duration of enoxaparin therapy was 3.8+/-1.5 days. Hemorrhage was documented in a total of 94 patients (17.3%). Major hemorrhage occurred in 14 patients (2.6%), injection-site hemorrhage occurred in 55 patients (10%), and minor hemorrhage (noninjection site) was documented in 25 patients (4.7%). There were two deaths attributed to hemorrhage. Patients with major hemorrhage were older than patients with minor or no hemorrhage (75.5+/-10.4 versus 66.8+/-15.2 years; p=0.03) and occurred in patients receiving enoxaparin for a longer period (5.14+/-3.8 days) than those with minor (4+/-2.5 days) or no hemorrhage (2.9+/-2.1 days). Major hemorrhage was significantly associated with impaired renal function, chronic liver disease, and concomitant treatment with warfarin or a proton pump inhibitor. Enoxaparin used in anticoagulant doses in unselected medical patients is not associated with more major hemorrhagic complications than observed in controlled clinical trials. Major hemorrhage may be more likely in older patients, in patients with chronic liver disease and impaired renal function, in patients receiving prolonged enoxaparin therapy, and in patients receiving warfarin or proton pump inhibitors.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Drug Evaluation; Enoxaparin; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Hospitals; Humans; Incidence; Liver Diseases; Male; Middle Aged; Prospective Studies; Proton Pump Inhibitors; Renal Insufficiency; Warfarin

The presence of antiphospholipid antibodies is associated with thromboembolic events, thrombocytopenia and numerous pregnancy complications such as recurrent miscarriage, preeclampsia and HELLP syndrome. This condition is known as the antiphospholipid syndrome (APS). We describe a rare case of recurrent liver necrosis postpartum in two consecutive pregnancies of woman with systemic lupus erythematosus (SLE) and positive antiphospholipid antibodies (aPL) who underwent complete recovery.

Topics: Adult; Antibodies, Antiphospholipid; Anticoagulants; Antiphospholipid Syndrome; Female; Heparin, Low-Molecular-Weight; Humans; Liver Diseases; Magnetic Resonance Imaging; Necrosis; Pregnancy; Pregnancy Complications; Recurrence; Warfarin

Although there are many reports describing spontaneous rupture of either the spleen or the liver, the simultaneous rupture of both organs is a rare event, especially during anticoagulant therapy. We report a case of spontaneous rupture of the spleen and liver in a patient on warfarin therapy for deep venous thrombosis.

Topics: Adult; Chemical and Drug Induced Liver Injury; Follow-Up Studies; Hepatectomy; Humans; Liver Diseases; Male; Risk Assessment; Rupture, Spontaneous; Splenectomy; Splenic Rupture; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography, Doppler; Venous Thrombosis; Warfarin

To correlate the concentration of plasma coagulation markers at baseline and during follow-up in patients with solid tumors and venous thromboembolic disease with the risk of recurrence and death.. Patients (N = 223) with first episode of venous thromboembolic disease received oral anticoagulation with warfarin for a target international normalized ratio of 2 to 3. Plasma coagulation markers were measured before instituting warfarin and at 3 monthly intervals, thereafter.. The median duration of oral anticoagulation was 6.7 months (range 2 weeks to 11 months). Major bleeding episodes occurred in 18 patients (8%), and minor hemorrhagic events occurred in 15 (6.7%) patients. Patients with advanced malignancy (P = 0.032), history of surgery (P = 0.057), and those with poor performance status (P = 0.001) were more likely to encounter major bleeding episodes. Recurrence of venous thromboembolic disease was diagnosed in 31 patients (14%). At univariate analysis, advanced stage of cancer (P = 0.03), performance status > 1 (P = 0.001), treatment with chemotherapy (P = 0.01), the presence of metastatic liver disease (P = 0.03), higher d-dimer (P = 0.001), and thrombin antithrombin complex levels (P = 0.01) were features predictive of recurrent venous thromboembolic disease. At multivariate analysis, poor performance status (P = 0.01) and d-dimer levels (P = 0.001) were predictors of recurrent venous thromboembolic disease. Persistent activation of coagulation as indicated by an upward trend in d-dimer (P = 0.001) and antithrombin (P = 0.001) was observed in patients who developed recurrent thrombosis. Similar upward trends in d-dimer (P = 0.001), antithrombin (P = 0.001), and prothrombin fragment F1 + 2 (P = 0.001) was observed in the 76 patients who died during the study period and in the patients who received chemotherapy.. Successful oral anticoagulation with warfarin in patients with cancer and venous thromboembolic disease is more likely to be achieved in patients with early stage tumors and good performance status. The persistence of activation of hemostasis as shown by plasma coagulation markers is a strong predictor of recurrence and poor outcome.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Female; Fibrin Fibrinogen Degradation Products; Humans; International Normalized Ratio; Liver Diseases; Logistic Models; Male; Middle Aged; Multivariate Analysis; Neoplasms; Recurrence; Thromboembolism; Time Factors; Treatment Outcome; Warfarin

Wide acceptance of the international normalised ratio (INR) and thromboplastins with low international sensitivity indices (ISIs) has inadvertently led to the application of the INR to patients other than those on anticoagulation treatment. I examined the degree of factor deficiency for a given INR in patients with liver disease and controls receiving stable-dose warfarin. The degree of factor V and VII, but not prothrombin, deficiencies for a given INR were greater in liver patients than controls. The INR measured with a low-ISI thromboplastin can quantify the coagulation status of patients with liver disease, but should not be interpreted as having the same meaning as the INR in patients receiving warfarin.

Topics: Adult; Case-Control Studies; Factor V; Factor VII; Humans; International Normalized Ratio; Liver Diseases; Prothrombin; Prothrombin Time; Thromboplastin; Warfarin

The dilute Russell viper venom time and kaolin clotting time (KCT) are very sensitive screening tests for lupus anticoagulant activity. However, due to the high turbidity of the kaolin reagent it is difficult to accommodate the KCT on the optical end point automation of today. We evaluated five recently reported screening tests (the silica clotting time, the Textarin/Ecarin ratio, the Taipan venom time, the factor V ratio, and a kaolin clotting time using low-turbidity kaolin) as potential alternatives to the KCT. The sensitivity and specificity of the silica clotting time compared well to KCT, detecting 10/12 KCT positive samples and showing equal sensitivity to dilution of lupus positive plasma. In addition, the silica clotting time allows for a confirmatory phospholipid correction procedure. False-positive results were seen in 2 of 15 warfarinised samples. A second assay utilising the ratio of extrinsic/intrinsic factor V assays was not affected by either warfarin or heparin. This assay also gave positive results with 3 of 23 samples previously screened as lupus negative but exhibiting anticardiolipin positivity. It was therefore concluded that a combination of the silica clotting time and dilute Russell viper venom time met the requirements of lupus sensitivity with demonstration of phospholipid dependence and optical end point compatibility. The factor V ratio is a useful second-line screen for both anticoagulated patients and anticardiolipin antibody-positive samples.

Topics: Anticoagulants; Antiphospholipid Syndrome; Autoimmune Diseases; Automation; Blood Coagulation Tests; Elapid Venoms; Endopeptidases; Evaluation Studies as Topic; Factor V; False Positive Reactions; Heparin; Humans; Kaolin; Liver Diseases; Lupus Coagulation Inhibitor; Lupus Erythematosus, Systemic; Nephelometry and Turbidimetry; Partial Thromboplastin Time; Peptide Hydrolases; Postoperative Period; Prothrombin; Prothrombin Time; Silicon Dioxide; Warfarin

A Kinetic Fibrinogen Assay (KFA), a method based on the kinetic reaction of the developing fibrin clot, was used to determine fibrinogen concentration in plasma. Two other methods employing different quantification principles were used for comparison: the von Clauss method and the procedure measuring protein concentration in an isolated and washed plasma clot (World Health Organization [WHO] method). All three methods quantified functional thrombin-coagulable fibrinogen. Plasma specimens were obtained from three groups of patients: those with liver disease and those taking either coumarin derivative or heparin. In all of these conditions, there are deviations from the normal process of fibrin clot formation. The KFA method yielded results that were consistent and provided excellent precision and accuracy allowing quantification of plasma fibrinogen in the range of 70-800 mg/dL (2-23.5 microM). The determination of fibrinogen by the KFA method was not adversely affected using plasma from patients treated with heparin and those undergoing coumarin therapy. Statistical analysis of the results indicated that the KFA method compared very favorably with the von Clauss and WHO methods. In assessing the clinical utility of each method, the WHO method was found to be labor intensive and time consuming; therefore, not suitable for routine use in a clinical laboratory. The von Clauss method required a trained laboratory technician and some laboratory manipulations. The KFA method was not only reliable and accurate, but also fully automated, making it the easiest and the fastest to perform routinely.

Topics: Anticoagulants; Blood Coagulation Disorders; Evaluation Studies as Topic; Fibrinogen; Hematology; Heparin; Humans; Kinetics; Liver Diseases; Osmolar Concentration; Warfarin

We report a patient on warfarin prophylaxis who had major intraperitoneal hemorrhage 17 days following percutaneous liver biopsy (PLBx). Selective hepatic angiography revealed a pseudoaneurysm of a branch of the right hepatic artery, associated with an arterio-portal venous fistula. Ultrasound with Doppler studies showed flow through the pseudoaneurysm. Embolization with platinum micro-coils resulted in cessation of flow through the pseudoaneurysm, and closure of the arterio-portal venous fistula. Anticoagulation was then resumed without recurrent bleeding. Pseudoaneurysms and arteriovenous fistulas may be mechanisms by which delayed bleeding occurs after PLBx. Doppler ultrasonography and hepatic angiography are useful in the evaluation and management of this event.

Topics: Aged; Aneurysm, False; Arteriovenous Fistula; Biopsy, Needle; Embolization, Therapeutic; Hematoma; Hepatic Artery; Humans; Liver Diseases; Male; Portal Vein; Time Factors; Warfarin

The recent introduction of thromboplastin reagents with low international sensitivity index (ISI) values into the US market for the purpose of generating a more precise international normalized ratio than high ISI thromboplastins could has necessitated an evaluation of the impact of the low ISI reagents on prothrombin time (PT) testing in general. In this study, PT testing with three thromboplastin reagents, one of which (presently used in our laboratory) has an ISI of 2.10 and the other two ISI values of 0.92 and 1.06, respectively, was performed on normal individuals, on quality control reference plasma specimens and single-factor-deficient plasma specimens, and on patients with liver disease, intravascular coagulation, and receiving oral anticoagulant therapy. We found that PTs of normal individuals determined by all three thromboplastins were virtually identical. The thromboplastins with a low ISI generated much longer PTs on abnormal reference plasma specimens than did the high ISI product. Low ISI reagents also produced longer PTs in all three groups of patients. However, the degree of prolongation was far greater for patients receiving warfarin than for the other two groups of patients. Conversion of the PT to an international normalized ratio minimized the discrepancy seen in the PT ratio in patients receiving oral anticoagulants. The two low ISI thromboplastins did not produce near-identical values of PT, PT ratio, or international normalized ratio on plasma specimens obtained from patients who received warfarin therapy. The critical value set for PT with a high ISI thromboplastin would not be adequate if the reagent is to be replaced with a low ISI product.

Topics: Administration, Oral; Disseminated Intravascular Coagulation; Humans; Liver Diseases; Prothrombin Time; Quality Control; Reference Standards; Regression Analysis; Sensitivity and Specificity; Thromboplastin; Warfarin

Coagulation factors that interfere with the one-stage prothrombin time (PT) were investigated. PT responded with identical activities (adequately) against coagulation factors VII or X, only half as expected against factor IX, less than expected and nonlinearly against factor II. In multiple coagulation factor deficiencies PT did not differ from factor VII, which was the most reduced coagulation factor in warfarin therapy or liver disease. PT may also be influenced by factor VII at high activities.

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Chronic Disease; Humans; Liver Diseases; Prothrombin Time; Warfarin

Serum level of vitamin K1 (= phylloquinone, hereinafter K1) and K dependent blood coagulation factors were determined by HPLC in normal subject, liver cirrhosis, hepatocellular carcinoma, acute hepatitis, chronic hepatitis, chronic renal failure with hemodialysis and patients under warfarin therapy. Normal range of serum K1 concentration was decided on 0.20-2.30 (0.87 +/- 0.53, n = 96) ng/ml. Serum K1 level showed no significant differences among normal subject, various diseases and warfarin therapy. Correlation between serum K1 level and F-VII (r = 0.879, p less than 0.001) or protein C activity (r = 0.839, p less than 0.01) was found in patients whose thrombotest was 20% and less. However serum K1 level didn't correlate with any K dependent coagulation factors in patients if thrombotest was over 20%.

Topics: Adolescent; Adult; Blood Coagulation Factors; Female; Heart Diseases; Humans; Kidney Failure, Chronic; Liver Diseases; Male; Protein C; Vitamin K 1; Warfarin

Percutaneous fine-needle aspiration biopsy has gained wide acceptance due to its accuracy, ease of performance, and safety. This study was performed to evaluate the effect of needle size, coagulation impairment, or biopsy of different organs on risk of bleeding during the procedure. Multiple biopsy procedures were performed on the livers and kidneys of anesthetized pigs with 14-22-gauge Chiba-type needles. The procedures were performed under direct vision at laparotomy, and blood loss was measured. While larger needles generally produced more bleeding, the differences were statistically significant only when comparing 14- with 16-gauge needles and 16-gauge needles with the group of 18-, 20-, and 22-gauge needles in the liver. In the kidney, no significant difference was noted between 18-, 20-, and 22-gauge needles. Anticoagulation did not produce significantly greater blood loss but did allow separation of the group of 18- and 20-gauge needles from 22-gauge needles in the kidney. Renal biopsy resulted in greater overall blood loss than did liver biopsy.

Topics: Animals; Biopsy, Needle; Hemorrhage; Kidney Diseases; Liver Diseases; Needles; Reference Values; Swine; Warfarin

Topics: Animals; Antibodies, Monoclonal; Carrier Proteins; Complement Inactivator Proteins; Enzyme-Linked Immunosorbent Assay; Glycoproteins; Liver Diseases; Mice; Mice, Inbred BALB C; Protein S; Warfarin

Guidelines for the management of patients receiving chronic anticoagulation therapy who require liver biopsy are not clearly defined. In patients with normal coagulation, liver biopsy is a relatively safe procedure with a morbidity of less than 0.1% and a mortality of less than 0.01%. We report a patient with a prosthetic aortic valve who developed a large subcapsular hematoma 12 days after a percutaneous liver biopsy as a consequence of warfarin toxicity. Based on the experience with this patient, reinstitution of anticoagulant therapy should be avoided for at least 72 h after a percutaneous liver biopsy. Intravenous heparin should be resumed first, and warfarin added if no bleeding has occurred after an additional 48-72 h. The prothrombin time should be maintained at 1.5 times the baseline.

Topics: Biopsy, Needle; Carcinoma, Hepatocellular; Chemical and Drug Induced Liver Injury; Hematoma; Humans; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Prothrombin Time; Time Factors; Warfarin

Plasma levels of protein S (PS) antigen, both total and free fractions, were measured together with C4b-binding protein (C4bp) and protein C (PC) antigen in 39 patients with disseminated intravascular coagulation (DIC), 34 with liver disease, 17 with collagen disease, 17 with diabetes mellitus, and 51 under stabilized warfarin treatment. In patients with DIC, mean concentrations of total PS and free PS were normal, while PC was reduced and C4bp were elevated. Total PS, free PS, C4bp and PC were all decreased in liver disease, elevated in diabetes mellitus, and normal in collagen disease. In warfarin-treated patients, total PS, free PS and PC were moderately decreased, but the decrease in C4bp was minimal. The concentration of PS correlated positively with PC in liver disease, diabetes mellitus, and during oral anticoagulation, but did not in DIC. These results indicate that PS and PC behave similarly when liver synthetic function is principally affected, but in contrast to PC, PS is hardly consumed during intravascular coagulation.

Topics: Administration, Oral; Adult; Aged; Anticoagulants; Antithrombin III; Carrier Proteins; Collagen Diseases; Complement Inactivator Proteins; Diabetes Mellitus; Disseminated Intravascular Coagulation; Factor VIII; Glycoproteins; Humans; Liver Diseases; Middle Aged; Protein C; Protein S; Serum Albumin; von Willebrand Factor; Warfarin

We measured des-gamma-carboxyglutamic acid prothrombin (protein induced by vitamin K absence or antagonist-Factor II: [PIVKA-II]) in plasmas of normal subjects, patients with thrombotic disease, those with hepatic disease including hepatocellular carcinoma, and those with carcinoma of other tissues, and compared the results with results of blood coagulation tests used for the examination of hepatic function. In addition, in the patients with hepatic disease, PIVKA-II and alpha-fetoprotein (AFP) levels were compared. The PIVKA-II level was frequently high in patients with thrombotic disease given warfarin therapy and those with hepatocellular carcinoma. However, in patients with thrombotic disease who were not given warfarin therapy, no significant correlation was seen between the PIVKA-II value and the results of the thrombotest or hepaplastin test, suggesting no association between the PIVKA-II level and the degree of impairment of hepatic function. In 70 patients with hepatocellular carcinoma, the percentage of patients positive for PIVKA-II (greater than or equal to 0.1 micrograms/ml) and those positive for AFP (greater than or equal to 20 ng/ml) were similar (77% and 74%, respectively). Pearson's correlation of coefficient between the PIVKA-II value and the AFP value in the 70 patients was 0.463. However, false-positive rates in patients with hepatic disease other than hepatocellular carcinoma were lower for PIVKA-II. Combined assessment of PIVKA-II and AFP increased positive rates and allowed exclusion of false-positive patients. The plasma PIVKA-II level is suggested to be useful as an indicator of warfarin control in patients with thrombotic disease, as a marker of hepatocellular carcinoma, and is particularly of value when assessed in combination with AFP.

Topics: Biomarkers; Biomarkers, Tumor; Blood Coagulation Factors; Carcinoma, Hepatocellular; Humans; Liver Diseases; Liver Neoplasms; Protein Precursors; Prothrombin; Warfarin

A homogeneous EIA (H-EIA) technique for plasma protein C antigen using horseradish peroxidase (HRP) was developed. This technique, which avoids the bound/free separation and washing procedures and shortens the assay time to 30 min, has several advantages over the conventional EIA technique. The measurement was valid for 1.0% to 200% of the plasma protein C level and had intraassay coefficients of variation of 2.3-11.0%. The results of this assay correlated well with those of conventional sandwich EIA (x) with a regression equation of y = 0.782x + 6.637, r = 0.911 (n = 59). This method, which may also be applicable to automatic assay systems, is considered to be suited for clinical laboratory use.

Topics: Antigens; Humans; Immunoenzyme Techniques; Liver Diseases; Protein C; Reference Values; Reproducibility of Results; Thrombophlebitis; Warfarin

We describe the simple and rapid enzyme immunoassay of protein C in human plasma with use of a Cobas Fara centrifugal analyzer. The antibody, labeled with horseradish peroxidase, is reacted with antigen (protein C) for 15 min. The peroxidase activity of the resulting antigen-antibody conjugate is measured at 500 nm for 5 min in the presence of excess H2O2, phenol, and 4-aminoantipyrine, as compared with that of free conjugates. Results are calculated from a stored standard curve and expressed as a percentage of the value determined for a pooled specimen of normal adult plasma. The standard curve is linear from 0% to 200%. The CV is generally less than 4% for different concentrations of protein C. In liver cirrhosis, hepatocellular carcinoma, therapy with warfarin, thrombosis, and disseminated intravascular coagulation, protein C concentrations are about 40-70% of normal. Results obtained with the present homogeneous enzyme immunoassay correlated well with those by enzyme-labeled immunosorbent assay (r = 0.97).

Topics: Adult; Blood Proteins; Disseminated Intravascular Coagulation; Enzyme-Linked Immunosorbent Assay; Horseradish Peroxidase; Humans; Hydrogen Peroxide; Immunoenzyme Techniques; Liver Diseases; Protein C; Reference Values; Thrombosis; Warfarin

Protein S is a vitamin K-dependent plasma protein which serves as the cofactor for activated protein C. Protein S circulates in both an active, free form and in an inactive complex with C4b-binding protein. To elucidate the role of protein S in disease states and during oral anticoagulation, we developed a functional assay for protein S that permits evaluation of the distribution of protein S between free and bound forms and permits determination of the specific activity of the free protein S. In liver disease, free protein S antigen is moderately reduced and the free protein S has significantly reduced specific activity. In disseminated intravascular coagulation, reduced protein S activity occurs due to a redistribution of protein S to the inactive bound form. During warfarin anticoagulation, reduction of free protein S antigen and the appearance of forms with abnormal electrophoretic mobility significantly decrease protein S activity. After the initiation of warfarin, the apparent half-life of protein S is 42.5 h. In patients with thromboembolic disease, transient protein S deficiency occurs due to redistribution to the complexed form. Caution should be exercised in diagnosing protein S deficiency in such patients by use of functional assays.

Topics: Adult; Aged; Blood Coagulation; Disseminated Intravascular Coagulation; Half-Life; Humans; Immunosorbent Techniques; Liver Diseases; Middle Aged; Protein C; Warfarin

Three mouse monoclonal antibodies (RFF-VII/1, RFF-VII/2, and RFF-VII/3) which bind specifically to different epitopes on human factor VII antigen were raised. Two of the antibodies, RFF-VII/1 and RFF-VII/2, bound strongly to factor VII antigen (VII:Ag), but only RFF-VII/1 and RFF-VII/3 were potent inhibitors of factor VII coagulation activity (VII:C). RFF-VII/1 and RFF-VII/2 were used in a one step, double monoclonal immunoradiometric assay for VII:Ag. This was highly reproducible and detected as little as 0.05U/dl VII:Ag. Values for VII:Ag obtained for plasma samples from normal subjects (n = 20), patients with liver disease (n = 20), patients treated with warfarin (n = 20), and those congenitally deficient in factor VII (n = 7) correlated very well (r = 0.96) with data obtained in a radioimmunoassay using polyclonal rabbit antiserum to factor VII. This simple and sensitive monoclonal antibody based assay offers a convenient method for the detection of VII:Ag in various disease states.

Topics: Animals; Antibodies, Monoclonal; Antigens; Factor VII; Factor VII Deficiency; Humans; Liver Diseases; Mice; Mice, Inbred BALB C; Radioimmunoassay; Warfarin

A high affinity monoclonal antibody to factor VII (RFF-VII/1), coupled to sepharose, was used to immunodeplete factor VII from normal plasma. The plasma could be used as a substrate in a one stage coagulation assay and performed as well as, or better than, commercially available factor VII deficient plasma or plasma from congenitally deficient factor VII patients. Plasma from normal donors (n = 20), patients with liver disease (n = 20), and patients receiving warfarin (n = 20), or congenitally factor VII deficient patients (n = 7) was assayed for VII:C concentration in a one stage coagulation assay. The concentration of VII:C detected with the immunodepleted plasma substrate was comparable in all cases with that seen with a commercially available substrate (r = 0.95).

Topics: Antibodies, Monoclonal; Blood Coagulation Factors; Chromatography; Electrophoresis, Polyacrylamide Gel; Factor VII; Factor VII Deficiency; Humans; Liver Diseases; Methods; Warfarin

In vitro coagulation produces a consumption of heparin co factor II (HC II) of 8-10% both in plasma from normal individuals and patients whereas antithrombin (AT) consumption ranges 40-50%. In blood from heparin treated patients consumption is similar or greater. In blood from warfarin treated patients, consumption is decreased. Addition of heparin prior to clotting has little effect on HC II consumption, but high heparin concentration reduces AT consumption. Addition of dermatan sulfate has no effect on AT consumption, but increases HC II consumption dramatically. In consumption coagulopathy, the HC II levels are as low as AT, possibly reflecting intravascular consumption accelerated by vascular glycosaminoglycans.

Topics: Antithrombins; Blood Coagulation; Dermatan Sulfate; Disseminated Intravascular Coagulation; Glycoproteins; Heparin; Heparin Cofactor II; Humans; In Vitro Techniques; Liver Diseases; Warfarin

The authors describe the technic and standardization of an assay to measure plasma protein C activity feasible for clinical laboratory use. It is modified from an assay of Francis and Patch (Thromb Res 1983; 32:605-613) to enhance protein C recovery in the barium citrate eluate, to eliminate the steps of addition and neutralization of heparin, and to use only commercially available reagents. The normal range for plasma protein C in the assay is 72-130% (+/- 2 SD) (0.7-1.30). Hepatocellular disease lengthening the prothrombin time by 3-4 seconds was associated with plasma protein C activity of 25% (0.25) to 35% (0.35). Although the assay is thought to accurately measure protein C activity in patients taking warfarin, one cannot evaluate such patients for hereditary functional protein C deficiency because treatment with warfarin will itself reduce the ratio of protein C activity to antigen. The assay can be used in a patient receiving heparin if the heparin is removed as described.

Topics: Antithrombin III; Citrates; Citric Acid; Humans; Liver Diseases; Partial Thromboplastin Time; Protein C; Protein C Deficiency; Reference Values; Thrombin; Thrombosis; Warfarin

Protein C is a natural vitamin K-dependent plasma anticoagulant, deficiencies of which have been found in patients with recurrent thrombosis and warfarin-induced skin necrosis. To appreciate more fully the role of protein C in disease states and during oral anticoagulation, a new functional assay for protein C involving adsorption of plasma protein C on a Ca+2-dependent monoclonal antibody, elution, quantitative activation, and assessment of plasma anticoagulant activity, has been developed. When oral anticoagulation is initiated, the anticoagulant activity of protein C decreases to a greater extent than either the amidolytic or immunologic levels. During stabilized warfarin treatment, there is no correlation between either amidolytic or antigenic levels and the functional protein C activity, suggesting that measurement of protein C anticoagulant activity may be necessary to reflect adequately the anticoagulant protection afforded by this protein. In contrast, there was a strong correlation between anticoagulant and amidolytic and immunologic levels in liver failure and disseminated intravascular coagulation. Two patients with thromboembolic disease have been identified who exhibit a marked decrease in anticoagulant activity, but who have normal immunologic and amidolytic levels. Thus, this assay permits assessment of protein C in individuals who have received anticoagulant treatment and identification of a new class of protein C-deficient individuals.

Topics: Adult; Aged; Antigens; Blood Coagulation; Chromogenic Compounds; Chronic Disease; Dipeptides; Disseminated Intravascular Coagulation; Factor VII; Factor X; Glycoproteins; Humans; Immunosorbent Techniques; Liver Diseases; Middle Aged; Protein C; Thrombophlebitis; Warfarin

Heparin cofactor II (HC II) is a recently characterized protein that is capable of neutralizing thrombin but not activated factor X. Recent evidence suggests that it may be a physiologically important regulator of thrombin activity. We evaluated and modified a method for clinical laboratory determination of this protein and then utilized the method to analyze HC II activity in various clinical samples. Low levels were associated with liver disease, consumptive coagulopathy, and preeclampsia; normal levels were seen with uncomplicated pregnancy, oral anticoagulant therapy, hereditary antithrombin III (AT III) deficiency, and in 31 patients evaluated for a thrombotic tendency. Except in hereditary AT III deficiency, decreased HC II activity was associated with decreased AT III activity. The potential clinical role of this assay is discussed.

Topics: Antithrombin III; Antithrombin III Deficiency; Antithrombins; Dermatan Sulfate; Disseminated Intravascular Coagulation; Female; Glycoproteins; Heparin Cofactor II; Humans; Liver Diseases; Methods; Pre-Eclampsia; Pregnancy; Thrombosis; Warfarin

An enzyme-linked immunosorbent assay (ELISA) for measuring human protein C by using two monoclonal antibodies directed toward the heavy chain of protein C is reported. This assay enabled the determination of protein C in concentrations of 10 to 400 ng/ml in less than 3 hours with a single antigen-antibody reaction. Within-run and between-run coefficients of variation were less than 8%. The mean concentrations of protein C in plasma of 42 normal subjects, 24 patients with liver disease, 27 with DIC, 48 with warfarin therapy and 15 with congenital protein C deficiency, were 4.2, 3.0, 2.3, 2.1 and 1.9 micrograms/ml, respectively. The results obtained with the present ELISA correlated well with those of radioimmunoassay (r = 0.935, n = 81) as well as those of Laurell's Rocket method (r = 0.910, n = 81) by using rabbit anti-human protein C serum. The present method was sensitive and specific for measurement of protein C and also PIVKA-protein C in plasma.

Topics: Antibodies, Monoclonal; Biomarkers; Disseminated Intravascular Coagulation; Enzyme-Linked Immunosorbent Assay; Female; Glycoproteins; Humans; Immunoenzyme Techniques; Immunologic Techniques; Liver Diseases; Male; Protein C; Protein Precursors; Prothrombin; Warfarin

Specific radioimmunoassays, sensitive to plasma levels of less than 1% of normal, were developed for protein C and Factor X. In 31 normal subjects, mean plasma antigen levels were as follows: protein C, 3.23 +/- 0.79 microgram/mL (2 SD); Factor X, 7.74 +/- 1.81 microgram/mL. In patient son chronic warfarin therapy, protein C and factor X were depressed equivalently: protein C, 42% +/- 20% (of a pooled plasma reference); Factor X, 44% +/- 24%. Protein C antigen fell much more rapidly than Factor X antigen when warfarin therapy was begun, creating an initial period of potential hypercoagulability. In patients with severe liver disease, mean protein C antigen (25% +/- 17%) was lower than Factor X antigen (51% +/- 29%). Protein C antigen levels did not appear to be a sensitive indicator of compensated intravascular coagulation or systemic fibrinolysis induced by infusion of streptokinase. Clinical implications of these findings are discussed.

Topics: Blood Coagulation Factors; Cross Reactions; Disseminated Intravascular Coagulation; Factor X; Female; Glycoproteins; Hematologic Diseases; Hemostasis; Humans; Kinetics; Liver Diseases; Lupus Erythematosus, Systemic; Pregnancy; Protein C; Radioimmunoassay; Streptokinase; Warfarin

The purpose of this experiment was to compare the toxic effects of aflatoxin B1 (AFB1) and warfarin in pigs and to determine whether these have an additive effect in these pigs fed dietary Cd. Cadmium was provided daily through the diets of 2 concentrations (0 or control, and 83 micrograms/g of diet) during the 40 days of the experiment. At the start of the 5th week, AFB1 and warfarin were given in 5 daily doses (each dose 0.2 mg/kg of body weight) and the effects were determined for 10 days (starting with the 1st treatment day). Aflatoxin B1 given to the pigs fed the control diet (0 Cd) was toxic, inducing significantly increased alkaline phosphatase, sorbitol dehydrogenase, and aspartate aminotransferase activities and the prothrombin time (PT) and activated partial thromboplastin time (APTT) and significantly decreased values in serum total protein, alpha-globulin, beta-globulin, gamma-globulin, and fibrinogen. There was no effect on blood urea nitrogen. The treatment with warfarin was more effective in producing earlier and significantly longer PT and APTT. In the pigs fed the diet with the added Cd, differences in activity of alkaline phosphatase, sorbitol dehydrogenase, aspartate aminotransferase values, but not blood urea nitrogen, as well as differences in intensity and duration of response in PT and APTT occurred when pigs were dosed daily for 5 days after AFB1 or warfarin. It is concluded that dietary Cd (83 micrograms/g of diet) in young pigs has an inhibitory effect on AFB1 toxicity and an enhancing synergistic effect with warfarin.

Topics: Aflatoxin B1; Aflatoxins; Animal Feed; Animals; Blood Proteins; Blood Urea Nitrogen; Cadmium; Cadmium Poisoning; Carcinogens; Chemical and Drug Induced Liver Injury; Liver Diseases; Male; Swine; Swine Diseases; Warfarin

gamma-Carboxyglutamic acid residues on prothrombin are synthesized from glutamic acid on a prothrombin precursor in the liver through a vitamin K-dependent carboxylase. In the absence of vitamin K or in the presence of vitamin K antagonists, an inert form of prothrombin - abnormal prothrombin - circulates in the blood. We have developed specific immunoassays for native and abnormal human prothrombin. The prothrombin concentration in our normal subjects was 108 +/- 19 microgram per milliliter. The abnormal-prothrombin concentration varied over four orders of magnitude between the limits of detection in normal plasma and the level in patients with cirrhosis (0 to 5 microgram per milliliter), acute hepatitis (0 to 33 microgram per milliliter), or vitamin K deficiency (32 to 100 microgram per milliliter) and in those treated with sodium warfarin (12 to 65 microgram per milliliter). These studies indicate that abnormal prothrombin is not a component of normal plasma but appears in a variety of hepatic and nutritional disorders characterized by impaired hepatic vitamin-K-dependent carboxylation.

Topics: Adult; Aged; Carbon-Carbon Ligases; Epitopes; Female; Hepatitis; Humans; Ligases; Liver; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Prothrombin; Prothrombin Time; Vitamin K Deficiency; Warfarin

Four coagulation factors (II, VII, IX, X) are synthesized in the liver as precursor forms. Vitamin K is necessary for their conversion to functional factors. Factor II precursor is antigenically similar to factor II and can be activated to form thrombin by Echis carinatus venom. Forty-one patients with liver disease and 30 patients with vitamin K deficiency (Warfarin treated), were compared with 51 normal patients. Rats with CCl4-induced hepatic necrosis and animals given Warfarin were also studied. The following measurements were made: standard prothrombin time; Echis clotting time; factor II coagulant assay with thromboplastin; factor II assay with Echis venom; and factor II antigen (human) by electroimmunoassay. In animals and humans with liver disease, factor II was reduced, as measured by all techniques. With vitamin K deficiency functional factor II was reduced, but factor II antigen and Echis factor II activity were normal. THe data suggest that the prothrombin time and Echis coagulation methods can be used to differentiate whether the coagulopathy in liver disease is due to reduced precursor levels of factor II, vitamin K deficiency (ie, impaired formation of functional from precursor factor II), or both.

Topics: Animals; Antigens; Blood Coagulation Tests; Humans; Immunodiffusion; Liver Diseases; Prothrombin; Rats; Vitamin K Deficiency; Warfarin

A monospecific rabbit antibody to human plasma P component was used in a quantitative immunoelectrophoretic system. The assay readily detected levels as low as 0.3 microgram/ml, the equivalent of 0.008 U/ml of a normal plasma pool. he average coefficient of variation of duplicate determinations from five sets of nine dilution points of normal plasma was 6.6%. Among normal individuals, groups of 50 adults, 24 children, and 43 term and preterm newborns were each significantly different (p less than 0.001) and the level was positively correlated with age. Three fetal samples of approximately 20 weeks' gestation were near the lower limit of detection of the assay. P component levels in selected groups of patients demonstrated a 1.5 fold elevation of the mean level in 15 patients with high erythrocyte sedimentation rates, no difference in the mean level of 23 patients on warfarin or 16 patients with plasma cell dyscrasia or chronic lymphocytic leukemia, and a depression of the mean level to one fourth of normal in 14 patients with alcoholic liver disease. Among the latter, the prolongation of the prothrombin time was correlated with the depression of P component (p less than 0.05). Conditioned media, even after 10-fold concentration, and lysed cell fractions of cultured adult fibroblasts, B and T lymphocytes, and endothelial and smooth muscle cells failed to demonstrate P component. Circulating levels of P component increase during growth and development to adult life and the hepatocyte is the most likely site of synthesis. Although homologous in structure, C-reactive protein levels are distinguished by their marked response to inflammation and their elevation in most of the patients with hepatocellular damage.

Topics: Adolescent; Adult; Aging; Amyloid; Child; Child, Preschool; Female; Humans; Immunoelectrophoresis; Infant; Infant, Newborn; Liver Diseases; Male; Middle Aged; Warfarin

Therapeutic doses of oral anticoagulants have been associated with spontaneous hemorrhage and rupture of apparently normal abdominal viscera. To our knowledge, this is the second reported case of such rupture involving the liver. The patient had sudden severe epigastric pain and signs of acute abdomen and shock. Discrete microscopic changes in the liver may precede massive hemorrhage.

Topics: Aged; Autopsy; Female; Hematoma; Hemorrhage; Humans; Liver Diseases; Rupture, Spontaneous; Warfarin

A coupled amidolytic assay for factor VII (VII) has been developed that when used with a clotting assay for VII enables detection of activated VII. In the assay, VII in a test material determines generation of factor Xa in a mixture of purified factor X, tissue factor, and calcium; factor Xa is measured with a chromogenic substrate. Factor VII activity in the coupled amidolytic assay (VIIam) correlated well with VII activity in a one-stage clotting assay (VIIc) in 57 healthy subjects, 5 patients with hereditary VII deficiency, and 11 patients with liver disease. Activation of plasma VII by kaolin, clotting, or cold strikingly increased VIIc but not VIIam levels. Thus the ratio VIIc/VIIam (VII activity ratio) is a measure of VII activation. In 27 warfarin-treated patients the mean VII activity ratio was significantly decreased, reflecting a greater decline in VIIc than in VIIam. This probably stems from partially carboxylated VII being able to act during the 3-min incubation of the amidolytic assay but unable to act rapidly enough to affect the clotting assay. Measurement of VIIc/VIIam should enable evaluation of the activity state of VII in thrombotic disorders and in components for transfusion therapy.

Topics: Blood Preservation; Cold Temperature; Factor VII; Factor X; Humans; Kaolin; Liver Diseases; Methods; Warfarin

Activated partial thromboplastin times (APTT's) performed with a semi-automated electrical-conductivity type of clot timer on plasmas from patients with hepatic disease and intravascular coagulation, and on warfarin or heparin therapy, were significantly lower than when done on the same plasmas with either a manual optical method or an automated optical-endpoint instrument. Results of APTT's done on normal plasmas by the three methods were not significantly different. Substitution of different activator-phospholipid reagents resulted in some variability in results, but these differences were less than those between the different done with both the electrical clot timer and the automated optical instrument on prepared plasmas containing 5.0 or 1.0% of factor II, V, VIII, IX, OR X revealed shorter times with the electrical clot timer only in the case of factor II- and factor V-deficient plasmas. APTT's done on normal plasmas to which 0.1 or 0.3 units per ml. of heparin had been added vitro also were shorter with the electrical clot itmer than the automatic optical instrument. Prothrombin times done on normal and abnormal control plasmas and on a series of plasmas from patients on warfarin therapy showed no significant difference between the two methods.

Topics: Autoanalysis; Blood Chemical Analysis; Blood Coagulation Tests; Erythrocyte Aggregation; Factor V Deficiency; Factor X Deficiency; Hemophilia A; Hemophilia B; Heparin; Hydrogen-Ion Concentration; Hypoprothrombinemias; Liver Diseases; Optics and Photonics; Phospholipids; Prothrombin Time; Thromboplastin; Time Factors; Warfarin

Topics: Aged; Angina Pectoris; Chemical and Drug Induced Liver Injury; Erythrityl Tetranitrate; Female; Humans; Liver Diseases; Nitroglycerin; Prothrombin Time; Rupture; Warfarin

Topics: Agranulocytosis; Anus Diseases; Anus Neoplasms; Blood Coagulation Disorders; Blood Platelet Disorders; Blood Platelets; Blood Transfusion; Colitis, Ulcerative; Colonic Diseases; Colonic Neoplasms; Factor V Deficiency; Factor VII Deficiency; Gastrointestinal Hemorrhage; Hemophilia A; Humans; Hypoprothrombinemias; Liver Diseases; Lymphoma; Rectal Diseases; Warfarin

Topics: Aged; Alcoholism; Allopurinol; Arrhythmias, Cardiac; Chloral Hydrate; Colchicine; Digoxin; Drug Synergism; Gastrointestinal Hemorrhage; Gout; Hospitals, Teaching; Humans; Liver Diseases; Male; Middle Aged; Nitroglycerin; Patient Care Team; Pharmacists; Pharmacy Service, Hospital; Quinidine; Warfarin; Washington

Topics: Adult; Aged; Alkaline Phosphatase; Aspartate Aminotransferases; Bilirubin; Blood Coagulation Factors; Child; Factor IX; Factor VII; Factor X; Female; Hemophilia B; Hepatitis A; Hepatitis B Antigens; Humans; Liver Diseases; Liver Function Tests; Male; Middle Aged; Poisoning; Prothrombin; Warfarin

Topics: Absorption; Age Factors; Antipyrine; Chloral Hydrate; Environmental Exposure; Ethanol; Female; Humans; Kinetics; Liver Diseases; Male; Pharmaceutical Preparations; Pharmacogenetics; Phenylbutazone; Pregnancy; Sex Factors; Smoking; Time Factors; Warfarin

Topics: Antibodies; Antigen-Antibody Reactions; Antigens; Blood Coagulation Tests; Blood Proteins; Factor VII; Factor VII Deficiency; Humans; Immune Sera; Liver Diseases; Neutralization Tests; Vitamin K Deficiency; Warfarin

Topics: Anticoagulants; Arrhythmias, Cardiac; Blood Cell Count; Cerebrovascular Disorders; Coronary Disease; Diabetes Mellitus; Dicumarol; Heart Failure; Heparin; Humans; Hypertension; Kidney Diseases; Liver Diseases; Myocardial Infarction; Peptic Ulcer; Pulmonary Embolism; Shock; Thromboembolism; Thrombophlebitis; Thrombosis; Varicose Veins; Warfarin