warfarin and Critical-Illness

Prothrombin complex concentrate (PCC) is an inactivated concentrate of factors II, IX, and X, with variable amounts of factor VII. Guidelines recommend the use of PCC in the setting of life-threatening bleeds, but little is known on the most effective dosing strategies and how the presenting international normalized ratio affects response to therapy.. This review aims to highlight available data on monitoring techniques, address shortcomings of currently available data, the reversal of life-threatening and critical bleeds with PCC, and how this product compares to other therapeutic options used in critically ill patients.. PCC has been identified as a potential therapy for critically bleeding patients, but patient-specific factors, product availability, and current data should weigh the decision to use it. Most data exist regarding patients experiencing vitamin K antagonist-induced bleeding, more specifically, those with intracranial hemorrhage. PCC has also been studied in trauma-induced hemorrhage; however, it remains controversial, as its potential benefits have the abilities to become flaws in this setting.. Health care professionals must remain aware of the differences in products and interpret how three- versus four-factor products may affect patients, and interpret literature accordingly. The clinician must be cognizant of how to progress when treating a bleeding patient, propose a supported dosing scheme, and address the need for appropriate factor VII supplementation. At this point, PCC cannot be recommended for first-line therapy in patients with traumatic hemorrhage, and should be reserved for refractory bleeding until more data are available.

Topics: Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Factors; Critical Illness; Dose-Response Relationship, Drug; Factor VIIa; Hemorrhage; Humans; International Normalized Ratio; Plasma; Recombinant Proteins; Shock, Hemorrhagic; Vitamin K; Warfarin

Central venous catheters (CVCs) are used in a wide variety of patients. Associated complications are thrombosis and infection. It is a matter of debate whether thromboprophylaxis is beneficial.. We performed a systematic review of 3 different patient populations to render the available information in the literature more accessible to clinical practice: patients receiving parenteral nutrition (PN), patients with cancer, and patients admitted to intensive care units.. Prophylaxis with heparin added to PN was found to give a nonsignificant reduction in the incidence of catheter-related thrombosis (pooled relative risk of randomized studies, 0.77; 95% confidence interval [CI], 0.11-5.48). In cancer patients, both low-dose warfarin and low-molecular-weight heparin significantly reduced the incidence of catheter-related thrombosis (relative risk of randomized studies, 0.25 [95% CI, 0.09-0.70] and 0.10 [95% CI, 0.01-0.71], respectively). So far, intensive care patients have hardly been studied with respect to thromboprophylaxis and the incidence of CVC thrombosis. Any effect of the type of catheter could not be established because of small numbers. There was no apparent increase in bleeding events with prophylactic anticoagulation in patients with CVCs.. In the small number of patients studied, the addition of heparin to PN did not significantly decrease the risk of catheter-related thrombosis, whereas warfarin and dalteparin did decrease the thrombosis risk in cancer patients with CVCs. There is no apparent increase in bleeding events with prophylactic anticoagulants in patients with CVCs.

Topics: Anticoagulants; Antineoplastic Agents; Catheterization, Central Venous; Critical Illness; Dalteparin; Heparin; Humans; Intensive Care Units; Neoplasms; Parenteral Nutrition; Randomized Controlled Trials as Topic; Risk Factors; Venous Thrombosis; Warfarin

To evaluate efficacy of antithrombotic agents in critically ill patients with elevated troponin I level during intensive care unit (ICU) admission.. It was a retrospective observational study which was conducted in a tertiary teaching hospital in Taipei, Taiwan. All patients hospitalized in ICU for >3 days and with available serum troponin I data from December 2015 to July 2017 were included. Patients with definite diagnosis of acute myocardial infarction (AMI) were excluded. We divided patients with troponin I elevation into three groups; no prescription, chronic prescription and new prescription of antithrombotic agents during ICU admission. We defined new prescription when patients were on antithrombotic agents, including antiplatelet agents, direct oral anticoagulants, and warfarin after troponin I was found to be elevated at ICU admission and chronic prescription, if antithrombotic agents were on medication list more than 30 days before ICU admission. Primary outcomes were 30-day and one-year all-cause mortality. Of 597 subjects who met inclusion criteria, 407 (68%) patients had elevated troponin I (>0.1 ng/mL) on ICU admission. These patients had increased 30-day [hazard ratio (HR), 1.679; 95% confidence interval (CI), 1.132-2.491; p = 0.009] and one-year (HR, 1.568; 95% CI, 1.180-2.083; p = 0.002) all-cause mortality compared with those without elevated troponin I. In patients with elevated troponin I, there was no significant difference of 30-day all-cause mortality among three groups (p = 0.051) whereas patients on chronic prescription showed significant survival benefit in one-year all-cause mortality when compared to those without or with new prescription (p = 0.008).. In critically ill patients, elevated troponin I in the absence of AMI was associated with poor prognosis. Newly prescribed antithrombotic agents in ICU didn't reveal the difference in short and long-term prognosis while chronic antithrombotic agent use was associated with better one-year survival rate, suggesting that these drugs play a protective role in this high-risk population.

Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Critical Illness; Disease-Free Survival; Female; Fibrinolytic Agents; Hospital Mortality; Humans; Intensive Care Units; Male; Middle Aged; Retrospective Studies; Survival Rate; Troponin I; Warfarin

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

Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the therapeutic dose. Warfarin sensitivity has been reported to be associated with increased incidence of international normalized ratio (INR) > 5. However, whether warfarin sensitivity is a risk factor for adverse outcomes in critically ill patients remains unknown. In the present study, we aimed to evaluate the utility of different machine learning algorithms for the prediction of warfarin sensitivity and to determine the impact of warfarin sensitivity on outcomes in critically ill patients.. Nine different machine learning algorithms for the prediction of warfarin sensitivity were tested in the International Warfarin Pharmacogenetic Consortium cohort and Easton cohort. Furthermore, a total of 7,647 critically ill patients was analyzed for warfarin sensitivity on in-hospital mortality by multivariable regression. Covariates that potentially confound the association were further adjusted using propensity score matching or inverse probability of treatment weighting.. We found that logistic regression (AUC = 0.879, 95% CI: 0.834-0.924) was indistinguishable from support vector machine with a linear kernel, neural network, AdaBoost and light gradient boosting trees, and significantly outperformed all the other machine learning algorithms. Furthermore, we found that warfarin sensitivity predicted by the logistic regression model was significantly associated with worse in-hospital mortality in critically ill patients with an odds ratio (OR) of 1.33 (95% CI, 1.01-1.77).. Our data suggest that the logistic regression model is the best model for the prediction of warfarin sensitivity clinically and that warfarin sensitivity is likely to be a risk factor for adverse outcomes in critically ill patients.

Topics: Algorithms; Anticoagulants; Critical Illness; Drug Resistance; Hospital Mortality; Humans; International Normalized Ratio; Metabolism, Inborn Errors; Warfarin

To compare the demographical profile, indications, efficacy, and contributors to adverse outcome following administration of 4F-PCC in patients on warfarin with supratherapeutic INR.. Retrospective cross-sectional study was performed in a community based teaching hospital. All patients 18 years and older on warfarin with supratherapeutic INR, who had received 4F-PCC between January 2014 and December 2018 were eligible and included in the study.. 44 patients were included in the analysis. The mean age of the patients was 79.5 years. The male to female ratio was 1:1. Patients were on warfarin for atrial fibrillation, thromboembolism in 79.5% (N-35), and 20.5% (N-9) respectively. Indications for use of 4F-PCC were active bleeding in 93% (N-41) of patients. The common sites of bleeding were gastrointestinal, intracranial, and musculoskeletal which were seen in 54.5% (N-24), 29.5% (N-13) and 6.8% (N-3) respectively. The median number of doses of 4F-PCC administered was 1 per patient. The mean dose administered was 2,883u. Clinical improvement was documented in 84% (N-37) of patients. Mortality was seen in 16% (N-7) of patients. BMI greater than 30, anemia, hypotension, presence of intracranial bleed, the requirement of blood products, and mechanical ventilation were associated with higher odds for mortality. Hypotension and requirement of mechanical ventilation were statistically significant.. 4F-PCC continues to be an effective agent in the rapid reversal of warfarin therapy in patients with supratherapeutic INR presenting with major bleeding events. Most patients have clinical improvement with a single, weight-adjusted dose.

Topics: Aged; Anticoagulants; Blood Coagulation Factors; Critical Illness; Cross-Sectional Studies; Female; Humans; International Normalized Ratio; Male; Retrospective Studies; Warfarin

Patients with major bleeding are commonly admitted to the ICU. A growing number are on either oral or parenteral anticoagulation, but the impact of anticoagulation on patient outcomes is unknown. We sought to examine this association between anticoagulation therapy and mortality, as well as the independent effects of warfarin compared to direct oral anticoagulants.. Analysis of a prospectively collected registry (2011-2017) of consecutive ICU patients admitted with major bleeding (as defined by International Society on Thrombosis and Haemostasis clinical criteria).. Two hospitals within a single tertiary care level hospital system.. We analyzed 1,598 patients identified with major bleeding, of which 245 (15.3%) had been using anticoagulation at the time of ICU admission. Of patients on anticoagulation, 149 were using warfarin, and 60 were using a direct oral anticoagulant.. None.. The primary outcome, in-hospital mortality, was analyzed using a multivariable logistic regression model. Patients with anticoagulation-associated major bleeding had higher in-hospital mortality (adjusted odds ratio, 1.49; 95% CI, 1.16-1.92). Among survivors, anticoagulation use was associated with longer median hospital length of stay, and higher mean costs. No differences in hospital mortality were seen between warfarin- and direct oral anticoagulant-associated major bleeding. Patients with warfarin-associated major bleeding had longer median length of stay (11 vs 6 d; p = 0.02), and higher total costs than patients with direct oral anticoagulant-associated major bleeding.. Among ICU patients admitted with major bleeding, pre-admission anticoagulation use was associated with increased hospital mortality, prolonged length of stay, and higher costs among survivors. As compared to direct oral anticoagulants, patients with warfarin-associated major bleeding had increased length of stay and costs. These findings have important implications in the care of ICU patients with major bleeding.

Topics: Aged; Anticoagulants; Cohort Studies; Critical Illness; Female; Hemorrhage; Hospital Mortality; Humans; Intensive Care Units; Length of Stay; Male; Middle Aged; Warfarin

A 20-year-old male affected by transfusion-dependent β-thalassemia (β-thal), was prescribed intensive chelation therapy with deferoxamine (DFO) and deferiprone (DFP) because of severe hepatic and cardiac iron overload and β-blocker and warfarin to manage a previous event of atrial fibrillation (AFib) and heart failure. After a few months, he developed critical liver failure, renal tubulopathy and severe electrolyte imbalance. Laboratory and instrumental evaluations were performed to carry out differential diagnosis of acute liver failure and an exclusion diagnosis of drug induced liver injury (DILI) was made. The cholestatic pattern suggested warfarin as the main causative agent and polypharmacy, liver iron overload and heart failure as aggravating factors. Warfarin is a drug commonly prescribed in thalassemia patients who often need polypharmacy for the management of anemia- and iron-related complications. Strict monitoring and multidisciplinary approaches are mandatory to avoid preventable mortality in this fragile population.

Topics: Adrenergic beta-Antagonists; beta-Thalassemia; Chelation Therapy; Chemical and Drug Induced Liver Injury; Critical Illness; Deferiprone; Heart Failure; Humans; Iron Overload; Male; Warfarin; Young Adult

The scientific rationale for administering fresh frozen plasma (FFP) rests on the assumptions that patients are at risk of adverse effects from inadequate coagulation factors, and that FFP transfusions can decrease those risks. There is a general but unfounded enthusiasm for FFP use across a range of clinical specialties in hospital practice. Plasma for transfusion is most often used when a patient has abnormal results on coagulation screening tests, either as therapy in the face of bleeding, or in patients who are not bleeding as prophylaxis before invasive procedures or surgery. Laboratory abnormalities of coagulation are considered by many clinicians to help predict bleeding before invasive procedures where bleeding risk exists; FFP is presumed to improve the laboratory results and reduce this risk. However, most guideline indications for the prophylactic use of FFP are not supported by evidence from good-quality randomised trials. In fact, the strongest randomised controlled trial evidence indicates that prophylactic plasma for transfusion is not effective across a range of clinical settings. This is supported by data from non-randomised studies in patients with mild-moderate abnormalities in coagulation tests. It is also crucial to clearly understand the risks associated with use of FFP, as no studies have taken adequate account of the extent to which adverse effects might negate the clinical benefits of treatment with FFP. New trials are needed to evaluate the efficacy and adverse effects of plasma, both in bleeding and non-bleeding patients, and to determine whether presumed benefits outweigh the real risks. In addition, new haemostatic tests that better define the risk of bleeding and monitor the effectiveness of FFP use should be validated.

Topics: Algorithms; Anticoagulants; Blood Coagulation Disorders; Blood Transfusion; Coagulation Protein Disorders; Critical Illness; Hemorrhage; Humans; Plasma; Transfusion Reaction; Warfarin

Rituximab, a chimeric monoclonal CD20 antibody, is useful in the treatment of B-cell lymphomas and certain autoimmune diseases. We report a successful outcome of rituximab for life threatening hypercoagulable state associated with lupus anticoagulant (LA). A 30-year-old woman initially presented 10 years ago with DVT and positive serology for SLE and LA. While on Coumadin, she suffered from recurrent DVT in the legs and arms, pulmonary emboli, Budd-Chiari syndrome, mesenteric vein thrombosis, bone infarcts, recurrent strokes, and chronic ITP. All measures including plasmapheresis and monthly IV cyclophosphamide were of no benefit. She was recently admitted with spontaneous subdural hematoma with INR of 3.8. Upon discontinuation of anticoagulation for surgical drainage, she developed acute abdomen from thrombosis and recurrent DVT. Because she had failed prior standard measures, 4 weekly infusions of rituximab (375 mg/m2) were given following 2 rounds of plasmapheresis. Subsequently, she made a remarkable recovery over the next month and has been free of thrombosis on Coumadin for over 15 months. LA, IgM antibodies to cardiolipin, and B2GP1 were consistently positive. After rituximab therapy, LA became negative and IgM antibodies to cardiolipin decreased and ITP went into remission. Rituximab induced a lasting remission in a woman suffering from life-threatening hypercoagulable state associated with LA. Her clinical remission was associated with disappearance of LA.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Autoantibodies; Critical Illness; Disease-Free Survival; Female; Humans; Lupus Coagulation Inhibitor; Recurrence; Remission Induction; Rituximab; Thrombophilia; Treatment Failure; Vascular Diseases; Warfarin

Topics: Aged; Combined Modality Therapy; Critical Illness; Female; Follow-Up Studies; Hematemesis; Humans; Intensive Care Units; Postoperative Care; Pulmonary Embolism; Radiography; Respiration, Artificial; Risk Assessment; Thrombectomy; Warfarin

A patient was admitted to the intensive care unit because of respiratory failure, and warfarin therapy was started at 2 mg/day for the treatment of pulmonary embolism, together with other medications. Despite the low dosage of warfarin, international normalized ratio (INR) was markedly elevated from 1.15 to 11.28 for only 4 days, and bleeding symptoms concurrently developed. Vitamin K2 was infused along with discontinuation of warfarin. One day later, the INR was found to have decreased, and bleeding was also improved. An objective causality assessment indicated a probable relationship between clotting abnormality and warfarin administration, although the degree of elevation of the INR was unusual in the light of the daily warfarin dose and duration of its exposure. Based on the clinical status of the patient, it was suspected that several conditions contributed to the abnormal hypersensitivity to warfarin. Contributory factors probably included pharmacokinetic interactions with co-administrated drugs, vitamin K deficiency caused by decreased dietary intake, reduced gut bacterial production, impaired intestinal absorption and hepatic synthetic capacity, and increased consumption of clotting factors. In view of our experience in the present case, it should be stressed that close monitoring of coagulation capacity is necessary in critically ill patients in order to avoid fatal haemorrhage after initiating warfarin therapy regardless of the dosage.

Topics: Aged; Anticoagulants; Critical Illness; Drug Hypersensitivity; Hemorrhage; Humans; International Normalized Ratio; Male; Pulmonary Embolism; Risk Factors; Warfarin

When 'catastrophic' is applied as an adjective to the antiphospholipid syndrome, it implies a characteristic presentation due to predominantly small blood vessel thrombosis leading to rapidly progressive failure of multiple organs and a frequently fatal outcome. We present the case of a 48-year-old woman who presented with the 'catastrophic' antiphospholipid syndrome without previous history of coagulation disorder or connective tissue disease that illustrates the difficulties in diagnosing and managing this disorder. We also review the factors that have been reported to have a role in the development of this condition and show how this case throws light on its pathogenesis.

Topics: Anti-Inflammatory Agents; Anticoagulants; Antiphospholipid Syndrome; Antirheumatic Agents; Critical Illness; Female; Humans; Hydroxychloroquine; Methylprednisolone; Middle Aged; Prednisolone; Respiratory Distress Syndrome; Treatment Outcome; Warfarin; White People