International Normalized Ration Research Articles

Investigation of the relationship between coagulation parameters and mortality in COVID-19 infection.

This study, which included patients over the age of 18 who were diagnosed with coronavirus disease 2019 (COVID-19) in the emergency clinic, aims to determine the relationship between coagulation parameters and mortality. Epidemiologic data such as age, gender, medical history, vital parameters at emergency department admission, clinical findings, coagulation parameters such as d-dimer, prothrombin time (PT), active partial thromboplastin time (aPTT), international normalized ration (INR), fibrinogen, and platelet were evaluated. Patients with positive computerized tomography (CT) findings and positive polymerase chain reaction (PCR) together were included in the study. It was revealed that d-dimer, fibrinogen, INR, and PT values were higher in the elderly group. It was shown that there was a significant relationship between hospitalization days (ward or intensive care unit) and d-dimer levels. It was observed that d-dimer, fibrinogen elevation was significantly associated with prognosis by increasing mortality, and that platelet and aPTT values were also associated with prognosis and were lower in the mortality group. On the other hand, in receiver operating characteristic (ROC) analysis, the sensitivity and specificity data were 80.3%/80.0% for d-dimer, 70.5%/72.2% for fibrinogen, 58.2%/59.4% for aPTT, and 59.7%/59.2% for platelet, respectively. The overall classification success was 88.6% and mortality prediction success was 37.7% in the regression model of some coagulation parameters (d-dimer, fibrinogen, aPTT, and platelet) which were effective on prognosis. In conclusion, it was determined that d-dimer, fibrinogen, aPTT, and platelet parameters were directly associated with mortality and when these coagulation parameters were used together with the clinical, vital, and demographic data of the patients, the success of mortality prediction increased significantly.

Bleeding risk in female patients undergoing intravesical injection of onabotulinumtoxinA for overactive bladder: a Danish retrospective cohort study

Introduction and hypothesisWe aimed to examine the risk of bleeding in female patients undergoing intravesical onabotulinumtoxinA (BTX-A) treatments and provide clinical recommendations for the perioperative management of patients on antithrombotic therapy prior to BTX-A treatments.MethodsThis was a retrospective cohort of Danish female patients, who had their first BTX-A treatment because of an overactive bladder at the Department of Gynecology and Obstetrics, Herlev and Gentofte University Hospital, between January 2015 and December 2020. Data extraction was from an electronic medical journal system. BTX-A, Botox® Allergan was injected in the detrusor at 10–20 sites. Significant bleeding during or after a BTX-A treatment was defined as persistent macroscopic hematuria. Bleeding reporting was based on information obtained from journal notes.ResultsWe included 400 female patients, who had a total of 1,059 BTX-A treatments. Median age at first BTX-A treatment was 70 years (IQR 21), and median number of BTX-A treatments was 2 (range 1–11). In total, 27.8% (n=111) received antithrombotic therapy. Within this group, 30.6% and 69.4% were on anticoagulant and antiplatelet therapy. No cases of hematuria were reported in our cohort. We found that no patients stopped their antithrombotic therapy, were bridged, or monitored by International Normalized Ration (INR) levels.ConclusionsWe suggest that BTX-A treatments might be classified as low-risk procedures. Discontinuation of antithrombotic therapy is not required in the perioperative management of this patient group.

Factor Xa Inhibitors for Patients after Mechanical Heart Valve Replacement?

Patients with a mechanical heart valve need a lifelong anticoagulation due to the increased risk of valve thrombosis and thrombo-embolism. Currently, vitamin K antagonists (VKA) are the only approved class of oral anticoagulants, but relevant interactions and side effects lead to a large number of patients not achieving the optimal therapeutic target international normalized ration (INR). Therefore, steady measurements of the INR are imperative to ensure potent anticoagulation within a distinctive range. Direct oral anticoagulants (DOACs) with newer agents could serve as a possible alternative to VKAs in this patient cohort. DOACs are approved for several indications, e.g., atrial fibrillation (AF). They only have a minor interaction potential, which is why monitoring is not needed. Thereby, DOACs improve the livability of patients in need of chronical anticoagulation compared with VKAs. In contrast to dual platelet inhibition using aspirin in combination with an ADP receptor antagonist and the direct thrombin inhibitor dabigatran, the oral factor Xa inhibitors apixaban and rivaroxaban show promising results according to current evidence. In small-scale studies, factor Xa inhibitors were able to prevent thrombosis and thrombo-embolic events in patients with mechanical heart valves. Finally, DOACs seem to represent a feasible treatment option in patients with mechanical heart valves, but further studies are needed to evaluate clinical safety. In addition to the ongoing PROACT Xa trial with apixaban in patients after aortic On-X valve implantation, studies in an all-comer collective with rivaroxaban could be promising.

The Cook Score: A Novel Assessment for the Prediction of Liver-Associated Clinical Events in a Diverse Population.

Transient elastography (TE) provides accurate quantification of liver fibrosis. Its usefulness could be significantly amplified in terms of predicting liver-associated clinical events (LACE). Our aim was to create a model that accurately predicts LACE by combining the information provided by TE with other variables in patients with chronic liver disease (CLD). We retrospectively reviewed the electronic medical records of patients who underwent liver elastography, at John H. Stroger Hospital in Cook County, Chicago, IL. The incidences of LACE were documented including decompensation of CLD, new hepatocellular carcinoma, and liver-associated mortality. Significant predicting factors were identified through a forward stepwise Cox regression model. We used the beta-coefficients of these risk factors to construct the Cook Score for prediction of LACE. Receiver-operating characteristic (ROC) curves were plotted for Cook Score to evaluate its efficiency in prediction, in comparison with MELD-Na Score and FIB-4 Score. A total of 3097 patients underwent liver elastography at our institution. Eighty-eight LACE were identified. Age (hazard ratio (HR) 1.04, p=0.002), aspartate aminotransferase to alanine aminotransferase ratio (HR 2.61, p<0.001), platelet count (HR 0.98, p<0.001), international normalized ration (INR) (HR 17.80, p<0.001), and liver stiffness measurement (HR1.04, p < 0.001) were identified as significant predictors. The Cook Score was constructed with two optimal cut-off points to stratify patients into low-, intermediate-, and high-risk groups for LACE. The Cook Score proved superior than MELD-Na Score and FIB4 Score in predicting LACE with an area under curve of 0.828. This novel score based on a large robust sample would provide accurate prediction of prognosis in patients with chronic liver disease and guide individualized surveillance strategy once validated with future studies.

Blood Management in Total Knee Arthroplasty: A Nationwide Analysis from 2011 to 2018.

Both advances in perioperative blood management, anesthesia, and surgical technique have improved transfusion rates following primary total knee arthroplasty (TKA), and have driven substantial change in preoperative blood ordering protocols. Therefore, blood management in TKA has seen substantial changes with the implementation of preoperative screening, patient optimization, and intra- and postoperative advances. Thus, the purpose of this study was to examine changes in blood management in primary TKA, a nationwide sample, to assess gaps and opportunities. The American College of Surgeons National Surgical Quality Improvement Program database was used to identify TKA (n = 337,160) cases from 2011 to 2018. The following variables examined, such as preoperative hematocrit (HCT), anemia (HCT <35.5% for females and <38.5% for males), platelet count, thrombocytopenia (platelet count < 150,000/µL), international normalized ration (INR), INR > 2.0, bleeding disorders, preoperative, and postoperative transfusions. Analysis of variances were used to examine changes in continuous variables, and Chi-squared tests were used for categorical variables. There was a substantial decrease in postoperative transfusions from high of 18.3% in 2011 to a low of 1.0% in 2018, (p < 0.001), as well as in preoperative anemia from a high of 13.3% in 2011 to a low of 9.5% in 2016 to 2017 (p < 0.001). There were statistically significant, but clinically irrelevant changes in the other variables examined. There was a HCT high of 41.2 in 2016 and a low of 40.4 in 2011 to 2012 (p < 0.001). There was platelet count high of 247,400 in 2018 and a low of 242,700 in 201 (p < 0.001). There was a high incidence of thrombocytopenia of 5.2% in 2017 and a low of low of 4.4% in 2018 (p < 0.001). There was a high INR of 1.037 in 2011 and a low of 1.021 in 2013 (p < 0.001). There was a high incidence of INR >2.0 of 1.0% in 2012 to 2015 and a low of 0.8% in 2016 to 2018 (p = 0.027). There was a high incidence of bleeding disorders of 2.9% in 2013 and a low of 1.8% in 2017 to 2018 (p < 0.001). There was a high incidence of preoperative transfusions of 0.1% in 2011 to 2014 and a low of <0.1% in 2015 to 2018 (p = 0.021). From 2011 to 2018, there has been substantial decreases in patients receiving postoperative transfusions after primary TKA. Similarly, although a decrease in patients with anemia was seen, there remains 1 out 10 patients with preoperative anemia, highlighting the opportunity to further improve and address this potentially modifiable risk factor before surgery. These findings may reflect changes during TKA patient selection, optimization, or management, and emphasizes the need to further advance multimodal approaches for perioperative blood management of TKA patients. This is a Level III study.

Management of oral anticoagulants prior to emergency surgery or with major bleeding: A survey of perioperative practices in North America: Communication from the Scientific and Standardization Committees on Perioperative and Critical Care Haemostasis and Thrombosis of the International Society on Thrombosis and Haemostasis

BackgroundThere is limited information on real‐world practice versus current clinical practice guidelines for oral anticoagulant reversal before emergency surgery. ObjectiveTo identify current practice/knowledge gaps for oral anticoagulant reversal emergency surgery among anesthesiologists. MethodsA 22‐question survey covering aspects of clinical practice relating to oral anticoagulant reversal was sent to American Society of Anesthesiology members with weekly reminders during data collection from October to December 2018. ResultsResponses were received from 2315 anesthesiologists of which 86% of respondents were United States based. Emergency surgery was defined as occurring within 4 hours of the decision to operate by 60% of respondents. Fresh frozen plasma (FFP) was used by 75% of respondents for vitamin K antagonist (VKA) reversal and by 54% for direct oral anticoagulant (DOAC) reversal in emergency surgery and 67% in major operative bleeding. Only 32% of institutions had emergency anticoagulant reversal protocols, and 54% of respondents selected an international normalized ration (INR) ratio goal for VKA reversal of ≤1.5. Only 13% initially consulted or coordinated management with hematologists, and the final decision regarding coagulation management was made by the respondent in 26% of cases. A coordinated approach with hematologists and cardiologists was reported by 64%, and over half (51%) required approval for prothrombin complex concentrate administration for emergency procedures. ConclusionsDespite recommendations to the contrary, FFP is extensively used for emergency VKA and DOAC reversal. There is a clear need for institutions to develop guideline‐informed recommendations/management algorithms based on input from medical professionals routinely involved in management of these patients. [Display omitted]

LC–MS/MS assay for assessing medical adherence in patients under warfarin maintenance therapy

Warfarin (WRN) use is plagued by response fluctuation which is managed by dose adjustment. The plasma WRN level had always been an abandoned prerequisite for dose adjustment. However, recent reports had correlated WRN level to the consumed dose. More importantly, the intra-individual alteration in WRN level was found proportional to response fluctuation. This renewed the interest to use WRN level prior to dose adjustment to account for dispensing errors or inadequate adherence. Detection of possibly interacting drugs may further assess compliance and enable a wiser dose adjustment.In this study, an LC–MS/MS assay was developed and validated for the determination of the WRN and the simultaneous detection of interacting drugs in citrated plasma samples normally collected for monitoring international normalized ration (INR). Samples were prepared by liquid-liquid extraction. Separation of WRN and interacting drugs (n = 19) was achieved on an Inertsil®C18 column using a gradient elution program. The assay was applied in 96 plasma samples from patients.The developed method was linear, accurate and precise for WRN determination with average recovery of 99.5 ± 8.4% and no relative matrix effect. WRN plasma level was measured in all samples and possible interacting drugs were detected. An improved WRN-response correlation was observed inter-individually when patient variability was reduced.Our results support the significance of WRN monitoring and suggest the additional monitoring of other interacting drugs for integrated evaluation of patient adherence. The developed method enables ruling-out inadequate adherence prior to unnecessary dose adjustment and highlights the need to strengthen patient education procedures.

Blood sugar changes and hospital mortality in multiple trauma

ObjectivesHyperglycemia with unknown mechanism plays a predictive role in determining the prognosis of multiple trauma patients. The exact time of blood sugar measurement and the role of blood sugar changes in the monitoring of these patients have not been well established. MethodsThis follow-up study was done on multiple trauma patients (>18years) with an Injury Severity Scores (ISS)>16. These patients didnʾt have any history of diabetes, underlying disease, or drug or alcohol use. Data collection was done by the questionnaire (checklist), and the patients were followed by the medical records. Cox regression was used to measure the effect of independent variables on the patients' hospital mortality. ResultsOf a total of 963 patients, 280 patients were enrolled. Of those, 202 were male (72.1%) and 78 were female (27.9%). Hospital mortality was 18 (6.4%). Cox regression analysis suggested that those who had high blood sugar 3h after admission had higher hospital mortality (P=0.04). Changes in blood sugar, ΔBS (BS 3h after admission – BS on admission), in these patients was also significantly correlated with hospital mortality (P<0.001). The multivariate model using the backward conditional method showed that ΔBS (P<0.001), international normalized ration (INR) (P<0.001), and heart rate (P=0.036) were significantly correlated with hospital mortality. ConclusionsIn multiple trauma patients, blood sugar changes in the early hours of admission to the emergency department may help predict hospital mortality, but further studies are needed. Blood sugar monitoring in these patients during this time frame may be helpful in predicting these patients' outcomes. In addition, coagulopathy and tachycardia were significantly associated with hospital mortality.

Coagulation Profile as a Risk Factor for 30-Day Morbidity and Mortality Following Posterior Lumbar Fusion.

A retrospective cohort study. The aim of this study was to identify associations between abnormal coagulation profile and postoperative morbidity and mortality in patients undergoing posterior lumbar fusion (PLF). The literature suggests that abnormal coagulation profile is associated with postoperative complications, notably the need for blood transfusion. However, there is little research that directly addresses the influence of coagulation profile on postoperative complications following PLF. The American College of Surgeons National Surgical Quality Improvement Program database (ACS-NSQIP) was utilized to identify patients undergoing PLF between 2006 and 2013. Nine thousand two hundred ninety-five patients met inclusion criteria. Multivariate analysis was utilized to identify associations between abnormal coagulation profile and postoperative complications. Low platelet count was an independent risk factor for organ space surgical site infections (SSIs) [odds ratio (OR) = 6.0, P < 0.001], ventilation >48 hours (OR = 4.5, P = 0.002), Acute renal failure (OR = 5.8, P = 0.007), transfusion (OR = 1.6, P < 0.001), sepsis (OR = 2.2, P = 0.037), reoperation (OR = 2.5, P = 0.001), and death (OR = 3.7, P = 0.049). High partial thromboplastin time (PTT) was an independent risk factor for ventilation >48 hours (OR = 5.6, P = 0.002), cerebrovascular accident (CVA)/stroke with neurological deficit (OR = 5.1, P = 0.011), cardiac arrest (OR = 5.4, P = 0.030), transfusion (OR = 1.5, P = 0.020), and death (OR = 4.5, P = 0.050). High International Normalized Ration (INR) was an independent risk factor for pneumonia (OR = 8.7, P = 0.001), pulmonary embolism (OR = 5.6, P = 0.021), deep venous thrombosis/Thrombophlebitis (OR = 4.8, P = 0.011), septic shock (OR = 8.4, P = 0.048), and death (OR = 9.8, P = 0.034). Bleeding disorder was an independent risk factor for organ space SSI (OR = 5.4, P = 0.01), pneumonia (OR = 3.0, P = 0.023), and sepsis (OR = 4.4, P < 0.001). Abnormal coagulation profile was an independent predictor of morbidity and mortality in patients undergoing PLF. As such, it should be considered in preoperative optimization and risk stratification.

Evaluation of SAMe-TT2R2 score and other clinical factors influencing the quality of anticoagulation therapy in non-valvular atrial fibrillation: a nationwide study in Spain

Objective: To assess the major clinical factors affecting the quality of anticoagulation and evaluate the predictive value of the SAMe-TT2R2 score to identify patients who will achieve a high average time in therapeutic range (T.T.R.) with vitamin K antagonist (V.K.A.) treatment. Research design and methods: This observational, cross-sectional, retrospective and nationwide multicenter study included 1524 patients from the primary care setting with non-valvular atrial fibrillation receiving V.K.A. (≥12 months). We performed a bivariate analysis to identify factors individually associated with the T.T.R. and a multiple regression analysis to identify the independent predictive factors. For the validation of the SAMe-TT2R2 score, the receiver operating characteristic (R.O.C.) curve was calculated and the Hosmer–Lemeshow test was used to test calibration. Results: A total of 94.8% of patients received acenocumarol (4.8% warfarin). A progressive decrease in mean T.T.R. was found when the SAMe-TT2R2 score increased from 0 points (72.1 ± 17.1%) to 4 points (64.1 ± 23.2%), p < 0.001. Other risk scores (CHADS2 and CHA2DS2-VASc, HAS-BLED) were also associated with the mean T.T.R. We found a significant association between low T.T.R. and the following clinical factors: female sex, three or more comorbidities, amiodarone treatment, dietary habits, bleeding history and the intake of ≥7 tablets per day besides V.K.A. (p < 0.01). Regarding SAMe-TT2R2 score validation, the R.O.C. curve showed significant capability, although not high, of discriminating good anticoagulation control (T.T.R. ≥65%) with an area under the curve of 0.562 (95% C.I. 0.533–0.592, p < 0.001) which increased, remaining modest, to 0.594 (95% C.I. 0.564–0.624, p < 0.001) when the factors not included in SAMe-TT2R2 score were added. Conclusion: In this cohort, the SAMe-TT2R2 score had a significant, although modest, ability to assess the likelihood of good international normalized ration (I.N.R.) control, and its predictive value might slightly improve by adding other simple clinical factors. Further research is needed to refine the predictive scales.

Clinical Characteristics of Atrial Fibrillation in Saudi Women Cohort and Its Clinical Impact in a Tertiary University Hospital

A retrospective study was conducted to evaluate the characteristics of atrial fibrillation in a cohort of Saudi women, and its impact on morbidity. A complete medical history was obtained and all participants underwent a complete review of clinical data including electrocardiogram, echocardiogram, blood pressure measurement, and thyroid examination. The following laboratory examinations were performed: international normalized ratio; thyroid stimulating hormone; triiodothyronine; thyroxine; total cholesterol; triglyceride; low-density and high-density lipoprotein. A history of hospitalizations, stroke and in-hospital mortality were recorded. We recruited 84 women; the mean age was 61.8 years and the mean body mass index was 28.45 kg/m2. The mean hemoglobin level of the patients was 12.2 g/dL and the mean thyroid stimulating hormone level was 3.75 mIU/L. The target international normalized ratio was achieved in 58% of treated patients; 70% of the under target International Normalized Ration patients had been hospitalized more than once and 19% had suffered a stroke. Overall, international normalized ratio demonstrates gaps in the management of women with atrial fibrillation, and the negative impact on patient outcome, indicating the need to tailor treatment plans to the goals and requirements of these patients.&#x0D;

Efficacy of Prothrombin Complex Concentrates for Oral Anticoagulant Therapy-related Major Hemorrhage

In patients admitted to accident and emergency departments for anticoagulant use-related major hemorrhage and requiring urgent surgery or life-saving invasive intervention, the international normalized ration (INR) value should be rapidly corrected and bleeding should be controlled. With prothrombin complex concentrate (PCC), when used at optimal dose levels, target INR values are achieved within 15 min. In this study, we aimed to discuss the efficacy of the used four-factor PCC in 10 patients who were admitted to the accident and emergency department because of oral anticoagulant use-related major bleeding. Of all the patients to whom PCC treatment was administered, targeted INR levels could not be attained in 2 patients (20%). For our cases with gastrointestinal bleeding, the average baseline INR value was 7.3, while the average INR value after PCC administration was 1.9. For our subdural hematoma cases, the median baseline INR value was 2.5, while the median INR value after PCC administration was 1.3. We believe that PCCs used in eligible patient groups, as in this case series, may provide the desired results at lower doses and that they may be safer with regard to complications. (JAEM 2015; 14: 37-40)

Elevated International Normalized Ratio as a Manifestation of Post-thrombolytic Coagulopathy in Acute Ischemic Stroke

A serious complication of intravenous tissue plasminogen activator (tPA) in acute ischemic stroke is hemorrhage. Coagulation factors that may potentially increase the risk of bleeding after tPA are not well understood. We retrospectively reviewed 284 acute ischemic stroke patients who received tPA. Post-tPA coagulopathy was defined as a documented elevation of international normalized ration (INR) > 1.5 within 24 hours after IV tPA without a known cause. We identified 21 (7.4%) patients with an elevated INR post-thrombolysis. The mean age was 68.3 years (standard deviation ± 11.9) and 57% were male. The mean initial National Institutes of Health Stroke Scale (pre-tPA) was 15.8 (range, 4-35). Liver disease or alcohol abuse was noted in 19%. There were 2 tPA protocol violations who received more than 90 mg tPA. The mean post-tPA INR was 2.03 (range, 1.5-4.7) and the elevation in INR was documented within a mean 5.4 hours (range, 1-15) after tPA initiation. Repeat INR levels returned to normal during their hospital stay in 19 patients. Hypofibrinogenemia was noted in 10 of 12 patients who had fibrinogen levels drawn within 48 hours after tPA initiation and in all 7 patients with fibrinogen levels drawn the same time as the elevated INR. Among the 6 patients with bleeding complications, 2 patients had symptomatic intracerebral hemorrhage. We report an under-recognized early transient coagulopathy associated with elevated INR in stroke patients after treatment with tPA.

Incidence of thrombotic events in chronic liver disease

Introduction: Chronic liver disease is labeled as a classic acquired bleeding disorder, however it has been demonstrated that these patients present thrombin production within normal range, which raises questions about the International Normalized Ration included in several prognosis stratification scores. Although this population does not seem to be protected from thrombotic events, the prophylaxis of deep vein thrombosis is mostly withheld from patients with chronic liver disease. Objectives: Our aim is to analyze the incidence of thrombotic events and the percentage of prophylaxis use in in-patients with diagnosis chronic liver disease.

Zastosowanie koncentratu czynników zespołu protrombiny w leczeniu zaburzeń hemostazy osoczowej po operacji transplantacji serca

Hemostasis involves complex processes meaning blood not to extravasate. It's temporary cessation is necessary to perform cardiac surgery procedure with cardiopulmonary bypass. In heart transplantation, standard procedures of heparine neutralization are insufficient. We present results obtained from the group of 10 patients (8 men and 2 women) in mean age of 41±15 years, who underwent heart transplantation procedure with Lower-Shumway technique in moderate hypothermia (28°C). Mean cardiopulmonary bypass time was 218±20min, cross clampling aortic time was 114±18min and organ cold ischemia time was 221±16min. Postoperative human prothrombin complex was given after INR result (2.2±0.3) was obtained followed by normalized activated clotting time (ACT) 124±17seconds. In high risk patients undergoing cardiac surgery procedure, standard international normalized ration (INR) measurements following ACT results are required to obtain more detailed information concerning plasma hemostasis disturbances. Prothromplex Total NF (Baxter International Inc, USA) is a safe option to correct the problem without risk of overloading the patients circulatory system.

“The End of Good Luck’’—Long-Term Survival Without Anticoagulation

Long-term anticoagulation in patients with metallic prosthetic valve disease is required according to current guidelines. We describe a patient with a functioning mitral mechanical valve without anticoagulation for 27 years. A 46-year-old man admitted to the emergency department with complains of palpitation. The patient had a mitral valve replacement because of severe mitral stenosis. He discontinued warfarin treatment 1 month after surgery because of the unavailability of this drug in Turkey. Transthoracic echocardiography revealed functioning metalic mitral valve with a mean gradient of 9 mm Hg. Fluoroscopy showed normal excursions of the mechanical mitral valve. Transesophageal echocardiography was performed and revealed fresh thrombus formation in the left atrial appendix. Admission international normalized ration (INR) level was 1.79. Due to the higher INR level and long-term survival, genetic analysis of warfarin polymorphism was performed. There was a homozygous mutation in the vitamin K epoxide reductase complex 1 (VKORC1) 1173C>T and 1639G>A genotypes. The possible explanations of long-term survival and baseline higher INR level were linked to the mutation in warfarin metabolism. We also briefly review the literature.

Menorrhagia and ecchymoses in an adolescent girl treated with sertaline

Dear Editor, Selective serotonin reuptake inhibitors (SSRIs) are considered a first line treatment for depression and anxiety disorders in children and adolescents. In addition to their common side effects such as nausea, vomiting, diarrhea, agitation, headache, insomnia, somnolence, anxiety, and sexual dysfunction, SSRIs have also been associated with bleeding complications. Case reports have described adult patients with various bleeding disorders (e.g., ecchymoses, purpura, epistaxis), while observational studies have focused on upper gastrointestinal bleeding, intracranial bleeding, and bleeding during surgery (Weinrieb et al. 2005). Abnormal bleeding has been reported in children and adolescents taking SSRIs. Bleeding in these cases included spontaneous bruises, epistaxis, and hemorrhagic gastritis (Weinrieb et al. 2005). We report a case of an adolescent girl who manifested menorrhagia and ecchymoses after 3 weeks of sertraline treatment. This patient was referred to our outpatient unit at the age of 16 years for treatment of major depressive disorder and posttraumtic stress disorder related to physical abuse over the previous 2 years by her father from whom she was removed and placed in a foster home. Fluvoxamine treatment was initiated at 50 mg/day but was withdrawn after 5 days due to a rash. Sertraline was administered at 25 mg/day. This dose was well tolerated and was increased to 50 mg/day after 1 week. Three weeks later, the patient reported spontaneous bruises on her arms and legs, and menorrhagia lasting for 12 days. Her complete blood cell count, hepatic function tests, bleeding time, protrombine time, partial protrombine time, activated partial protrombine time, international normalized ration (INR), clotting time, and fibrinogen level were within the normal limits. Physical examination revealed no abnormality other than ecchymoses. A genital ultrasound revealed no abnormality and normal flow on color Dopplers. Her symptoms subsided after sertraline discontinuation and did not reoccur with clomipramine treatment at 75 mg/day. This patient had no personal or family history of a bleeding disorder, trauma, or self-injurious behavior. She did not take any other medication except sertraline. No comorbid mental disorders were found to which ecchymoses could have been attributed. Menorrhagia and ecchymoses of our patient are attributed to sertraline treatment, after excluding other etiologies of bleeding. Decrease of serotonin concentration in platelets during SSRI administration might be the cause of impaired platelet function and adverse bleeding events. Several other mechanisms of SSRI-induced bleeding diathesis that have been proposed include blockade of calcium mobilization, inhibition of nitric oxide synthase, and drug-induced immune thrombocytopenia. Agents with the highest degree of serotonin reuptake inhibition (SRI)—fluoxetine, paroxetine, sertraline and clomipramine—are more frequently associated with abnormal bleeding and hemostatic abnormalities (Meijer et al. 2004). Moreover, a trend towards more bleeding events with higher dosage of SRI medications was found (van Walraven et al. 2001). This may explain bleeding complications under sertaline treatment compared to other SRI drugs used in our patient. The dosage of clomipramine 75 mg/day might not have been high enough and the duration of fluvoxamine treatment was too short to cause bleeding complications in our patient. We could not find any abnormal V. Boricevic Marsanic (*) : E. Kusmic Psychiatric Hospital for Children and Youth, Kukuljeviceva 11, 10 000 Zagreb, Croatia e-mail: vlatka.boricevic@zg.t-com.hr

Lamotrigine-associated reversible severe hepatitis: A case report

Anticonvulsant hypersensitivity syndrome is a severe idiosyncratic reaction to antiepileptic drugs. We report a case of a woman with lamotrigine-associated hepatitis who recovered spontaneously with supportive treatment. A 43-year-old woman was being treated with oxcarbazepine for depression and was started on lamotrigine 2 weeks prior to her presentation. The patient then developed nausea and a generalized pruritic macular rash, and was found to have elevated liver enzymes, which peaked at AST, 6079 IU/L; ALT, 6900 IU/L; total bilirubin, 3.9 mg/dL(66.7 micromol/L); alkaline phosphatase, 149 IU/L; international normalized ration (INR), 1.9. The patient showed no signs of encephalopathy and her clinical examination was essentially normal except for very mild jaundice and a diffuse erythematous pruritic macular rash. The patient was hydrated and managed with supportive care. On the third day of hospitalization, her liver enzymes had improved substantially and she was discharged. At follow-up 1 month later the patient's liver enzymes were within the normal range. We hypothesize that lamotrigine was directly responsible for the patient's rash and liver impairment given the time sequence of drug introduction and resolution of symptoms and liver enzyme abnormality once the drug was withdrawn. The patient suffered severe transaminitis when lamotrigine was added to oxcarbazepine, which resolved after termination of the medication and supportive management. We recommend monitoring the hepatic function in patients who have just been initiated on lamotrigine, especially if they develop jaundice.

Effectiveness of Warfarin among Patients with Cancer

Among patients treated with warfarin for venous thromboembolism (VTE), cancer patients have more thrombotic and hemorrhagic events than patients without cancer. Is this also the case when cancer patients are anticoagulated for other indications? The objective of the study is to evaluate the effectiveness of warfarin, given for any indication, among patients with cancer in a community setting. We identified patients with cancer from a larger prospective cohort of 6,761 patients from 101 clinical sites in the United States, matched to controls without cancer. The proportion of time spent in the therapeutic range, international normalized ration (INR) variability, and the rate of thromboembolic and major hemorrhagic events were compared between the two groups. Ninety-five patients undergoing treatment for cancer were matched to 283 patients without cancer. The cancer group spent less time in the target INR range (54 vs 66%, P < .001) and had more variable INR values (standard deviation around the mean INR value 1.30 vs 0.71, P < .001). There were more thrombotic events in the cancer group than in the control group (5 vs 0 events, P < .001). These analyses were repeated after excluding all of the patients anticoagulated for VTE; the results were unchanged. Compared to matched controls, cancer patients receiving warfarin spend less time in the target INR range, have more variable INR values, and have more thrombotic events. These effects are not dependent on whether the patient is anticoagulated for VTE or another indication.

Design Considerations for the Warfarin-Antiplatelet Recurrent Stroke Study

The Warfarin-Antiplatelet Recurrent Stroke Study is a multicenter, randomized, double-blind study comparing warfarin against aspirin in the prevention of recurrent stroke. No patient takes two active medications or two placebos. Warfarin is used in 2 mg doses sufficient to keep the international normalized ration (INR) at 1.4–2.8 while aspirin is given as 325 mg q.id. All patients are treated as if they were on true warfarin. Blood drawn at the local sites are sent to a single laboratory in the USA where the prothrombin time/INRs are determined. To maintain blinding, the values reaching the local investigator by fax are correct if the patient is truly assigned to warfarin but normal INR values for patients in the true aspirin arm are falsified by a computer program to mimic those values expected for the dose and duration of therapy had the patient actually been on warfarin. The sample size planned is > 1,900 patients, enough to detect a 30% reduction in the frequency of stroke and death in the warfarin group compared with aspirin if differences this large exist.