Abnormal vaginal bleeding in women of reproductive age treated with edoxaban or warfarin for venous thromboembolism: a post hoc analysis of the Hokusai-VTE study.

OBJECTIVE: To investigate the characteristics and outcome of abnormal vaginal bleeding in women receiving edoxaban or warfarin for treatment of venous thromboembolism (VTE). DESIGN AND SETTING: Post hoc analysis of the Hokusai-VTE study, a multicentre, randomised, double-blind trial comparing edoxaban with warfarin for acute symptomatic VTE. POPULATION: Women below 50 years receiving edoxaban or warfarin for treatment of VTE. METHODS: We collected data on diagnostic measures, treatment, and clinical outcome of abnormal vaginal bleeding events. MAIN OUTCOME MEASURES: Occurrence of major and clinically relevant nonmajor (CRNM) abnormal vaginal bleeding events. RESULTS: In all, 628 women aged under 50 years were treated with edoxaban and 665 with warfarin. The rate of abnormal vaginal bleeding was 15/100 person-years (py) (95% CI 11-19) in women receiving edoxaban and 9/100 py (95% CI 6-12) in the warfarin group (hazard ratio: 1.7, 95% CI 1.1-2.5). Major abnormal vaginal bleeding occurred in eight (1.3%) women on edoxaban and in three (0.9%) women receiving warfarin [odds ratio (OR) 2.8; 95% CI 0.8-10.8], and CRNM abnormal vaginal bleeding occurred in 53 (8.4%) women treated with edoxaban and in 37 (5.6%) on warfarin therapy (OR 1.6, 95% CI 1.0-2.4). Over 85% of all vaginal bleeds were characterised by heavy menstrual bleeding. Major bleeds frequently required treatment, and in more than 75% of patients anticoagulant therapy was adjusted. The severity of clinical presentation and course of major and CRNM bleeds was mild in most patients. CONCLUSIONS: Abnormal vaginal bleeding occurred more frequently in women treated with edoxaban than with warfarin. Reassuringly, most events could be managed conservatively and had a mild outcome. TWEETABLE ABSTRACT: Abnormal vaginal bleeding occurred more frequently in women treated with edoxaban than with warfarin.

Serum-free light chain assessment in hepatitis C virus-related lymphoproliferative disorders.

OBJECTIVE: To evaluate the relevance of serum-free light chain (FLC) assessment in hepatitis C virus (HCV)-related lymphoproliferative disorders, including mixed cryoglobulinemia (MC) and B cell non-Hodgkin lymphoma (B-NHL). PATIENTS AND METHODS: A total of 59 patients infected with HCV were prospectively followed, including patients without MC (n = 17), with asymptomatic MC (n = 7) and with MC vasculitis (n = 35, 9 of whom had B-NHL). Clinical and biological data were recorded at the time of the initial evaluation and at the end of follow-up. Serum FLC quantitation was carried out using a serum FLC assay. RESULTS: The mean (SD) serum kappa FLC level was higher in patients with asymptomatic MC (27.9 (8.6) mg/litre), MC vasculitis (36.7 (46.2) mg/litre) and B-NHL (51.3 (78.3) mg/litre) than without MC (21.7 (17.6) mg/litre) (p = 0.047, 0.025 and 0.045, respectively). The mean serum FLC ratio was higher in patients with MC vasculitis (2.08 (2.33)) and B-NHL (3.14 (3.49)) than in patients without MC (1.03 (0.26)) (p = 0.008). The rate of abnormal serum FLC ratio (>1.65) correlated with the severity of HCV-related B cell disorder: 0/17 (0%) without MC, 0/7 (0%) asymptomatic MC, 6/26 (23%) MC vasculitis without B-NHL and 4/9 (44%) B-NHL (p = 0.002). Serum kappa FLC levels and the serum FLC ratio correlated with the cryoglobulin level (r = 0.32, p<0.001 and r = 0.25, p = 0.002, respectively) and the severity of the B cell disorder (r = 0.26, p = 0.045 and r = 0.41, p = 0.001, respectively). Among patients with an abnormal serum FLC ratio at baseline, the FLC ratio correlated with the virological response to HCV treatment. CONCLUSIONS: In patients infected with HCV, an abnormal serum FLC ratio appears to be a very interesting marker, as it is consistently associated with the presence of MC vasculitis and/or B-NHL. After antiviral therapy, the serum FLC ratio could be used as a surrogate marker of the control of the HCV-related lymphoproliferation.

Anti-CD20 monoclonal antibody (rituximab) treatment for cryoglobulinemic vasculitis: where do we stand?

Mixed cryoglobulinemia (MC) vasculitis represents a complication of the B cell response to a variety of chronic inflammatory diseases. Recent reports describe the use of monoclonal antibodies directed to CD20 antigen (rituximab), a transmembrane protein expressed on pre-B lymphocytes and mature lymphocytes. The goal of this article is therefore to review published data in order to better analyse the efficacy and tolerance of rituximab treatment in patients with MC vasculitis. After systematic review of the literature and exclusion of review papers, 13 manuscripts were identified that reported on a total number of 57 cases of MC secondary to hepatitis C virus (HCV) infection (75.4%) or essential mixed cryoglobulinemia (24.6%). Previous treatments failed to control the main signs of vasculitis; these were either HCV (n = 37) or immunomodulating treatments. Most patients (48 out of 57) received four weekly consecutive intravenous infusions of 375 mg/m(2) of rituximab. The duration of follow-up after rituximab therapy was 9.7 months. Rituximab infusions had great efficacy on the main vasculitis signs, with a clinical response in 80-93% patients. A relapse of MC was noted in 14 out of 36 (39%) patients. A relatively small number of side effects were reported. We conclude that rituximab therapy for patients with mixed cryoglobulinemia vasculitis, HCV-induced or essential, shows great efficacy on the main vasculitis signs in the majority of reported patients. A relapse of cryoglobulinemia vasculitis was frequently noted. Randomised controlled trials with long-term study are needed to form definitive conclusions on the benefit/risk ratio of rituximab therapy in such patients.

Antipsychotic drugs and the risk of recurrent venous thromboembolism: A prospective cohort study.

BACKGROUND: Numerous studies have suggested that antipsychotic drugs are associated with an increased risk for a first episode of venous thromboembolism (VTE). However, after anticoagulation discontinuation, the impact of antipsychotic drugs on the risk of recurrent VTE (rVTE) remains unknown. OBJECTIVE: To estimate the risk of rVTE in association with antipsychotic drugs. METHODS: Between May 2000 and December 2012, we included all consecutive patients with a first unprovoked symptomatic VTE and who discontinued anticoagulation. During follow-up, exposure to antipsychotic drugs was systematically assessed. RESULTS: A total of 736 patients with a first unprovoked symptomatic VTE were followed-up during a median period of 27.0 months (interquartile range (IQR) 6.2-60.0). Patients' median age was 66.0 years (IQR 49.0-76.0), 404 (54.9%) were men, and 61 (8.3%) were exposed to antipsychotics during follow-up. The incidence rate of r VTE was 12.1% person-year (95% CI 7.2-20.5) in antipsychotics users compared with 8.3% person-year (95% CI 7.1-9.8) in non-users (p = 0.20). Multivariate analysis showed a significant increased risk of recurrence associated with antipsychotic exposure (adjusted hazard ratio 1.9, 95% CI 1.1-3.3). CONCLUSIONS: In this cohort study, exposure to antipsychotic drugs was found to be associated with an increased risk of rVTE among patients with a previous first unprovoked symptomatic VTE and who discontinued anticoagulation. Larger studies are needed to confirm and further explore this association.

Protein S Heerlen mutation heterozygosity is associated with venous thrombosis risk.

Hereditary Protein S (PS) deficiency is a rare coagulation disorder associated with an increased risk of venous thrombosis (VT). The PS Heerlen (PSH) mutation is a rare S501P mutation that was initially considered to be a neutral polymorphism. However, it has been later shown that PSH has a reduced half-life in vivo which may explain the association of PSH heterozygosity with mildly reduced levels of plasma free PS (FPS). Whether the risk of VT is increased in PSH carriers remains unknown. We analyzed the association of PSH (rs121918472 A/G) with VT in 4,173 VT patients and 5,970 healthy individuals from four independent case-control studies. Quantitative determination of FPS levels was performed in a subsample of 1257 VT patients. In the investigated populations, the AG genotype was associated with an increased VT risk of 6.57 [4.06-10.64] (p = 1.73 10-14). In VT patients in whom PS deficiency was excluded, plasma FPS levels were significantly lower in individuals with PSH when compared to those without [72 + 13 vs 91 + 21 UI/dL; p = 1.86 10-6, mean + SD for PSH carriers (n = 21) or controls (n = 1236) respectively]. We provide strong evidence that the rare PSH variant is associated with VT in unselected individuals.

Oral contraception and menstrual bleeding during treatment of venous thromboembolism: Expert opinion versus current practice: Combined results of a systematic review, expert panel opinion and an international survey.

INTRODUCTION: The optimal management of oral contraception and menstrual bleeding during treatment of venous thromboembolism (VTE) is largely unknown. We aimed to elicit expert opinion and compare that to current practice as assessed by a world-wide international web-based survey among physicians. METHODS: 10 international thrombosis experts and 10 abnormal uterine bleeding experts independently completed a questionnaire containing three hypothetical patient cases each with four different scenarios, and additional queries covering different severities of VTE, patient circumstances, hormonal contraceptives and both thrombotic and bleeding complications. The consensus percentage was set a priori at ≥70%. The same questionnaire with randomized case scenarios was presented to international physicians via newsletters of the ISTH and national scientific communities. Differences between the expert groups and daily clinical care were assessed. RESULTS: Expert recommendations were divergent and differed in several important points from clinical practice. In contrast to common practice in which contraceptives are discontinued at the moment of a VTE diagnosis, the thrombosis experts agreed to continue oral contraception (OC) during the anticoagulation treatment period. Also, experts reached consensus on treating patients with anticoagulation-associated abnormal uterine bleeding with tranexamic acid, although this is not supported by strong evidence from the literature. No consensus was reached on the optimal anticoagulant drug class. CONCLUSIONS: International experts' opinions on handling of contraceptives and management of anticoagulant-associated abnormal uterine bleeding in female VTE patients are divergent and management in clinical practice is heterogeneous. There is a great need of further studies on these topics.

Net clinical benefit of hospitalization versus outpatient management of patients with acute pulmonary embolism.

Essentials Clinical benefit of hospitalization vs. outpatient treatment in pulmonary embolism (PE) is unknown. We performed a propensity matched cohort study of hemodynamically stable PE patients. Regardless of the risk assessment, hospitalized patients had the highest rate of adverse event. If confirmed, ambulatory care of normotensive PE patients may be preferred whenever possible. SUMMARY: Background The decision to hospitalize or not patients with acute pulmonary embolism (PE) is controversial. Despite the advantages of close monitoring, hospitalization by itself may lead to in-hospital complications and potentially worsen the prognosis of PE patients. Objectives To determine the net clinical benefit of hospitalization vs. outpatient management of normotensive patients with acute pulmonary embolism (PE). Methods Retrospective cohort propensity score analysis (radius marching with replacement). Hemodynamically stable PE patients treated as outpatients or inpatients were matched to balance out differences for 28 patient characteristics and known risk factors for adverse events. The primary outcome was the rate of adverse events at 14 days, including recurrent venous thromboembolism, major bleeding or death. Results Among 1127 eligible patients, 1081 were included in the matched cohort, 576 treated as inpatients and 505 as outpatients. The 14-day rate of adverse events was 13.0% for inpatients and 3.3% for outpatients (adjusted OR, 5.07; 95% CI, 1.68-15.28). The 3-month rate was 21.7% for inpatients and 6.9% for outpatients (OR, 4.90; 95% CI, 2.62-9.17). In the high-risk subgroup (Pulmonary Embolism Severity Index class III-V; n = 597), the 14-day rate of adverse events was 16.5% for hospitalized patients vs. 4.5% for outpatients (OR, 4.16; 95% CI, 1.2-14.35). Conclusion Outpatient treatment of hemodynamically stable PE patients seems to be associated with a lower rate of adverse events than hospitalization and, if confirmed, may be considered as first-line management in patients not requiring specific in-hospital care, regardless of their initial risk stratification, if proper outpatient care can be provided.

[Multiple myeloma and venous thrombosis. Which thromboprophylaxis should be given?]. / Myélome multiple et thrombose veineuse. Quelle thromboprophylaxie faut-il proposer ?

Multiple myeloma is a malignant plasma cells dyscrasia that mainly affects patients older than 65 years. These patients are at a higher risk for venous thromboembolism (VTE) because of cancer status, intrinsic risk factors, and exposure to prothrombotic therapies. The risk for VTE appears higher during the first months of myeloma treatment and decreases over time. Exposure to immunomodulatory drugs (IMIDs) such as thalidomide or lenalidomide in association with high doses of dexamethasone or anthracyclin-based chemotherapy is associated with a four-fold increased risk for VTE. Low-dose aspirin, preventive-dose of low molecular weight heparin (LMWH) or vitamin K antagonists were tested for primary prevention of VTE in myeloma patients receiving chemotherapy. The International Myeloma Working Group (IMWG) suggests stratifying VTE risk to decide which patients should receive VTE prevention. Then, the IMWG suggests giving low-dose aspirin to low VTE risk patients and LMWH or vitamin K antagonists to patients at high risk for VTE. For daily practice, it seems reasonable to start preventive doses of LMWH for 3 to 6 months in ambulatory myeloma patients receiving combined therapy with IMID and in all myeloma patients admitted to hospital.

Is there still room for additional common susceptibility alleles for venous thromboembolism?

UNLABELLED: Essentials Genetic architecture of venous thromboembolism (VTE) remains to be fully disentangled. 11 newly discovered candidate polymorphisms were genotyped in 3019 VTE cases and 2605 controls. None of the 11 polymorphisms were significantly associated with VTE risk. Additional major efforts are needed to identify VTE-associated genetic variants. SUMMARY: Background Through a meta-analysis of 12 genome-wide association studies, the International Network against VENous Thrombosis (INVENT) consortium identified two novel susceptibility loci for venous thromboembolism (VTE). This project has also generated other candidates that need to be confirmed. Objectives To assess the association with VTE of common single-nucleotide polymorphisms (SNPs) that demonstrated strong statistical, but not genome-wide, significance in the INVENT cohorts. Patients/methods Eleven SNPs were genotyped and tested for association with VTE in three case-control studies totaling 3019 patients and 2605 healthy individuals. Results and conclusions None of the tested SNPs showed evidence for association with VTE. Different strategies are needed to decipher the whole spectrum of common and rare genetic variations associated with VTE risk.

[Second degree atrioventricular block in mixed connective tissue disease]. / Syndrome de Sharp et bloc de conduction auriculo-ventriculaire aigu du second degré. A propos d'une observation.

INTRODUCTION: Mixed connective tissue disease (MCTD) is characterized by overlapping features of progressive systemic sclerosis, dermatomyositis and systemic lupus erythematosus, and by high rate of antibodies to an extractable nuclear antigen ribonucleoprotein. Cardiac manifestations in MTCD are rare. EXEGESIS: A 58 years old man was admitted for mild fever, a impairment of the general status, muscular pain and a Raynaud's phenomenon. Biologic abnormalities were an inflammatory syndrome, elevated serum CPK and high rate anti-RNP antibodies. Diagnosis of mixed connective tissue disease was made. Shortly after, a Wenckebach atrioventricular block occurred. Systemic corticosteroids were efficient. CONCLUSION: Heart blocks are rarely described in MCTD. Three cases have been reported. It's a systemic complication resulting of an inflammatory process often responsive to steroids.

[Echographic diagnosis of systolic murmur among 280 young French militaries. Implications for the expertise in military medicine]. / Diagnostic échographique d'un souffle cardiaque systolique au sein d'une population de 280 jeunes militaires français. Implications en médecine d'expertise militaire.

UNLABELLED: Clinically discovering a systolic murmur is frequent among the young military population. When this murmur does not sound benign, a transthoracic echocardiography (TTE) is made to detect any cardiopathy, which could cause sudden cardiac death. The aim of this study was to evaluate the interest of systematic TTE in the assessment of any cardiac systolic murmur (CSM) among militaries. METHODS: We ran a retrospective monocentric study in the "Clermont-Tonnerre" military hospital in Brest. We included all patients sent for TEE, aged 15 to 30 years old, from the 1st January 2010 until the 31st July 2013. RESULTS: Two hundred and eighty TTES assessing CSM were performed. We found 28/280 (10%) echocardiographic abnormalities: 13 were bicuspid aortic valves (4.6%), 6 were ventricular septal defects (2.15%), 3 were atrial septal defects (1.07%), 4 were mild mitral regurgitations (1.43%), one mild pulmonary stenosis (0.35%) and one aortic stenosis (0.35%). No hypertrophic cardiomyopathy was found. Concerning military expertise, 11 (3.92%) patients among these 28 with abnormal TEE were considered unfit for work or "fit for work with limitations". CONCLUSION: Assessing a cardiac systolic murmur with TEE lead to the diagnosis of a cardiomyopathy in 10% of the case. This study enhances the importance of systematic TEE when a CSM is detected in the young military, in order to determine if those soldiers can still fulfill their military duty.

[Encephalopathy and acute renal failure during acyclovir treatment]. / Encéphalopathie et insuffisance rénale aiguë au cours d'un traitement par aciclovir.

INTRODUCTION: Adverse neurological and renal effects can occur in patients taking acyclovir. Neurotoxicity of acyclovir results from an accumulation of the antiviral and its metabolites in the bloodstream. This can be observed in the elderly or in patients with chronic renal failure, generally in dialysis patients. Acute renal failure results from intratubular crystallization of acyclovir. OBSERVATION: A 78-year-old right-handed woman was admitted in an emergency setting for aphasia. Analysis of the cerebrospinal fluid was normal, but herpetic meningo-encephalitis was suspected and intravenous treatment was initiated with acyclovir. After the second infusion, the patient began to suffer from visual hallucinations, confusion and acute renal failure. Herpes PCR was negative in the cerebrospinal fluid, and the adverse drug reactions regressed completely after 72 hours. CONCLUSION: Renal function has to be checked often in patients given acyclovir for appropriate dose titration. Patients recover prompt from the adverse effects at drug withdrawal.

The risk of venous thromboembolism in renal cell carcinoma patients with residual tumor thrombus.

BACKGROUND: The clinical importance of tumor thrombus in patients with renal cell carcinoma is unknown. We sought to determine the long-term risk of venous thromboembolism (VTE) in patients with residual tumor thrombus postextraction, and to evaluate the impact of residual tumor thrombus on overall survival. PATIENTS/METHODS: A cohort study of patients with stage III-IV renal cell carcinoma undergoing nephrectomy was undertaken. The primary endpoint was the risk of VTE during a 2-year follow-up period. The secondary endpoint was 2-year overall survival. RESULTS: A total of 170 surgical renal cell carcinoma patients were included, 97 (57.1%) of whom had tumor thrombus. Patients with residual tumor thrombus following surgery had a higher risk of developing VTE than those with complete tumor thrombus resection (hazard ratio [HR] 8.7, 95% confidence interval [CI] 1.7-43.4) and no tumor thrombus (HR 6.5, 95% CI 1.7-24.7). Patient with residual tumor thrombus did not have worse overall survival than those with tumor thrombus completely resected or those without tumor thrombus. CONCLUSIONS: The presence of residual tumor thrombus is an important risk factor for VTE among renal cell carcinoma patients.