Background: It is unclear whether thrombophilia testing provides any further information on risk of recurrence or guidance in management of patients with a first episode of idiopathic venous thromboembolism(VTE). Furthermore, after the introduction to clinical practice of clinical prediction rules, thrombophilia screening could be less relevant in anticoagulation decision making. We assessed the potential impact of thrombophilia screening on the decision of maintaining anticoagulation beyond the initially planned anticoagulation period in patients with an unprovoked VTE, before and after the introduction of a clinical prediction rule into practice.Patients/Methods: We conducted a single center, retrospective cohort study of consecutive patients with a diagnosis of unprovoked VTE, including a study period of 12 years. Two groups were compared, before and after 2008.Results: We included 1033 patients of which 85.2% were tested for thrombophilia and 26.2% were identified with any thrombophilia. A similar proportion of patients continued on anticoagulation after 6 months (54.1% vs 57.1%, respectively). The proportion of patients continuing anticoagulation based on the thrombophilia screen remained small (13.9% vs 12.7%, respectively). Continuing anticoagulation beyond the initial period planned resulted in a 75% risk reduction in VTE recurrence, independent of the presence of thrombophilia (HR 0.25, 95% CI 0.12-0.55; P < 0.001).Conclusions: Thrombophilia screening continues to have little relevance in clinical decision making for anticoagulation. Prolonging anticoagulation beyond 6 months in an at-risk population decreased the risk of VTE recurrence regardless of their thrombophilia status. (C) 2016 Elsevier Ltd. All rights reserved.

SUMMARYDuring the first trimester of human pregnancy, cytotrophoblasts proliferate within the tips of the chorionic villi to form cell columns that anchor the placenta to the uterus. This migration coincides with a widespread change in the adhesion molecule repertoire of these trophoblasts. Kisspeptin and its receptor, KISS1R, are best known as potent triggers of gonadotropin‐releasing hormone secretion. The kisspeptin/KISS1R signaling system is also highly expressed in the human placenta, where it was demonstrated to inhibit extra‐villous trophoblast (EVT) migration and invasion in vitro. Here we show that kisspeptin, in a dose‐ and time‐dependent manner, induces increased adhesion of human EVTs to type‐I collagen, a major component of the human placenta. This increased adhesion was both rapid and transient, suggesting that it likely occurred through the activation of KISS1R secondary effectors such as PKC and ERK, which underwent rapid and transient kisspeptin‐dependent activation in EVTs. We then showed that inhibition of both PKC and ERK1/2 attenuated the kisspeptin‐dependent increase in EVT adhesion, suggesting that these molecules are key positive regulators of trophoblast adhesion. We therefore propose that kisspeptin/KISS1R signaling potentiates EVT adhesion to type‐I collagen via “inside‐out signaling.” Furthermore, kisspeptin treatment increased mouse blastocyst adhesion to collagen I, suggesting that kisspeptin signaling is a key regulator of trophoblast function during implantation as well as early placentation. Mol. Reprod. Dev. 81: 42–54, 2014. © 2013 Wiley Periodicals, Inc.

To the Editor: Alcoholic hallucinosis is a well-known phenomenon consisting of vivid auditory hallucinations that begin immediately following the reduction or cessation of alcohol consumption.1 The estimated prevalence of alcohol hallucinosis is 7.4% among alcohol-dependent inpatients,2 a subset of whom will develop chronic hallucinations that resemble paranoid schizophrenia.3 Here, we present a case of chronic alcohol hallucinosis previously diagnosed and treated as schizophrenia. Case report. Mr A, a 32-year-old man, was admitted recently to the inpatient psychiatry ward after several visits to the outpatient psychiatry service. Mr A complained of auditory pseudohallucinations that began in adolescence. These were described as 3 adult male voices with origin inside the head that are ego-dystonic and frequently attempt to persuade him to hurt himself. His hallucinatory experiences were identified during an inpatient stay for alcohol rehabilitation about 5 years earlier at another center. At the time of discharge, he was given the diagnosis of schizophrenia (DSM-IV-TR criteria) and was started on clozapine treatment. Mr A began drinking alcohol to excess at the age of 14 years, with self-report ranging from 7 to 48 standard drinks per day. Mr A smokes tobacco daily and cannabis occasionally and has been a heavy user of several other substances. Previously known treated diseases were unremarkable and stable. Mr A’s family history is significant for psychiatric illness, including mood disorders, substance use disorders, and suicide. There was no evidence of thought disorder. Results of physical examination and broad laboratory screens were unremarkable. Findings of noncontrast magnetic resonance imaging were similarly unremarkable. Outcomes of neuropsychological testing were remarkable for poor verbal memory, both immediate and delayed. A previous psychological report was obtained and noted third- to fifth-grade capabilities in reading, spelling, mathematics, and verbal comprehension as well as strong visuospatial ability. Clozapine therapy was ceased by slow taper. Mr A was monitored closely but was unable to notice any subjective changes. The nursing and medical staff were similarly unable to note any objective changes. Mr A was discharged 16 days following the cessation of clozapine therapy. He will be assessed for a therapeutic trial of a newer neuroleptic agent such as risperidone or lurasidone and anticraving medications such as acamprosate. Here, we present a unique case of what we believe to be persistent alcoholic hallucinosis occurring for many years. Our patient was initially diagnosed with schizophrenia; however, upon further inspection, we do not believe this to be the case. He has insight into his illness and has no evidence of thought disorder or negative symptoms, and his illness has not run the typical course of schizophrenia. Furthermore, he lacks the characteristic memory loss and confabulation typical of Korsakoff’s psychosis. Misdiagnosis resulted in exposing the patient to the risks of superfluous pharmacotherapy, in this case, metabolic syndrome, cardiac arrhythmias, and blood dyscrasia. We suggest that alcoholic hallucinosis should be suspected in patients who present with auditory hallucinations and significant alcohol use history and who are refractory to best-practice pharmacotherapy for schizophrenia.

To the Editor: Asenapine, marketed as Saphris, is a relatively new psychopharmaceutical agent approved in 2009 for the treatment of acute mania or mixed episodes in the context of bipolar I disorder as well as schizophrenia.1 Asenapine has a unique receptor profile and has been shown to be effective and well tolerated by patients experiencing an acute manic episode.2,3 Adverse effects of long-term use are not yet known, but the incidence of cardiovascular disease and diabetes is expected to be substantially lower than with older neuroleptic agents.4 Here we present the first published case of asenapine overdose of known quantity and route. Case report. Mr A, a 49-year-old man, presented to the emergency department (ED) after having ingested 74 tablets of asenapine in the ED parking lot several minutes previously. He was currently undergoing a course of electroconvulsive therapy (ECT), having been diagnosed with bipolar disorder with mixed episodes and borderline personality disorder (both according to DSM-IV-TR criteria) and was 1 day postdischarge from the inpatient psychiatry unit. The quantity of ingested tablets was confirmed by the patient’s mental health outreach worker after examination of packages in the patient’s car. Mr A had made previous suicide attempts using ibuprofen and clonazepam in overdose. Because the ED physician was unfamiliar with asenapine toxicity, the patient was admitted to the intensive care unit (ICU) for observation. Examination in the ED and ICU revealed a drowsy, yet easily rousable man who was unwilling to answer questions. Blood pressure was maintained at 149/88 mm Hg, pulse was 99 bpm, respiratory rate was 19/min, oxygen saturation was 98% on room air. Findings of cardiac, respiratory, and abdominal examinations were unremarkable. Urine drug screen was positive for amphetamines, marijuana, opiates, and benzodiazepines. There was no nausea or vomiting, and activated charcoal was not administered. Electrolytes, troponin I, international normalized ratio, complete blood cell count, and creatinine were all within normal laboratory values. Electrocardiogram showed only normal sinus rhythm. Mr A was determined to be medically stable by the ICU physician, and care was transferred to the psychiatric unit approximately 24 hours later. This patient’s bilateral ECT course was continued for a total of 10 treatments with good therapeutic effect and minimal side effects. He was subsequently discharged and has been followed by the outpatient psychiatry service, has received cognitive-behavioral therapy to address coping skills, and is doing well as of last contact. Here we present the first documented case of asenapine overdose with a known quantity and route of administration. Six previous cases of asenapine overdose have been noted at doses up to 400 mg, but the exact dose and route were not known.4 Similar to those cases, no specific adverse drug effects were observed. Notably, the bioavailability of asenapine is less than 2% when administered orally, compared to approximately 35% when given sublingually; this patient did not administer his overdose sublingually.4 Thus, despite ingesting 740 mg of asenapine, he was exposed to only the equivalent of 4 sublingual doses. Despite the large number of tablets and considerable concern from the ED, asenapine appears to be safe in overdose situations, likely due to its pharmacokinetic profile.

Abstract Abstract 546 The optimal strategy for peri-procedural warfarin management in patients with venous thromboembolic disease (VTE) is unknown because most studies to date have included small proportions of VTE patients. Guidelines are largely based on expert opinion and recommend low-molecular-weight heparin (LMWH) bridging in patients at high or moderate risk for VTE. LMWH bridging may be associated with an increased bleeding risk, which if occurs, would result in temporary cessation of anticoagulation (AC) potentially leading to a paradoxical increased thrombotic risk. We conducted a single-center retrospective cohort study to examine the effectiveness of conservative peri-procedural AC management in VTE (DVT or PE) patients. We included all patients from our institution's thrombosis unit between 1993 and 2011 who required peri-procedural AC management for planned procedures. The thrombosis unit has, on average, 800 patients on chronic AC for VTE. Patients were excluded if they had other indications for AC, had an acute VTE <90 days before the procedure, or had no follow-up after the procedure. Our centre uses a conservative bridging strategy in these patients consisting of holding warfarin 5 days before the procedure without administering LMWH. Postoperatively all patients resume warfarin as soon as they can swallow. For ambulatory procedures no LMWH is given after the procedure, whereas patients undergoing in-hospital procedures are usually given prophylactic LMWH starting the morning after surgery until discharge or when the INR is therapeutic, whichever occurs first. The primary outcome was incidence of VTE within 90 days of the procedure. Secondary outcomes were 90-day incidence of major and total bleeding and all-cause mortality. Confidence intervals for proportions were calculated using the Wilson's score method. Groups were compared using χ2 or Fisher's exact tests. Survival analysis was done using the Kaplan-Meier method. Two-sided p values ≤0.05 were considered statistically significant. During the study period there were 634 procedures in 416 patients (47.4% males). The mean age was 64.9 years (SD 15.8) and 79.1% of patients had idiopathic VTE. There were 156 procedures (24.6%) completed in-hospital. Pre- and post-procedure bridging was used in 15 (2.4%) and 153 (24.1%) procedures, respectively. The 90-day cumulative incidence of VTE was 0.63% (95% CI 0.25–1.61). The VTE events were 4 DVTs (postoperative day 3, 29, 41, 43) with no associated mortality. The 90-day cumulative incidence of major and total bleeding events was 1.58% (95% CI 0.86–2.88) and 3.47% (95% CI 2.30–5.20), respectively. All-cause mortality rate was 0.63% (95% CI 0.25–1.61); one patient died from a myocardial infarction 3 days after an abdominal aortic aneurysm repair, a second died from an ischemic stroke the morning of a colonoscopy and 2 patients had non-VTE related deaths. The effects of type of procedure and use of bridging on outcomes are shown in Table 1. The use of pre- or post-procedure bridging was not associated with VTE or bleeding. There were significantly more total bleeding events with inpatient procedures. There was a significant correlation between bleeding and VTE events: 13.6% of patients with any bleeding and 30% with major bleeding developed a VTE complication compared with 0.2% of those without bleeding. Spearman's correlation coefficients were 0.311 and 0.470, respectively (p<0.001). Two postoperative DVTs (50%) developed after warfarin was held for an extended period of time (1 major bleed, 1 neurosurgical complication). Conservative peri-procedural AC management in VTE patients on warfarin for at least 3 months results in a low risk of thrombotic and bleeding events. A randomized controlled trial in chronically anticoagulated VTE patients is needed to provide definitive conclusions but a conservative approach appears promising.Effect of Type of Procedure and Bridging on OutcomeOutcomeVTE N (%)No (N=630)Yes (N=4)PInpatient procedure154 (24.4%)2 (50%)0.255Pre-procedure bridging15 (2.4)0 (0)1Post-procedure bridging151 (24)2 (50)0.247Total Bleeding N (%)No (N=612)Yes (N=22)Inpatient procedure146 (23.9)10 (45.5)0.039Pre-procedure bridging15 (2.5)0 (0)1Post-procedure bridging147 (24)6 (27.3)0.800Major bleeding N (%)No (N=624)Yes (N=10)Inpatient procedure153 (24.5)3 (30)0.714Pre-procedure bridging15 (2.4)0 (0)1Post-procedure bridging151 (24.2)2 (20)1 Disclosures: Lazo-Langner: Pfizer Inc.: Honoraria; Leo Pharma: Honoraria.

Kisspeptin and its receptor, GPR54, are major regulators of the hypothalamic-pituitary-gonadal axis as well as regulators of human placentation and tumor metastases. GPR54 is a G(q/11)-coupled G protein-coupled receptor (GPCR), and activation by kisspeptin stimulates phosphatidy linositol 4, 5-biphosphate hydrolysis, Ca(2+) mobilization, arachidonic acid release, and ERK1/2 MAPK phosphorylation. Physiological evidence suggests that GPR54 undergoes agonist-dependent desensitization, but underlying molecular mechanisms are unknown. Furthermore, very little has been reported on the early events that regulate GPR54 signaling. The lack of information in these important areas led to this study. Here we report for the first time on the role of GPCR serine/threonine kinase (GRK)2 and beta-arrestin in regulating GPR54 signaling in human embryonic kidney (HEK) 293 cells, a model cell system for studying the molecular regulation of GPCRs, and genetically modified MDA MB-231 cells, an invasive breast cancer cell line expressing about 75% less beta-arrestin-2 than the control cell line. Our study reveals that in HEK 293 cells, GPR54 is expressed both at the plasma membrane and intracellularly and also that plasma membrane expression is regulated by cytoplasmic tail sequences. We also demonstrate that GPR54 exhibits constitutive activity, internalization, and association with GRK2 and beta- arrestins-1 and 2 through sequences in the second intracellular loop and cytoplasmic tail of the receptor. We also show that GRK2 stimulates the desensitization of GPR54 in HEK 293 cells and that beta-arrestin-2 mediates GPR54 activation of ERK1/2 in MDA-MB-231 cells. The significance of these findings in developing molecular-based therapies for treating certain endocrine-related disorders is discussed.