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Background The outcome of cancer patients with venous thromboembolism (VTE) may differ according to gender. Methods We used the RIETE database to compare the rate of VTE recurrences, major bleeding and mortality in patients with lung, colorectal, pancreatic, hematologic or gastric cancer during the course of anticoagulation, according to gender. Results As of January 2016, 11,055 patients with active cancer were enrolled: 1,727 had lung cancer, 1,592 colorectal, 840 hematologic, 517 pancreatic and 459 had gastric cancer. Compared with men ( N = 3,130), women ( N = 2,005) were more likely to have colorectal, pancreatic or hematologic cancer, and less likely to have lung cancer. Most patients (91%) were initially treated with low-molecular-weight heparin (LMWH), but women received higher daily doses per body weight. Then, 66% kept receiving LMWH for long-term therapy. During the course of anticoagulation, 302 patients developed recurrent VTE, 220 bled and 1,749 died. Compared with men, women had a similar rate of VTE recurrences or major bleeding, and a lower mortality (risk ratio [RR]: 0.90; 95% CI: 0.82–0.99). When separately comparing outcomes according to cancer site, women with lung cancer had a lower mortality (RR: 0.79; 95% CI: 0.70–0.92), those with colorectal cancer had a higher mortality (RR: 1.25; 95% CI: 1.02–1.54) and those with gastric cancer had a higher rate of VTE recurrences than men (RR: 2.47; 95% CI: 1.04–5.89). Conclusions VTE women with lung, colorectal, pancreatic, haematological or gastric cancer experienced a similar outcome during the course of anticoagulant therapy than men with similar cancers. [ABSTRACT FROM AUTHOR]

Introduction: Patients with cancer are at higher risk of venous thromboembolism (VTE) than the general population as the malignancy itself and treatment modalities, including medication and surgery, contribute to the risk of developing VTE. Furthermore, patients with cancer developing VTE have a worse prognosis than those without cancer. There are no multicentre prospective data on the occurrence and treatment of VTE in patients with cancer in Japan, and data on the outcomes, complications and incidence of VTE in these patients have not been reported. In addition, Japanese patients with cancer are traditionally treated with unfractionated heparin or warfarin; however, the use of direct oral anticoagulants, which became available in 2014, has not been sufficiently examined in this patient group. Therefore, this multicentre, prospective registry has been designed to capture VTE data from Japanese patients presenting with six cancer types., Methods and Analysis: This registry will enrol 10 000 patients with colorectal, lung, stomach, breast, gynaecological (including endometrial, cervical, ovarian, fallopian tube and peritoneal) or pancreatic cancer between March 2017 and March 2019 and follow them for 1 year. We plan to collect data on the incidences of symptomatic VTE, bleeding events, stroke, systemic embolic events, incidental VTE requiring treatment in patients, overall survival and symptomatic VTE event-free survival., Ethics and Dissemination: All patients will provide written informed consent. Data will remain anonymous and will be collected using an online electronic data capture system. Study protocol, amendments and informed consent forms will be approved by the institutional review board/independent ethics committee at each site prior to study commencement. Results will be disseminated at national meetings and published in peer-reviewed journals., Trial Registration Number: UMIN000024942., Competing Interests: Competing interests: All authors have received personal fees from Daiichi Sankyo during the conduct of study. KF has received research grants from Daiichi Sankyo. TK and KI are employees of Daiichi Sankyo., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Heparin is a highly sulfated glycosaminoglycan (GAG) of natural origin used as an anticoagulant and antithrombotic drug. These properties are principally based on the binding and activation of antithrombin (AT) through the pentasaccharide sequence GlcNAc/NS,6S-GlcA-GlcNS,3,6S-IdoA2S-GlcNS,6S (AGA*IA). Literature data show that the population of the 2 S 0 ring conformation of the 2-O-sulfo-α-l-iduronic acid (IdoA2S) motif correlates with the affinity and activation of AT. It was recently demonstrated that two synthetic AGA*IA-containing hexasaccharides (one G unit added at the reducing end), differing in the degree of sulfation of the IdoA unit, show comparable affinity and ability to activate AT, despite a different conformation of the IdoA residue. In this paper, the binding of these two glycans to AT was studied by isothermal titration microcalorimetry (ITC), transferred (tr-) NOESY, saturation transfer difference (STD) NMR spectroscopy and molecular dynamics (MD) simulations. Results indicated that both the IdoA2S and the IdoA units assume a 2 S 0 conformation when bound with AT, and so present a common binding epitope for the two glycans, centred on the AGA*IA sequence., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This review describes epidemiology of thromboembolic disease in China and abroad, evaluates trends in the development of anticoagulant drugs, and analyzes the market situation based on large amounts of accumulated data. Specifically, we describe advances in clinical application of anticoagulants and analyze the most commonly used anticoagulants in the market systematically., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Epistaxis is an active nose bleeding with a population occurrence of approximately 60%. Although epistaxis is a common clinical complaint, the majority of the cases are benign and caused by local induced factors (e.g., trauma and local inflammation). Nevertheless, it is also recognised that epistaxis can be induced after some drugs intake., Aims: Due to the increasing use of drugs or drug combinations that potentially may induce epistaxis, this review aims to alert healthcare professionals for this often neglected adverse drug effect and its possible complications., Methods: A comprehensive literature search was performed on PubMed and Google Scholar databases, considering the literature published from January 1985 to December 2015, using medical terms related to drug-induced epistaxis, nosebleeds and nasal blood supply., Results and Discussion: As expected, anticoagulant and antiplatelet drugs are the main pharmacotherapeutic agents associated with epistaxis, particularly warfarin, dabigatran, rivaroxaban and aspirin. However, it was reported that some selective serotonin reuptake inhibitors, intranasal corticosteroids, certain antibiotics and other drugs or drug associations can also be responsible for nosebleeds. Although most of these epistaxis episodes are mild to moderate, being spontaneously reversed or requiring only minor medical approaches to control it, there are several case reports, as well as retrospective and prospective studies, documenting severe epistaxis episodes after specific medicines intake. In these cases, some invasive medical interventions are demanded to manage the bleeding and avoid life-threatening consequences., Conclusion: This work provides an integrated and comprehensive review on drug-induced epistaxis bridging the gap in the current scientific literature addressing this topic. Therefore, the scientific information gathered and discussed will be valuable to raise awareness among doctors and pharmacists for this drug-related problem, as well as to promote their active pharmacovigilance and reinforce patient education., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

In patients who present with pulmonary embolism, right-heart thrombus is a rare condition that is associated with increased mortality rates, compared with pulmonary embolism alone. Thrombolytic therapy has been associated with a survival benefit in previous studies of pulmonary embolism arising from right-heart thrombus. However, older patients have been excluded from such studies because thrombolysis places them at excessively high risk of bleeding. We present a case, in a 92-year-old woman, of pulmonary embolism arising from right-heart thrombi that we successfully treated with heparin. [ABSTRACT FROM AUTHOR]

Acute upper gastrointestinal haemorrhage due to peptic ulcer bleeding remains an important cause of emergency presentation and hospital admission. Despite advances in many aspects of management, peptic ulcer bleeding is still associated with significant morbidity, mortality, and healthcare costs. Comprehensive international guidelines have been published, but advances as well as controversies continue to evolve. Important recent advances include the evidence supporting a more restrictive transfusion strategy aiming for a target haemoglobin of 70-90 g/l. Comparative studies have confirmed that the Glasgow-Blatchford score remains the most useful score for predicting the need for intervention as well as for identifying the lowest-risk patients suitable for outpatient management. New scores, including the AIMS65 and Progetto Nazionale Emorragia Digestiva score, may be more accurate in predicting mortality. Pre-endoscopy erythromycin appears to improve outcomes and is probably underused. High-dose oral proton pump inhibition (PPI) for 11 days after PPI infusion is advantageous in those with a Rockall score of 6 or more. Oral is as effective as parenteral iron at restoring haemoglobin levels after a peptic ulcer bleed and both are superior to placebo in this respect. Within endoscopic techniques, haemostatic powders and over-the-scope clips can be used when other methods have failed. A disposable Doppler probe appears to provide more accurate determination of both rebleeding risk and the success of endoscopic therapy than purely visual guidance. Non- Helicobacter pylori , non-aspirin/non-steroidal anti-inflammatory drug ulcers contribute an increasing percentage of bleeding peptic ulcers and are associated with a poor prognosis and high rebleeding rate. The optimal management of these ulcers remains to be determined., Competing Interests: Competing interests: The author declares that he has no competing interests.No competing interests were disclosed.No competing interests were disclosed.

Despite the immense growth in extracorporeal life support (ECLS) technology and experience, opportunity remains to better characterize the pharmacotherapeutic considerations during ECLS. Analgosedation can be particularly challenging in the ECLS population due to in drug-circuit interactions that may lead to decreased systemic concentrations and pharmacodynamic effect. ECLS also requires the use of antithrombotic agents to mitigate the prothrombotic state created by the artificial surface in the ECLS circuit. There are a number of coagulation monitoring tests available. However, optimal monitoring and management in ECLS has not been established. Heparin continues to be the anticoagulant of choice for most ECLS centers, however, there is growing interest in the use of parenteral direct thrombin inhibitors (DTI) in this population. Advances in understanding pharmacotherapeutic management have not kept up with the technological advances in this population. More investigation is warranted to gain a greater understanding of the pharmacotherapeutic implications, facilitate standardized evidence-based practices, and improve patient centered outcomes., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Essentials Prothrombin and partial thromboplastin time (PT/PTT) measure direct oral anticoagulants (DOACs). PT, PTT and specific tests for DOACs were performed on patients treated for atrial fibrillation. Normal PT/PTT don't exclude DOAC activity and their prolongation doesn't confirm DOAC action. The use of PT or PTT to evaluate DOAC activity could cause dangerous misinterpretations., Summary: Background Prothrombin time (PT) and activated partial thromboplastin time (APTT) have been proposed to measure the effect of oral anti-activated factor X (FXa) or anti-activated FII drugs, respectively. Aims To evaluate the relationships and responsiveness of PT and APTT versus direct oral anticoagulant (DOAC) concentrations measured with specific coagulation tests performed with different platforms in four Italian anticoagulation clinics. Methods Six hundred and thirty-five patients with atrial fibrillation participated in the study: 240 were receiving dabigatran, 264 were receiving rivaroxaban, and 131 were receiving apixaban. Blood was taken at trough and peak within the first month (15-25 days) of treatment. PT, APTT, diluted thrombin time (dTT) calibrated for dabigatran and anti-FXa calibrated for rivaroxaban or apixaban were determined. Results For dabigatran, the correlation between APTT and dTT ranged from r = 0.80 to r = 0.62. For rivaroxaban, the correlation between the anti-FXa assay and PT ranged from r = 0.91 to r = 0.73. For apixaban, the correlation between the anti-FXa assay and PT was lower than for the two other drugs (r = 0.81 to r = 0.54). Despite the above significant correlations, the responsiveness of PT or APTT was relatively poor. A discrepancy between global testing and DOAC plasma concentrations was shown in a considerable proportion of patients, depending on the platform and drug, with values ranging from 6% to 62%. Conclusions Overall, poor responsiveness of the screening tests to DOAC concentrations was observed. PT and APTT normal values cannot exclude DOAC anticoagulant activity, and PT or APTT prolongation is not always associated with DOAC anticoagulant effect as determined with specific tests., (© 2016 International Society on Thrombosis and Haemostasis.)

Introduction: Brazil is among the first countries approving the commercialization and clinical use of biosimilar enoxaparins. Our research group has performed quality control assessments of these drugs over the last decade. Areas covered: We have not found noticeable differences between Brazilian biosimilar enoxaparins and the original product regarding their physicochemical properties, disaccharide composition, anticoagulant activity, bioavailability and safety. Expert commentary: In spite of clinical and pharmacological advantages of enoxaparin, subcutaneous formulations of unfractionated heparin are employed by the Brazilian public health system for prevention and treatment of thromboembolism. The underuse of both original and biosimilar enoxaparins in Brazil directly correlates with their high cost.

Direct oral anticoagulants (DOACs) or non-vitamin K oral anticoagulants (NOACs) are increasingly used in the prevention of recurrent venous thromboembolism (VTE), including that associated with thrombophilia. The efficacy of DOACs in thrombophilic patients, especially those with severe trombophilia or triple positive antiphospholipid syndrome (APS) with arterial thromboembolic events, remains controversial. Most case reports and case series indicate that DOACs are an attractive therapeutic option in the vast majority of these patients at high risk of recurrent VTE with more concerns raised in high-risk APS patients and these deficient in protein S (PS). Adherence to DOACs is of paramount importance in these patients. In this review we presented available data on the management of patients with thrombophilia using rivaroxaban, dabigatran or apixaban at standard doses. Moreover, we also demonstrated the overall effects of DOACs on coagulation tests, particularly those determined during thrombophilia screening such as lupus anticoagulant, antithrombin, protein C, PS, activated protein C ratio. Despite the paucity of data from randomized studies, the current evidence supports the use of DOACs in thrombophilia, especially those who prefer such treatment or have unstable anticoagulation with vitamin K antagonists or unacceptable adverse events while using these drugs.

Background: The mechanisms behind the association of atrial fibrillation (AF) and dementia are unknown. We previously found a significantly increased risk of dementia in AF patients taking warfarin with a low percentage of time in therapeutic range. The purpose of this study was to determine the extent to which AF itself increases dementia risk, in addition to long-term anticoagulation exposure., Methods and Results: A total of 10 537 patients anticoagulated with warfarin (target INR 2-3), managed by the Clinical Pharmacist Anticoagulation Service with no history of dementia were included. Warfarin indication was for AF (n=4460), thromboembolism (n=5868), and mechanical heart valve(s) (n=209). Patients in the latter 2 categories were included only if they had no prior history of AF. The primary outcome was dementia. Patients with AF were older and had higher rates of hypertension, diabetes, heart failure, and stroke. AF patients experienced higher rates of total dementia (5.8% versus 1.6%, P<0.0001), Alzheimer disease (2.8% versus 0.9%, P<0.0001), and vascular dementia (1.0% versus 0.2%, P<0.0001). A propensity analysis of 6030 patients was performed to account for baseline demographics differences. Long-term risk of dementia remained significant in AF patients compared with matched non-AF patients (total dementia: hazard ratio [HR]=2.42 [1.85-3.18], P<0.0001; Alzheimer: HR=2.04 [1.40-2.98], P<0.0001; senile: HR=2.46 [1.58-3.86], P<0.0001). Low percent therapeutic range compared with a higher percent therapeutic range was associated with dementia risk in both AF (26-50% versus >75%: HR=2.51, P=0.005) and non-AF groups (≤25% versus >75%: HR=3.92, P<0.0001)., Conclusions: The presence of AF significantly increases risk of dementia, including Alzheimer's disease, compared with matched patients receiving warfarin anticoagulation for other reasons. Quality of anticoagulation management remains an important risk factor for dementia in all patients., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Due to its constantly growing incidence, obesity is an increasingly serious social and medical problem. Available data on the use of novel oral anticoagulants in morbidly obese and obese patients are very limited. However, we tried to summarize the available knowledge on the use of anticoagulants in this subpopulation of patients in everyday clinical practice. Studies on the clinical use of anticoagulants provide a poor basis for any adjustment of doses in obese patients as compared to patients with normal body weight. In our opinion, further studies are required in this particular population.

The anticoagulant drugs reduce the chance of formation of blood clots in the blood vessels and the heart. They are particularly important in the prevention and treatment of venous thrombosis, pulmonary embolism, cardiac arrhythmias, after myocardial infarction and after heart valve replacement. Anticoagulant treatment can have significant side effects, and it is necessary to supervise it by measuring. The measurement result is expressed as INR (International Normalized Ratio). For most of the patients the target value of INR ranges between 2.0 and 3.0. When INR is below 2.0, the risk of clot formation increases and when it is over 3.0 the risk of bleeding increases. The education about potential adverse complications and method of administration of the medicine is important in order to avoid adverse reactions in patients. The education begins immediately upon the introduction of the drug during the stay of a patient in the ward. The leading nursing diagnosis is: Patient's ignorance about specifics of administration of oral anticoagulant drugs due to the lack of specific knowledge. The objectives relating to the nursing diagnosis are that patient will: understand the importance of regular taking antocoagulant drugs and shall comply with the instructions; regularly control the laboratory parameters - INR, PV; regularly monitor secretions (appearance, color); know why he must be careful in consuming foods rich in vitamin K, which foods they are; know what conditions can reduce or increase the drug effects; promptly and properly react in case of occurrence of complications. [ABSTRACT FROM AUTHOR]

Direct oral anticoagulants may be effective and safe for treatment of venous thromboembolism (VTE) in cancer patients, but they have not been compared with low-molecular-weight heparin (LMWH), the current recommended treatment for these patients. The Hokusai VTE-cancer study is a randomised, open-label, clinical trial to evaluate whether edoxaban, an oral factor Xa inhibitor, is non-inferior to LMWH for treatment of VTE in patients with cancer. We present the rationale and some design features of the study. One such feature is the composite primary outcome of recurrent VTE and major bleeding during a 12-month study period. These two complications occur frequently in cancer patients receiving anticoagulant treatment and have a significant impact. The evaluation beyond six months will fill the current gap in the evidence base for the long-term treatment of these patients. Based on the observation that the risk of recurrent VTE in patients with active cancer is similar to that in those with a history of cancer, the Hokusai VTE-cancer study will enrol patients if whose cancer was diagnosed within the past two years. In addition, patients with incidental VTE are eligible because their risk of recurrent VTE is similar to that in patients with symptomatic disease. The unique design features of the Hokusai VTE-cancer study should lead to enrolment of a broad spectrum of cancer patients with VTE who could benefit from oral anticoagulant treatment.

This case report describes how new tools and technologies can drive a different approach in the management of arrhythmic patients. An unknown and asymptomatic atrial flutter was detected by the atrial sensor mounted in a single lead implantable cardioverter defibrillator. Moreover daily remote monitoring of the device allowed early notification and prompt clinical reaction. Anticoagulant therapy onset, radiofrequency ablation and the following anticoagulant therapy removal were driven by the device data transmissions.

Introduction: Dabigatran etexilate is used for preventing blood clots and tends to replace older anticoagulants in many of their indications. However, the 'one dose fits all' policy is subject to criticism. Recent findings assert the anxiety of the scientific community concerning the pharmacokinetic properties of dabigatran etexilate, that is, an important interindividual variability including an important genetic variant with a significant dependence of the renal function as route of elimination., Areas Covered: This meta-opinion provides an overview of the current knowledge and evidence on the dose tailoring of dabigatran etexilate. It also discusses the remaining challenges to benefit from this perspective strategy to enhance the benefit-risk balance of dabigatran etexilate. Data were searched in the published literature and on regulatory agencies' websites. Additionally, unpublished data were searched and discussed., Expert Opinion: Causality between dabigatran exposure and bleeding risk is now established and recommendations on how to best estimate the drug exposure are published. Additionally, simulating studies revealed that a dose adaptation based on dabigatran plasma concentration estimations could improve the benefit-risk profile of the drug. This accumulating evidence suggests that some patients under dabigatran etexilate may benefit from a tailoring of the dose beyond the ones already proposed by the manufacturer.

Background: According to the ISTH guidelines for lupus anticoagulant (LAC) testing, the second step in the three-step procedure (screening, mixing, and confirmation) is the mixing test, which improves the discrimination between the presence of an inhibitor and coagulation factor deficiencies such as those occurring in patients receiving vitamin K antagonists (VKAs)., Objectives: From a retrospective analysis of dilute Russell viper venom (dRVVT) results, we evaluated the impact of the mixing test result on the interpretation of LAC positivity., Methods: We interpreted the dRVVT clotting times with and without taking into account the results of the mixing test in a patient population with prolonged screening test (n = 267) with special attention to the patients receiving VKAs., Results and Conclusions: The number of samples classified as 'LAC positive' differed substantially depending on the method of interpretation; 170 and 235 of 267 samples were classified as LAC positive with the three- and two-step procedure, respectively. Discrepancy between the two-step (without mixing step) and the three-step procedure was due to not including a mixing test and was more pronounced in the VKA patient population. Screen/confirm ratios carried out on a 1:1 mix of patient and normal pooled plasma (NPP) gave a lower incidence of 59 of 267. We advise continuing to perform mixing test to avoid false-positives. In patients with discrepant results between the two- and three-step dRVVT interpretation, mainly observed in VKA-treated patients, we advise retesting of the patients preferable beyond the period of anticoagulant therapy and additional testing for anti-beta2GPI and/or anti-cardiolipin antibodies., (© 2015 International Society on Thrombosis and Haemostasis.)

Background: Adherence to American College of Chest Physicians (CHEST) guidelines for treatment of acute venous thromboembolism (VTE) has not been formally assessed in the United States, specifically in the subset of patients with renal impairment., Objective: Evaluate adherence to CHEST VTE treatment guidelines., Methods: This retrospective cohort study evaluated patients with acute VTE between January 1, 2010, and December 31, 2011, for the primary outcome of adherence to CHEST VTE treatment guidelines defined as (1) patients receiving an appropriate parenteral anticoagulant and dose based on renal function and weight, (2) at least 5 days of parenteral anticoagulation during warfarin initiation, and (3) an international normalized ratio (INR) value ≥2 documented before discontinuing parenteral agents. Secondary outcomes included recurrent thromboembolism and major bleeding across renal function categories., Results: Of the 1683 patients included in the final analysis, 1483 (88%) had complete data for all 3 elements of the primary outcome (dose, overlap duration, and INR ≥2.0). VTE guideline adherence was identified in 95% (1408/1483) of these patients. There were 20 major bleeds overall, which occurred in 1.1%, 1.1%, and 1.3% in patients with CrCl <30 mL/min, 30 to 59 mL/min, and ≥60 mL/min, respectively (P = 0.929). Also, 7 recurrent VTE events occurred-3 in patients with CrCl values of 30 to 59 mL/min (0.5%) and 4 in patients with CrCl ≥60 mL/min (0.4%; P = 0.797 across groups)., Conclusions: Adherence to CHEST guidelines was high and resulted in low rates of bleeding and recurrent VTE complications across renal function categories. Further studies of patients with CrCl <30 mL/min are needed., (© The Author(s) 2015.)

Rivaroxaban is increasingly used to treat patients with acute venous thromboembolism (VTE), a potentially life-threatening condition. Because absorption of rivaroxaban decreases from nearly 100% to 66% under fasting conditions, it is recommended that VTE patients take rivaroxaban with a meal. However, this recommendation is based on preclinical pharmacokinetic (PK) studies in healthy volunteers. So far, no clinical evidence is available to support this recommendation. We describe a case of a compliant young patient who developed recurrent pulmonary embolism during rivaroxaban treatment. PK studies provided evidence that malabsorption of rivaroxaban 20 mg due to irregular intake of meals during shift work was the leading cause of recurrent pulmonary embolism. When the patient was instructed to take rivaroxaban with a regular meal, peak plasma concentrations increased from 115 to 318 ng mL(-1) (+ 176%). Consequently, the importance of taking rivaroxaban with food may have a greater clinical relevance than data from preclinical PK studies suggest., (© 2015 International Society on Thrombosis and Haemostasis.)

The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for many indications. These agents include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. All 4 agents are licensed in the United States for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism and rivaroxaban and apixaban are approved for thromboprophylaxis after elective hip or knee arthroplasty. The NOACs are at least as effective as warfarin, but are not only more convenient to administer because they can be given in fixed doses without routine coagulation monitoring but also are safer because they are associated with less intracranial bleeding. As part of a theme series on the NOACs, this article (1) compares the pharmacological profiles of the NOACs with that of warfarin, (2) identifies the doses of the NOACs for each approved indication, (3) provides an overview of the completed phase III trials with the NOACs, (4) briefly discusses the ongoing studies with the NOACs for new indications, (5) reviews the emerging real-world data with the NOACs, and (6) highlights the potential opportunities for the NOACs and identifies the remaining challenges., (© 2015 American Heart Association, Inc.)

Background: Deep vein thrombosis leading to pulmonary embolism is one of the major complication after fracture. After a fracture occurs, the coagulation cascade activates thrombin, a protease that finally generates clotting. Dabigatran etexilate reduce clot formation by inhibiting thrombin. Dabigatran etexilate is a widely used drug for thromboprophylaxis. There is no study of the effects of dabigatran etexilate on fracture healing in the literature, so we aimed to evaluate the effects of dabigatran etexilate on fracture healing., Materials and Methods: Thirty-six female Sprague Dawley rats were divided into 6 groups, each consisting of 6 rats. In all rats, right tibias were used for the fracture model. An oral regimen of dabigatran etexilate suspension in 0.5% hydroxyethylcellulose was administered to the rats. Although the first and second groups received 10 mg/kg daily doses, the third and fourth groups received 50 mg/kg daily doses. The fifth and sixth groups were assigned as sham groups and only hydroxyethylcellulose solution was administered. The first, third and fifth groups were sacrificed on 14(th) days; whereas the second, fourth and sixth groups were sacrificed on 28(th) days. Results were evaluated radiologically and histologically., Results: Radiologically and histologically no statistically significant differences were observed on the 14(th) day between the first, third and fifth groups; and on the 28(th) days between the second, fourth and sixth groups., Conclusion: Radiological and histological evaluations revealed that fracture healing was not affected by dabigatran etexilate. We think that dabigatran etexilate can be used for the prophylaxis of thromboembolism in patients with fractures, but further clinical studies are mandatory.

Background: Although recombinant human soluble thrombomodulin (rhTM) is a widely used novel anticoagulant agent for disseminated intravascular coagulation (DIC) in Japan, its clinical efficacy in sepsis-induced DIC has not been demonstrated convincingly., Objective: To assess the benefits and harms of rhTM in sepsis-induced DIC patients., Methods: We conducted a systematic review and meta-analysis of rhTM therapy for sepsis-induced DIC for both randomized controlled trials (RCTs) and observational studies (retrospective case-control studies and/or prospective cohort studies) separately. All-cause mortality (28-30 days) as efficacy and serious bleeding complications as adverse effect were measured as primary outcomes. We assessed body of evidence quality at the outcome level by using the Grading of Evidence, Assessment, Development and Evaluation (GRADE) approach., Results: We analyzed 12 studies (838 patients/3 RCTs; 571 patients/9 observational studies). Pooled relative risk was 0.81 (95% CI, 0.62-1.06) in the RCTs, indicating non-significant reduction in mortality, and 0.59 (95% CI, 0.45-0.77) in the observational studies. Meta-regression analysis revealed a significant negative slope between effect size of rhTM therapy and baseline mortality rate in individual studies (P = 0.012), suggesting that probability of a beneficial effect with rhTM therapy increases with increasing baseline risk. Risk of serious bleeding complications was not significantly different between rhTM and control groups. We judged the quality of evidence as moderate for mortality and serious bleeding., Conclusions: The rhTM was associated with a trend in reduction of mortality at 28-30 days in sepsis-induced DIC patients. Further large rigorous trials are needed to confirm or refute these findings before implications for practice are clear., (© 2015 International Society on Thrombosis and Haemostasis.)

The aim of this study was to investigate whether anticoagulant and antiaggregant agents have protective effects against oxidative damage induced by peripheral ischemia-reperfusion (I/R). Groups were created as follows: control group, I/R group (sham group), I/R plus acetylsalicylic acid (Group I), I/R+clopidogrel (Group II), I/R+rivaroxaban (Group III), I/R+bemiparin sodium (Group IV), and I/R+enoxaparin sodium (Group V). In Groups I, II, III, IV, and V, drugs were administered daily for 1 week before I/R creation. Peripheral I/R was induced in the I/R groups by clamping the right femoral artery. The rats were sacrificed 1 hour after reperfusion. Nitrogen oxide levels, malondialdehyde (MDA) levels, paraoxonase-1 (PON1) activity, and prolidase activity were evaluated in both cardiac and renal tissues. There was no significant difference in nitrogen oxide levels between the groups. However, cardiac and renal MDA were significantly higher and PON1 activity was markedly lower in the I/R groups compared with the control group (p<0.05). Although elevated prolidase activity was detected in both the cardiac and renal tissue of the I/R groups, only the sham group and Group V had significantly higher renal prolidase activity (p<0.05). Group V had significantly higher cardiac MDA, PON1, prolidase levels, and renal prolidase activity compared with the sham group (p<0.05). Significant improvement in renal MDA levels was only observed in Group III, and marked improvement was observed in the cardiac MDA levels of Group II when compared with the sham group (p<0.05). Thromboprophylactic agents appear to provide partial or prominent protection against I/R injury., (Copyright © 2015. Published by Elsevier Taiwan.)

Background: The outcome of cancer patients with acute venous thromboembolism (VTE) may differ according to gender., Methods: We used the RIETE database to compare the rate of VTE (pulmonary embolism [PE] or deep vein thrombosis [DVT]) recurrences), major bleeding and mortality during the course of anticoagulation, according to gender., Results: As of August 2014, 11,055 patients with active cancer were enrolled in RIETE, of whom 5,104 (46%) were women. During the course of anticoagulation (mean: 142 days), 505 patients developed recurrent VTE, 429 bled and 2730 died. Compared with men, women had a significantly lower rate of fatal bleeding (risk ratio [RR]: 0.69; 95% CI: 0.47-0.99) and death (RR: 0.90; 95% CI: 0.83-0.97), and a non-significantly lower rate of PE recurrences (RR 0.83; 95% CI: 0.65-1.06) and major bleeding (RR: 0.89; 95% CI: 0.74-1.08)., Conclusions: During the course of anticoagulation, cancer women with VTE had a better outcome than men., (© 2015 Elsevier Ltd. All rights reserved.)

Introduction: Tooth extraction for patients treated by AVK and/or platelet aggregation inhibitor is performed according to local habits rather than to a consensus. We had for objective to assess hemorrhagic and thromboembolic risks for patients for whom treatment with AVK and/or platelet aggregation inhibitor was modified before tooth extraction., Materials and Methods: Ninety-three patient files were examined retrospectively. The following data was collected: epidemiological data, ASA score, nature and changes of antithrombotic therapy, preoperative INR, number teeth extracted, postoperative complications (bleeding and thromboembolic events)., Results: Thirty-seven patients were treated with oral anticoagulants, 41 by a platelet aggregation inhibitor, 10 by double platelet aggregation inhibitor therapy, and 5 by an AVK-platelet aggregation inhibitor combination. At D0, the mean INR was decreased to 1.4, 4 patients with high thromboembolic risk had received heparin relay treatment; the treatment was stopped for 9 of the 56 patients on monotherapy with antiplatelet therapy, 4 were switched from clopidogrel to lysine acetylate; clopidogrel was stopped for 7 patients under combination therapy. Seven hundred and twenty-six avulsions (mean 8.1 per patient) were performed, 41 patients presented with mild/moderate bleeding, easily resolved. A patient presented with delayed hemorrhage at D6 (AVK overdose). No thromboembolic complication was reported., Discussion: The modification of antithrombotic treatment, as for surgery at high risk of bleeding, seems to limit the risk of bleeding without increasing thromboembolic risk., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Introduction: Clinical trials have provided evidence about efficacy and safety of extended thromboprophylaxis among total hip replacement (THR) patients. There is a lack of evidence on effectiveness and safety of extended treatment in unselected patients from routine clinical practice. We examined the effectiveness and safety of short (1-6 days) and standard (7-27 days) compared with extended (≥28 days) thromboprophylaxis using population-based design., Material and Methods: Among all primary THR procedures performed in Denmark from 2010 through 2012 (n=16,865), we calculated adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for risk of symptomatic venous thromboembolism (VTE) and major bleeding, in addition to net clinical benefit, defined as the number of VTE avoided minus the number of excess bleeding events occurring among patients prescribed short-term and standard versus extended treatment., Results: The 90-day risks of VTE were 1.1% (short), 1.4% (standard), and 1.0% (extended), yielding aHRs of 0.83 (95% CI: 0.52-1.31) and 0.82 (95% CI: 0.50-1.33) for short and standard versus extended treatment. The risk of major bleeding was 1.1% (short), 1.0% (standard), and 0.7% (extended), resulting in aHRs of 1.64 (95% CI: 0.83-3.21) and 1.24 (95%CI: 0.61-2.51) for short and standard versus extended thromboprophylaxis. Direct comparison between benefits and harms using net clinical benefit analyses did not favor any of the three treatment durations. The same results were found for VTE or death., Conclusions: In a real-word observational cohort of unselected THR patients, we observed no difference in the risks of symptomatic VTE, VTE/ death or bleeding with respect to thromboprophylaxis duration., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Thrombotic events in congenital hypo-afibrinogenemia have been rarely reported, either in association or not with replacement therapy or thrombotic risk factors. We describe clinical findings and management of thrombosis of abdominal aorta with peripheral embolism in a patient with congenital afibrinogenemia. A review of arterial thrombosis in inherited hypo-afibrinogenemia was also performed. The patient with a severe bleeding history requiring prophylaxis with fibrinogen concentrates (FC) was admitted for ischaemia of the 4th right toe. An angio-CT of abdominal aorta showed a thrombosis from the origin of renal arteries to the carrefour with a distal floating part. No thrombotic risk factors were found; a previous traumatic lesion of aortic wall might have triggered the thrombus formation, whereas the role of FC prophylaxis remains uncertain. The patient was successfully treated with FC, enoxaparin followed by fondaparinux, and low-dose aspirin without bleeding or thrombosis recurrence. After 2 years, aortic thrombus was almost completely recovered. Sixteen hypo/afibrinogenemia patients with arterial thrombosis were found in Literature, showing that thrombosis often occurs at a young age, involves large vessels, its recurrence is not unusual, and therapeutic strategy is not defined yet. Our therapeutic approach was effective and also safe, but further studies are needed to improve the knowledge of pathogenesis and the anti-thrombotic management in this peculiar setting., (© 2014 John Wiley & Sons Ltd.)

Rivaroxaban is a direct factor Xa inhibitor approved for prevention of stroke, prevention and treatment of venous thromboembolism and secondary prevention of acute coronary syndrome in many countries. As the use of this agent increases, so does the potential for overdose, both intentional and unintentional. Clinical data on overdoses of rivaroxaban in humans are limited. We report the case of a 42-year-old man who took an overdose of 1400 mg of rivaroxaban and describe how resolution of the anticoagulant effect was monitored using readily available coagulation assays., (© 2014 International Society on Thrombosis and Haemostasis.)

Background: The peripartum management of anticoagulated patients poses important challenges for obstetric anesthesiologists, especially when deciding to perform neuraxial block. However, there is limited evidence evaluating anticoagulant prescribing practices and neuraxial block utilization in this setting. Our objective was to examine peripartum anticoagulant prescribing and anesthetic practices in a cohort of anticoagulated patients receiving subcutaneous enoxaparin, and subcutaneous or intravenous unfractionated heparin., Methods: We performed a retrospective study of anticoagulant prescribing patterns and anesthetic interventions among patients receiving enoxaparin and/or unfractionated heparin who delivered at a USA obstetric center over a seven-year period., Results: We identified 101 patients who received enoxaparin and/or unfractionated heparin before delivery. Thirty-nine (38.6%) patients received enoxaparin only, 41 (40.6%) patients received enoxaparin bridged to subcutaneous unfractionated heparin, 11 (10.9%) patients received enoxaparin and were converted to intravenous unfractionated heparin and 10 (9.9%) patients received only subcutaneous unfractionated heparin. The overall rate of neuraxial block utilization was 80.2%. The median [IQR] time-period between the last dose of enoxaparin and neuraxial block was significantly shorter for patients who received only enoxaparin vs. enoxaparin with subcutaneous unfractionated heparin (54h [12-192h] (n=26) vs. 216h [39-504h] (n=23), P=0.04). Among patients who received only subcutaneous unfractionated heparin, the time period between unfractionated heparin and neuraxial block was 24h [19-51h]., Conclusion: In this study, the neuraxial block rate was high among patients receiving enoxaparin and/or subcutaneous unfractionated heparin with patients undergoing relatively long periods off anticoagulation. Careful multidisciplinary planning is recommended for the peripartum management of anticoagulated pregnant patients., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction: Conventional Vacutainer® Sodium Citrate blood collection tubes contain a relatively high concentration of contaminating magnesium ions, which may result in shortening of the prothrombin time (PT) and the International Normalized Ratio (INR). Recently the manufacturer of Vacutainer® Sodium Citrate tubes introduced new tubes with a magnesium-poor stopper. The magnesium concentration in the new low-Mg tubes is significantly lower than that in the conventional plastic tubes. The purpose of the present study was to compare PT and INR determined in specimens drawn with the new tubes to those drawn with the conventional tubes., Materials and Methods: Venous blood specimens were collected from 22 healthy persons and 65 patients treated with vitamin K-antagonists using conventional Vacutainer® Sodium Citrate tubes and new, low-Mg Vacutainer® tubes. PT and INR were determined with four thromboplastin reagents, i.e., three brands of recombinant human tissue factor and one brand of combined rabbit brain reagent. Magnesium concentrations were determined in the citrate plasmas with a colorimetric method., Results: The differences in PT, INR and International Sensitivity Index (ISI) between the two tubes were significant when using three recombinant human thromboplastin reagents, but were not significant when using the rabbit thromboplastin. The PT and INR differences between the tubes correlated with the magnesium concentration differences (P<0.001). The INR bias between the four reagents was greater for specimens drawn with conventional tubes than the INR bias for specimens drawn with the new tubes., Conclusion: Agreement of INR between reagents is improved by using magnesium-poor tubes., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The lipoprotein lipase (LPL) pool is reduced by 50% in patients on hemodialysis (HD). LPL release by tinzaparin has not been investigated for peritoneal dialysis (PD). Therefore, the aim of this study was to investigate if tinzaparin differently alters the pool of LPL and triglyceride levels of patients on HD versus PD., Materials and Methods: Thirty-two patients on chronic PD or HD were matched to nearest age and gender. In order to release and thereby estimate the endothelial pool of LPL, all patients received a bolus of tinzaparin (75 units/kg). Blood samples were drawn for analysis of LPL activity and triglycerides (TG) between the groups., Results: The peak level of LPL released at 40 min after tinzaparin was similar in PD and HD patients. At 180 min, a slightly higher median level of LPL activity was noted in the PD patients (6.1 mU/mL (n = 6) versus 3.4 mU/mL (n = 16), p = 0.005). The TG concentration in plasma at 40 min was reduced relatively more in the PD patients than in the HD patients (p < 0.05). At 180 min, TG had returned to start levels in HD patients while they were still lowered in PD patients., Conclusions: The negative effect of uraemia on the LPL pool in HD patients, known from other studies, here is shown to be similar in PD patients. Tinzaparin administration releases the LPL pool during each HD but does not cause an exhaustion of the LPL system over time. In contrast to HD, the LPL pool is not altered during PD.

Purpose: To determine the effects of anticoagulation with intravenous unfractionated heparin (IVUH) during therapeutic hypothermia (TH) post-cardiac arrest., Methods: Single-center, retrospective, observational trial in the intensive care units of two hospitals within the Detroit Medical Center. Unresponsive survivors of cardiac arrest, receiving treatment doses of IVUH during TH were included. Patients were required to have at least 1 measured activated partial thromboplastin time (aPTT) during TH. Coagulation parameters were collected at 3 distinct temperature phases: baseline, TH, and post-re-warming (±37 °C) target aPTT defined as 1.5-2 times baseline., Results: Forty-six patients received IVUH during TH, with 211 aPTTs. Heparin starting rate was 13±4 units/kg/h. Average baseline, TH and post-TH aPTT were 34±12, 142±48, and 56±17 s, respectively. Using standard dosing strategies, initial aPTT was above the target range in 89% of patients. After re-warming, aPTT significantly decreased (142±48s vs. 56±17 s, p=0.005), and heparin dose significantly increased (7.9±3 vs. 9±4 units/kg/h, p<0.001). There was a significant difference between aPTT among all three groups, and heparin dose between TH and post-TH even after correcting for age, sex, body mass index, heparin rate, and APACHE II score (p<0.001). Three patients experienced a major bleeding event., Conclusions: Current dosing protocols for IVUH should not be utilized during TH. Heparin requirements are drastically reduced during TH and prolonged interruptions may be required to allow for adequate clearance of UH., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Pulmonary embolism is a relatively uncommon, but serious, postoperative complication of hip and knee arthroplasty; however, little information is available about the prevalence of pulmonary embolism in Taiwan., Methods: We report here a series of five patients who sustained a symptomatic pulmonary embolism after undergoing total knee arthroplasty (TKA). These patients were identified during a retrospective study of 1768 patients carried out between January 2007 and January 2010., Results: Five (0.28%) patients who sustained a symptomatic pulmonary embolism after TKA were identified in a series of 1768 patients. The diagnosis was confirmed by computed tomography angiography findings in four patients and an increased d-dimer level in one patient. All the patients were women, with a mean age of 68.0 years (range 64-76 years). The average body mass index of these patients was 32.6 kg/m(2) (24-38 kg/m(2)). Four patients underwent simultaneous bilateral TKA, and one patient who was undergoing unilateral TKA also underwent revision TKA for a previously treated contralateral knee. None of the patients had a history of pulmonary embolism, and none was given prophylaxis for venous thromboembolism. The time at which pulmonary embolism occurred ranged from 2 to 8 days in five patients. After treatment, no patient had died by the end of the follow-up period. These case reports highlight the equal incidence of pulmonary embolism after TKA in Taiwanese and Western populations., Conclusion: Steps to prevent pulmonary embolism should be undertaken in selected patients, such as these patients with a high body mass index and simultaneous bilateral TKA., (Copyright © 2013. Published by Elsevier B.V.)

Background: Sulfated galactans are polysaccharides with heterogeneous structures that frequently show anticoagulant activity. Their anticoagulant mechanisms are complex and distinct from those observed for heparin. Sulfated galactans act through a combination of effects involving serpin-dependent and serpin-independent mechanisms. Interestingly, these polymers can also induce blood coagulation due to activation of factor XII (FXII)., Objectives: The structure of a complex sulfated galactan from the red alga Acanthophora muscoides was characterized by solution nuclear magnetic resonance. This polysaccharide and another previously characterized algal sulfated galactan from Botryocladia occidentalis were each used in in vitro and in vivo anticoagulant and antithrombotic assays to understand the possible structural determinants of their functional effects., Results and Conclusions: The serpin-dependent anticoagulant effects and FXII-related procoagulant effects of the sulfated galactans decreased in parallel with the molecular size. The serpin-independent anticoagulation also correlated with the chemical structure of the sulfated galactans. The sulfated galactan from A. muscoides, which showed mostly serpin-independent anticoagulant activity and reduced activation of FXII, drastically reduced arterial thrombus formation. However, the sulfated galactans produced opposite effects on venous thrombosis; this difference appears to result from the tenuous balance between the various effects on coagulation, including serpin-dependent and serpin-independent anticoagulation and FXIIa-dependent procoagulation. This study of novel sulfated polysaccharides with distinct effects on coagulation and thrombosis helps to establish the minimal structural-function relationship required for the development of antithrombotic drugs., (© 2013 International Society on Thrombosis and Haemostasis.)

Background: New oral anticoagulants may simplify long-term therapy by eliminating the need for laboratory monitoring. Edoxaban is an oral, direct inhibitor of factor Xa that is given in a fixed dose once daily., Objective and Methods: The Hokusai-VTE study is a randomized, double-blind trial to evaluate whether initial low molecular weight heparin (LMWH) followed by edoxaban (60 mg once daily) is non-inferior to LMWH followed by warfarin (International Normalized Ratio of 2.0-3.0) for the prevention of recurrent thromboembolism in patients with acute symptomatic venous thromboembolism (VTE). The primary efficacy outcome is symptomatic recurrent VTE during the 12-month study period. The principal safety outcome is clinically relevant bleeding (major or non-major) occurring during or within 3 days of stopping study treatment. A clinical events committee adjudicates all suspected outcome events. A unique study design feature is the flexible treatment duration of between 3 and 12 months to simulate usual clinical practice, and enabled by: (i) double-blinding to minimize bias that could occur if knowledge of the patient's treatment influenced the duration of therapy; and (ii) follow-up for 12 months of all patients and inclusion in the primary efficacy analysis, regardless of the duration of therapy received. A second innovative design feature is the strategy for achieving an appropriate time in therapeutic range in the warfarin group, with central tracking for each participating center and feedback to the investigators., Conclusion: The standard methods combined with innovative design features should achieve study results that are both scientifically valid and relevant to clinical practice., (© 2013 International Society on Thrombosis and Haemostasis.)