Dose Of Low Molecular Weight Heparin Research Articles

Prescribing Errors With Low-Molecular-Weight Heparins.

Low-molecular-weight heparins (LMWHs) are used in the prevention and treatment of venous thromboembolism (VTE). Bleeding is the primary major complication of LMWH therapy, which is associated with dose. The administration of appropriate dosages of LMWHs depends on the patient's risk of VTE, risk of bleeding, bodyweight, and renal function. Therefore, LMWH prescribing is prone to errors. However, no earlier study has explored the frequency of prescribing errors with LMWH. The aim of the study was to determine the frequency and determinants of in-hospital LMWH-prescribing errors. A cross-sectional study was conducted to examine the frequency and determinants of LMWH prescribing errors between April and August 2014. We randomly selected 500 patients 18 years and older with at least one LMWH prescription during inpatient hospitalization. A prescribing error was a deviation from the internal hospital guidelines. Logistic regression estimated determinants of prescribing error. A prescribing error was present with 34% of all LMWH users. The most frequently recorded error was a dose that was not adjusted to body weight and/or renal function (85%). Prophylactic LMWH prescribing in medical wards was associated with a higher risk of prescribing error as compared with surgical wards. The frequency of prescribing errors was 34% in a tertiary care hospital. Being a patient with prophylactic LMWH use on a medical ward is a determinant for LMWH prescribing error. Interventions that will lead to better electronic recording of body weight and more awareness among medical doctors may reduce the total number of prescribing errors.

Mandatory Risk Assessment Reduces Venous Thromboembolism in Bariatric Surgery Patients.

Bariatric surgery patients are at high risk for venous thromboembolism (VTE), and chemoprophylaxis is recommended. Sheikh Khalifa Medical City (SKMC) is an American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) member since 2009. We report the rates of VTE in bariatric surgery patients from 2010 to 2016 compared to ACS NSQIP bariatric surgery programs before and after switching from heparin to low molecular weight heparin (LMWH), initiating mandatory risk assessment using Caprini scoring for VTE and adopting an aggressive strategy for high-risk patients regarding dosage of LMWH and chemoprophylaxis after discharge. During the study period, there were 1152 cases (laparoscopic Roux-en-Y gastric bypass (LRYGB) 625 and laparoscopic sleeve gastrectomy (LSG) 527) at Bariatric & Metabolic Institute (BMI) Abu Dhabi compared to 65,693 cases (LRYGB 32,130 and LSG 33,563) at ACS NSQIP bariatric surgery programs. VTE rates remained stable at ACS NSQIP bariatric surgery programs from 2010 to 2016 (0.45, 0.45, 0.45, 0.25, 0.35, 0.3, and 0.3%). In contrast, VTE rates at BMI Abu Dhabi decreased from 2.2% in 2011 to 0.35% after we adopted an aggressive strategy to VTE without an increase in bleeding complications. LRYGB patients with VTE had higher OR time, leak, collection, and mortality at ACS NSQIP hospitals compared to those at BMI Abu Dhabi. In contrast, rates were similar in LSG patients with VTE. Changing our approach to VTE management led our VTE rates to decrease and become like those of ACS NSQIP bariatric surgery patients in LSG and LRYGB.

Influence of acetylsalicylic acid and low-molecular weight heparins on the formation of renal hematoma after shock wave lithotripsy.

To investigate the risk of renal hematoma (RHT) after shock wave lithotripsy (SWL) among patients on acetylsalicylic acid (ASA) or low-molecular-weight heparin (LMWH). Retrospective analysis of 434 patients treated with SWL for nephrolithiasis and ureterolithiasis of the proximal ureter. Primary endpoint was detection of RHT by ultrasound the day after SWL. Secondary outcome variables included transfusion of erythrocyte concentrate(s), interventions, hospital readmission or death due to RHT within 30days of SWL. Binary logistic regression analysis was used including a post hoc one-way analysis. Of 434 patients, 33 (7.6%) and 67 (15.4%) patients were medicated with ASA and LMWH, respectively. RHT was detected in 20 of 434 (4.6%) patients. Of those, 3 (20%) were on ASA, 6 (35%) were on LMWH, 1 (5%) was on ASA and LMWH, and 10 (50%) had no anticoagulation. Univariate analysis showed a statistically significant higher risk for RHT among patients on ASA (p=0.04) and LWMH (p=0.02) with an untreated urinary tract infection (UTI) (p=0.008) and history of cardiovascular disease (p=0.028). On multivariate analysis, ASA medication, untreated UTI (OR 4.4, 95% CI 1.31-14.75, p=0.016 and OR 5.79, 95% CI 1.65-20.32, p=0.03) and a therapeutic dose of LMWH (OR 10.4, 95% CI 1.74-62.27, p=0.01) were independent predictors for RHT. Before SWL, a patient risk profile should be evaluated. If feasible, LMWH in therapeutic dosing should be avoided, and ASA should be discontinued. UTI should be treated before SWL in any case. http://www.clinicaltrials.gov ; Identifier NCT02875717.

Major bleeding risks of different low‐molecular‐weight heparin agents: a cohort study in 12 934 patients treated for acute venous thrombosis

Background Low-molecular-weight heparins (LMWHs) are considered members of a class of drugs with similar anticoagulant properties. However, pharmacodynamics and pharmacokinetics between LMWHs differ, which may result in different bleeding risks. As these agents are used by many patients, small differences may lead to a large effect on numbers of major bleeding events. Objectives To determine major bleeding risks for different LMWH agents and dosing schedules. Methods A cohort of acute venous thrombosis patients from four anticoagulation clinics who used an LMWH and a vitamin K antagonist were followed until they ceased LMWH treatment or until major bleeding. Exposures were classified according to different types of LMWHs and for b.i.d. and o.d. use. Cumulative incidences for major bleeding per 1000 patients and risk ratios were calculated and adjusted for study center. Results The study comprised 12 934 patients with a mean age of 59 years; 6218 (48%) were men. The cumulative incidence of major bleeding was 2.5 per 1000 patients (95% confidence interval [CI], 1.7-3.5). Enoxaparin b.i.d. or o.d. was associated with a relative bleeding risk of 1.7 (95% CI, 0.2-17.5) compared with nadroparin o.d. In addition, a nadroparin b.i.d. dosing schedule was associated with a 2.0-fold increased major bleeding risk (95% CI, 0.8-5.1) as compared with a nadroparin o.d. dosing schedule. Conclusions Absolute major bleeding rates were low for all LMWH agents and dosing schedules in a large unselected cohort. Nevertheless, twice-daily dosing with nadroparin appeared to be associated with an increased major bleeding risk as compared with once-daily dosing, as also suggested in a meta-analysis of controlled clinical trials.

Empirically Reduced Dosages of Tinzaparin in Patients with Moderate-to-Severe Renal Insufficiency Lead to Inadequate Anti-Xa Levels

Background: Due to the higher molecular weight of tinzaparin, the low molecular weight heparin (LMWH) is less dependent on renal excretion than other LMWH preparations. However, several international guidelines recommend the same preemptive dosage reduction for all therapeutic dose LMWHs prescribed in renal insufficient patients, to ensure that there is no accumulation of anticoagulant activity and increased risk of bleeding. This study is aimed at assessing whether a preemptive dosage reduction of tinzaparin in all renal insufficient patients (comprising 25% reduction in patients with Modification of Diet in Renal Disease - estimated glomerular filtration rate (MDRD-eGFR) 30-60 mL/min/1.73 m² and 50% reduction in patients with MDRD-eGFR <30 mL/min/1.73 m²) leads to adequate anti-Xa levels. Methods: We selected the anti-Xa levels of in-hospital patients (≥18 years) with moderate-to-severe renal insufficiency (MDRD-eGFR <60 mL/min/1.73 m²), on therapeutic dosages of tinzaparin. Anti-Xa levels were measured using a chromogenic assay. Results: Preemptive dosage reduction resulted in a median anti-Xa activity of 0.50 IU/mL (interquartile range [IQR] 0.38-0.60). In 92.3% of patients the anti-Xa level was below the target anti-Xa level of >0.85 IU/mL for therapeutic indications. Unadjusted dosages led to a median anti-Xa activity of 0.74 IU/mL (IQR 0.56-0.92). The preemptive dosage reduction was significantly associated with anti-Xa activity below therapeutic range (p = 0.007). No difference in anti-Xa activity was observed between patients with moderate (0.71 IU/mL, IQR 0.61-0.95) versus severe (0.65 IU/mL, IQR 0.41-1.06) renal insufficiency in whom an unadjusted dose had been administered (p = 0.77). None of the anti-Xa levels were above the upper margin of the presumed therapeutic range of 2.0 IU/mL. Conclusion: In renal insufficient patients, the preemptive dosage reduction of tinzaparin leads to inadequate anti-Xa levels.

Venous thromboembolism — recommendations on the prevention, diagnostic approach and management. The 2017 Polish Consensus Statement

The 2017 Polish Consensus Statement (PCS 2017) includes updated recommendations on the prevention, diagnostic approach, and management of venous thromboembolism (VTE). For VTE without cancer, the authors of PCS 2017 recommend apixaban, edoxaban, rivaroxaban, and dabigatran over vitamin K antagonists (VKA) as long-term anticoagulant therapy. For VTE with cancer, the authors of PCS 2017 recommend low molecular weight heparins (LMWH) over VKA, apixaban, edoxaban, rivaroxaban and dabigatran. For extended secondary prevention of deep venous thrombosis (DVT), PCS 2017 recommends apixaban, edoxaban, rivaroxaban, dabigatran, VKA, and sulodexide. For extended secondary prevention of pulmonary embolism (PE), PCS 2017 recommends apixaban, edoxaban, rivaroxaban, dabigatran and VKA. For extended secondary prevention in patients with idiopathic DVT and a high risk of bleeding complications, the authors of PCS 2017 recommend NOT to stop anticoagulation and use sulodexide. For extended secondary prevention in patients with idiopathic PE and a high risk of bleeding, the authors of PCS 2017 recommend NOT to stop anticoagulation and suggest treatment with apixaban, edoxaban, rivaroxaban, and dabigatran in reduced doses adjusted to the risk of bleeding. For VTE treated with anticoagulants, PCS 2017 recommends against insertion of a vena cava filter. For patients with DVT, PCS 2017 suggests USING compression stockings routinely to prevent postthrombotic syndrome. For subsegmental PE without proximal DVT, PCS 2017 suggests clinical surveillance over anticoagulation with a low risk of recurrent VTE, and anticoagulation over clinical surveillance with a high risk of recurrent VTE. The 2017 Polish Consensus Statement suggests thrombolytic therapy for PE with hypotension, and systemic therapy over catheter-directed thrombolysis. For recurrent VTE on a non-LMWH anticoagulant, PCS 2017 suggests LMWH, and for recurrent DVT and/or PE on LMWH, PCS 2017 suggests increasing the dose of LMWH.

TropicALL study: Thromboprophylaxis in Children treated for Acute Lymphoblastic Leukemia with Low-molecular-weight heparin: a multicenter randomized controlled trial

BackgroundVenous thromboembolism (VTE) is a common and severe complication during treatment of acute lymphoblastic leukemia (ALL). An important cause is the intensive use of asparaginase. Prospective cohort studies in which prophylactic low-molecular-weight heparin (LMWH) was used to prevent VTE showed lower VTE risk than in historic control cohorts, with a negligible bleeding risk. However, the efficacy of thromboprophylaxis with LMWH during ALL treatment has never been investigated in a randomized design. Here, we present the protocol of a randomized controlled trial in which the efficacy and safety of thromboprophylaxis with high prophylactic dose LMWH versus no thromboprophylaxis will be assessed in children treated for primary ALL with asparaginase.Methods/DesignThromboprophylaxis in Children treated for Acute Lymphoblastic Leukemia with Low-molecular-weight heparin (TropicALL) is a multicenter, randomized controlled open-label trial conducted in the Netherlands. Patients between 1 and 19 years of age with primary ALL, who are treated within the Dutch Childhood Oncology Group (DCOG) ALL-11 or 12 study will be randomized to thromboprophylaxis with LMWH once daily, (dose of 85 IU/kg (intervention arm A)), or to no thromboprophylaxis (arm B, standard of care) during asparaginase courses of ALL treatment. Primary efficacy endpoint is symptomatic objectified VTE during ALL treatment; secondary efficacy endpoints are overall survival and the composite of symptomatic and asymptomatic objectified VTE. Primary safety endpoints are major bleeding, clinically relevant non-major bleeding and minor bleeding. A total of 324 patients will be included to obtain a relative risk reduction of 75% with a power of 80%, using a two-sided test with significance level α = 0.05.DiscussionThis trial will be the first to assess efficacy and safety of thromboprophylaxis with LMWH during asparaginase treatment for ALL in children in a randomized design.Trail registrationNederlands Trial Register NTR4707. Registered 30 July 2014.

Antepartum Venous Thromboembolism Prophylaxis Dosing With Low Molecular Weight Heparin in Obese Population [34C

INTRODUCTION: To determine adequacy of venous thromboembolism prophylaxis dosing with low-molecular-weight heparin (LMWH) in pregnant women based on anti-Xa concentrations, with focus on the obese population. METHODS: A retrospective cohort identified 50 subjects treated with prophylactic LMWH during pregnancy at the University of Kansas Medical Center between January 2012 and May 2016 were identified from the electronic medical record. Subjects were excluded if they did not deliver at our medical center, were not monitored with anti-Xa levels, or were receiving prophylaxis for proteinuria. The data abstracted from the chart included subject demographics, BMI, indication for pharmacologic thromboprophylaxis, LMWH dosing, anti-Xa levels, weight gain, and potential complications. Fischer exact test and ANOVA were used for statistical analysis. RESULTS: 31 subjects were identified who were treated with an initial starting LMWH dose of 40mg daily. Of these, only 32.26% (10/31) had a prophylactic anti-Xa level (0.2-0.4). When stratified by BMI at treatment start, 58.82% (10/17) with BMI &lt; 30.0 compared to 0% (0/14) subjects with BMI &gt;30.0 reached a prophylactic anti-Xa level (p=0.0008). When stratified by gestational age at treatment start, 45% (9/20) in the first trimester, 33.33% (3/9) in the second trimester, and 0% (0/2) of subjects in the third trimester were at a prophylactic anti-Xa level on daily 40mg LMWH (p=0.24). CONCLUSION: Pregnant women with initial BMI &gt;30.0 treated with daily 40mg LMWH are not likely to achieve a prophylactic anti-Xa level. BMI or weight-based dosing should be considered and patients should be monitored with anti-Xa levels during pregnancy.

Enhancement of trophoblast differentiation and survival by low molecular weight heparin requires heparin-binding EGF-like growth factor.

Does low molecular weight heparin (LMWH) require heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF) signaling to induce extravillous trophoblast differentiation and decrease apoptosis during oxidative stress? LMWH increased HBEGF expression and secretion, and HBEGF signaling was required to stimulate trophoblast extravillous differentiation, increase invasion in vitro and reduce trophoblast apoptosis during oxidative stress. Abnormal trophoblast differentiation and survival contribute to placental insufficiency syndromes, including preeclampsia and intrauterine growth restriction. Preeclampsia often manifests as a pro-thrombotic state, with unsuccessful transformation of the spiral arteries that reduces oxygen supply and can produce placental infarction. LMWH improves placental function by increasing blood flow. Recent data suggest that the actions of LMWH transcend its anti-coagulative properties, but the molecular mechanism is unknown. There is evidence that LMWH alters the expression of human HBEGF in trophoblast cells, which regulates human trophoblast pathophysiology. HBEGF, itself, is capable of increasing trophoblast survival and invasiveness. First-trimester placental explants and the HTR-8/SVneo cell line, established using extravillous trophoblast outgrowths from first-trimester villous explants, were treated in vitro with LMWH to examine the effects on HBEGF signaling and trophoblast function under normal physiological and pathological conditions. A highly specific antagonist of HBEGF and other inhibitors of HBEGF downstream signaling were used to determine the relationship between LMWH treatment and HBEGF. Placental tissues (n = 5) were obtained with IRB approval and patient consent from first-trimester terminations. Placental explants and HTR-8/SVneo cells were cultured on plastic or Matrigel™ and treated with a therapeutic dose of LMWH (Enoxaparin; 10 IU/ml), with or without CRM197, pan Erb-B2 Receptor Tyrosine Kinase (ERBB) inhibitor, anti-ERBB1 or ERBB4 blocking antibodies, or pretreatment of cells with heparitinase I. Extravillous differentiation was assessed by immunocytochemistry to determine the relative levels of integrins α6β4 and α1β1. Trophoblast invasiveness was assessed in villous explants by measuring outgrowth from villous tips cultured on Matrigel, and by invasion assays with HTR-8/SVneo cells cultured on Matrigel-coated transwell insert. Placental explants and HTR-8/SVneo cells were exposed to oxidative stress in a hypoxia-reoxygenation (H-R) model, measuring cell death by TUNEL assay, caspase 3 cleavage, and BCL-2α expression. LMWH induced extravillous differentiation, according to trophoblast invasion assays and integrin (α6β4-α1β1) switching. Treatment with LMWH rescued cytotrophoblasts and HTR-8/SVneo cells from apoptosis during exposure to reoxygenation injury, based on TUNEL, caspase 3 cleavage and BCL-2α expression. Experiments using CRM197, ERBB1 and ERBB4 blocking antibodies, pan-ERBB inhibitor and removal of cell surface heparin demonstrated that the effects of LMWH on trophoblast invasion and survival were dependent upon HBEGF signaling. N/A. The primary limitation of this study was the use of only in vitro experiments. Patient demographics from elective terminations were not available. These data provide new insights into the non-coagulation-related aspects of perinatal LMWH treatment in the management of placental insufficiency disorders. This research was supported by grants from the National Institutes of Health (HD071408 and HL128628), the March of Dimes, and the W. K. Kellogg Foundation. There were no conflicts or competing interests.

Graduated Compression Stockings as an Adjunct to Low Dose Low Molecular Weight Heparin in Venous Thromboembolism Prevention in Surgery: A Multicentre Randomised Controlled Trial

The evidence base upon which current global venous thromboembolism (VTE) prevention recommendations have been made is not optimal. The cost of purchasing and applying graduated compression stockings (GCS) in surgical patients is considerable and has been estimated at £63.1 million per year in England alone. The aim was to determine whether low dose low molecular weight heparin (LMWH) alone is non-inferior to a combination of GCS and low dose LMWH for the prevention of VTE. The randomised controlled Graduated compression as an Adjunct to Pharmacoprophylaxis in Surgery (GAPS) Trial (ISRCTN 13911492) will randomise adult elective surgical patients identified as being at moderate and high risk of VTE to receive either the current "standard" combined thromboprophylactic LMWH with GCS mechanical thromboprophylaxis, or thromboprophylactic LMWH pharmacoprophylaxis alone. To show non-inferiority (3.5% non-inferiority margin) for the primary endpoint of all VTE within 90 days, 2236 patients are required. Recruitment will be from seven UK centres. Secondary outcomes include quality of life, compliance with stockings and LMWH, overall mortality, and GCS or LMWH related complications (including bleeding). Recruitment commenced in April 2016 with the seven UK centres coming "on-line" in a staggered fashion. Recruitment will be over a total of 18 months. The GAPS trial is funded by the National Institute for Health Research Health Technology Assessment in the UK (14/140/61).

The value and impact of anti-Xa activity monitoring for prophylactic dose adjustment of low-molecular-weight heparin during pregnancy: a retrospective study.

: Low-molecular-weight heparin (LMWH) is the anticoagulant drug class of choice for the prevention of thrombosis during pregnancy and often used for prevention of severe obstetrical complications, yet the optimal dosage is still a matter of debate. Although several studies have evaluated LMWH dose adjustment methods based on anti-Xa levels, no definitive conclusion as yet exists. This extensive retrospective study sought to address the rationale of regular anti-Xa activity monitoring in pregnant patients given LMWH prophylaxis. We evaluated pregnant patients receiving LMWH prophylaxis with three or more anti-Xa measurements. The initial LMWH dose was fixed and adjusted for obesity. The desired anti-Xa activity was 0.2-0.6 IU/ml and LMWH dose was increased for anti-Xa levels less than 0.3 IU/ml. Of the 173 enrolled women, 79% required LMWH dose adjustment (56%: one dose increase; 20%: two; 3%: three). In the vast majority of patients, LMWH dose was increased before substantial body weight gain. The number of dose adjustments positively correlated with BMI, though not with body weight gain. Based on our study findings, we recommend conducting LMWH dose adjustments based on anti-Xa levels, monitored regularly during pregnancy to keep the anti-Xa activity within the desired range.

Patient compliance with venous thromboembolism prophylaxis (VTE).

Venous thromboembolic disease (VTE) comprises pulmonary embolism (PE) and deep vein thrombosis (DVT), and causes morbidity and mortality, particularly in trauma and orthopaedic patients. Prevalence of 0.9% and 1.2% respectively are reported, with mortality rates up to 13.8%. Chemical thromboprophylactic agents including low molecular weight heparin (LMWH) are considered cost effective in reducing VTE risk. Evidence for anti-platelets including Aspirin for VTE prophylaxis is less compelling and is not supported as monotherapy. There has been no published data on patient compliance with LMWH in trauma outpatients. We aimed to determine whether trauma outpatients accept LMWH after discussing their VTE risk and the evidence for prophylaxis. For those accepting prophylaxis, we also investigated their compliance for the duration of immobilisation. Lower limb injured patients treated with external immobilisation over a 6 month period at our major trauma centre were included. On completion of immobilisation, they were requested to complete a 17-point questionnaire. Patients declining injectable subcutaneous LMWH as prophylaxis were offered Aspirin 75mg as a second line agent. Seventy-five questionnaires were completed and five were excluded. Nineteen patients required surgical intervention for their injury, 51 were managed non-operatively. Thirty-one patients accepted LMWH and 30 chose Aspirin as an alternative. Nine patients declined or were not commenced on prophylaxis. Nineteen reported no missed Aspirin doses and 25 reported no missed LMWH doses. No patients reported missed doses due to pain, side effects or cessation of treatment for another reason. The mean average pain score recorded on the VAS was 3.8. No patients in the study were diagnosed with a VTE. LMWH is a recognised chemical thromboprophylactic and is well tolerated by patients for VTE risk reduction in lower limb immobilised outpatients. With poor evidence supporting Aspirin as a solo prophylactic agent, our local policy has withdrawn Aspirin for this purpose.

Inhibition of inflammation induced shedding of the endothelial glycocalyx with low molecular weight heparin

The endothelial surface layer (ESL) consists of the endothelial cell (EC) glycocalyx and adsorbed proteins, and forms a barrier between blood and the EC. Enzymatic shedding of the ESL in response to cytokines may expose receptors for leukocyte (WBC) adhesion and increase vascular permeability. Thus, intravital microscopy was used to explore stabilization of the ESL with low molecular weight heparin (LMWH) to mitigate structural changes with inflammation. Following bolus infusions (i.v.) of LMWH (0.12–1.6mg/kg), shedding of glycans in response to 10−7M fMLP was measured by loss of fluorescently labeled lectins bound to the EC and WBC-EC adhesion was monitored in post-capillary venules of rat mesentery. During a 30min exposure to fMLP, a 50% reduction in fluorescence (indicative of glycan shedding) occurred at the lowest dose of LMWH whereas a 50% increase occurred (indicative of ESL compaction) at the highest dose. Shedding was reduced by LMWH in a dose dependent manner with an EC50 of 0.6mg/kg. Concomitant WBC-EC adhesion increased over 3-fold for all doses of LMWH. However, at a dose of 1.6mg/kg, WBC-EC adhesion did not rise significantly during the initial 10min exposure to fMLP. Correlation of WBC adhesion with intensity of the lectin stain for all measurements revealed a significant 40% reduction in adhesion as intensity increased 50%. This relationship was attributed to LMWH inhibition of heparanase and/or binding to components of the glycocalyx that resulted in mitigation of glycan shedding, compaction of the lectin stain and stabilization of the glycocalyx.

Role of low-molecular-weight heparins in prevention of thromboembolic complication after transarterial chemoembolization in hepatocellular carcinoma.

Portal vein thrombosis (PVT) is a common complication after transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC). This is the first clinical study to evaluate the role of low-molecular-weight heparins (LMWHs) with TACE in HCC for the prevention of thromboembolism complications (PVT). This study was carried out on 40 patients with HCC requiring TACE who presented to the Tropical Medicine Department, Tanta University and Interventional Radiology Department of Ain-Shams University Hospitals starting from April 2015. Patients were divided in two groups: group I included 20 patients with HCC treated by TACE only. Group II included 20 patients with HCC treated by TACE and an adjuvant dose of LMWH. Radiological assessment of efficacy of procedure and detection of PVT as a complication was performed using ultrasound abdomen and pelvis and triphasic spiral computed tomography with contrast. This study was carried out on 40 patients with HCC requiring TACE who presented to the Tropical Medicine Department of Tanta University and Interventional Radiology Department of Ain-Shams University Hospitals. The incidence of PVT after TACE was higher in group I than group II, with seven cases in group I and only one case in group II. LMWH with TACE in HCC is strongly recommended for prevention of thromboembolism complications (PVT). However, larger randomized-controlled studies are needed to confirm these obvious findings.

Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for the initial treatment of venous thromboembolism.

Low molecular weight heparins (LMWHs) have been shown to be effective and safe in preventing venous thromboembolism (VTE). They may also be effective for the initial treatment of VTE. This is the third update of the Cochrane Review first published in 1999. To evaluate the efficacy and safety of fixed dose subcutaneous low molecular weight heparin compared to adjusted dose unfractionated heparin (intravenous or subcutaneous) for the initial treatment of people with venous thromboembolism (acute deep venous thrombosis or pulmonary embolism). For this update the Cochrane Vascular Information Specialist (CIS) searched the Cochrane Vascular Specialised Register (15 September 2016). In addition the CIS searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 15 September 2016) and trials' registries. Randomised controlled trials comparing fixed dose subcutaneous LMWH with adjusted dose intravenous or subcutaneous unfractionated heparin (UFH) in people with VTE. Two review authors independently selected trials for inclusion, assessed for quality and extracted data. Six studies were added to this update resulting in a total of 29 included studies (n = 10,390). The quality of the studies was downgraded as there was a risk of bias in some individual studies relating to risk of attrition and reporting bias; in addition several studies did not adequately report on the randomisation methods used nor on how the treatment allocation was concealed.During the initial treatment period, the incidence of recurrent venous thromboembolic events was lower in participants treated with LMWH than in participants treated with UFH (Peto odds ratio (OR) 0.69, 95% confidence intervals (CI) 0.49 to 0.98; 6238 participants; 18 studies; P = 0.04; moderate-quality evidence). After a follow-up of three months, the period in most of the studies for which oral anticoagulant therapy was given, the incidence of recurrent VTE was lower in participants treated with LMWH than in participants with UFH (Peto OR 0.71, 95% CI 0.56 to 0.90; 6661 participants; 16 studies; P = 0.005; moderate-quality evidence). Furthermore, at the end of follow-up, LMWH was associated with a lower rate of recurrent VTE than UFH (Peto OR 0.72, 95% CI 0.59 to 0.88; 9489 participants; 22 studies; P = 0.001; moderate-quality evidence). LMWH was also associated with a reduction in thrombus size compared to UFH (Peto OR 0.71, 95% CI 0.61 to 0.82; 2909 participants; 16 studies; P < 0.00001; low-quality evidence), but there was moderate heterogeneity (I² = 56%). Major haemorrhages occurred less frequently in participants treated with LMWH than in those treated with UFH (Peto OR 0.69, 95% CI 0.50 to 0.95; 8780 participants; 25 studies; P = 0.02; moderate-quality evidence). There was no difference in overall mortality between participants treated with LMWH and those treated with UFH (Peto OR 0.84, 95% CI 0.70 to 1.01; 9663 participants; 24 studies; P = 0.07; moderate-quality evidence). This review presents moderate-quality evidence that fixed dose LMWH reduced the incidence of recurrent thrombotic complications and occurrence of major haemorrhage during initial treatment; and low-quality evidence that fixed dose LMWH reduced thrombus size when compared to UFH for the initial treatment of VTE. There was no difference in overall mortality between participants treated with LMWH and those treated with UFH (moderate-quality evidence). The quality of the evidence was assessed using GRADE criteria and downgraded due to concerns over risk of bias in individual trials together with a lack of reporting on the randomisation and concealment of treatment allocation methods used. The quality of the evidence for reduction of thrombus size was further downgraded because of heterogeneity between studies.

Uterine CD56dim and CD16+ Cells in Refractory Antiphospholipid Antibody-Related Pregnancy Loss and Chromosomally Intact Abortuses: A Case-Control Study.

Aim:To evaluate the role of uterine natural killer (uNK) CD56dim and CD16+ cells in patients with refractory antiphospholipid, antibody-mediated, recurrent, pregnancy loss.Settings and Design:A case–control study was conducted between 2012 and 2015 at a university hospital.Patients and Methods:A group of 118 women with a history of antiphospholipid antibody syndrome experiencing fetal loss in spite of low dose aspirin (LDA) and low molecular weight heparin (LMWH) treatment in the current pregnancy were included in this study. A group of 32 patients undergoing an elective termination of viable pregnancies before 20 weeks were taken as controls. Suction evacuation was performed to collect abortus specimens, and uterine wall curettage was performed to collect decidua specimens, which were then stained using monoclonal antibodies specific to CD56 and CD16.Statistics:Statistical analyses were performed using the Statistical Package for the Social Sciences version 18 software. Chi-square and Fisher exact tests were used for making comparison between the groups.Results:Abnormal fetal karyotype was found in nine (9/97) cases of the study group, which means that abnormal karyotype accounts for only 9.3% of the causes of failure of treatment. Abnormal karyotype was found in four cases of the control group. Only cases with normal karyotyping were subjected to decidual uNK cells analysis. We found that CD56dim and CD16+ were found in the decidua of 79 cases (79/97), which means that aberrant natural killer cells expression might account for 81.4% of the cases of refractory antiphospholipid antibody (APA)-mediated recurrent pregnancy loss.Conclusion:CD56dim and CD16+ uNK cells might be correlated with refractory APA-mediated recurrent pregnancy loss.

Interm Report of the Highlow Study: A Randomized Controlled Trial Comparing Two Doses of Low Molecular Weight Heparin for the Prevention of Pregnancy-Associated Recurrent Venous Thromboembolism

INTRODUCTIONWomen with a history of venous thromboembolism (VTE) have a 2% to 10% absolute risk of developing pregnancy-associated recurrent VTE. Based on these figures, current guidelines recommend postpartum thromboprophylaxis in all pregnant women with a history of VTE. Women with a moderate or high risk of recurrent VTE (i.e. women with a history of VTE that is either unprovoked or associated with a hormonal or minor risk factor), should also receive thromboprophylaxis antepartum.The optimal dose of low-molecular-weight heparin (LMWH) for thromboprophylaxis in pregnant women at moderate or high risk of recurrent VTE is currently unknown, as only two very small prospective trials, both with methodological limitations, have evaluated pharmacological prevention of recurrent VTE in this population. Therefore, the major international guidelines suggest the use of either a prophylactic or intermediate (half-therapeutic) dose of LMWH in this setting, without a preference of one dose over the other. The Highlow study is an investigator-initiated, multicenter, international, open-label, randomized controlled trial (RCT) that compares the efficacy and safety of a fixed dose of LMWH versus an intermediate dose of LMWH for the prevention of pregnancy-associated recurrent VTE (NCT 01828697; www.highlowstudy.org). The rationale and design features of the Highlow study were recently published [Bleker SM, Thromb Res, 2016]. Here, we present an interim report.METHODSIn April 2013, we enrolled the first patient in the Highlow study. For the current report, we analyzed the enrolment rates and baseline characteristics of patients in the Highlow study between 1 April 2013 and 28 June 2016. Twelve centers recorded eligible women that did not give informed consent. Using the enrolment data from these centers, we analyzed the percentage of women giving informed consent, and reasons for not giving consent. All characteristics were summarized using descriptive statistics.RESULTSA total of 222 pregnant patients with a history of VTE that fitted the in- and exclusion criteria of the Highlow study were enrolled in 43 centers in 5 countries (Figure 1). The inclusion rate has been growing exponentially over time (Figure 2). In 12 centers that recorded eligible women not giving consent, 101 of 149 identified patients gave informed consent (68%). Patients who declined participation either did not give a specific reason (N=22; 46%), preferred a low dose of LMWH (N=20; 42%), preferred an intermediate dose (N=2; 4%), preferred a therapeutic dose (N=2; 4%), refused antepartum prophylaxis (N=1; 2%) or had been advised by another physician not to participate (N=1; 2%).On 28 June 2016, baseline data in the CRF had been completed for 181 patients. Six patients participated twice. The mean age was 33 years ± 5.1, with a mean body mass index of 26.7 ± 5.9. The majority had a history of lower limb deep vein thrombosis (N=102; 56%) or pulmonary embolism (N=72, 40%). Of all previous VTE, the majority was hormone-related (N=97; 54%) or related to pregnancy (N=58; 32%). In total, 34 (19%) of prior VTE were unprovoked, and in only 19 cases (11%) a minor risk factor had been present. Thrombophilia screening had been performed previously in 101 patients (56%) and more than half of them (59 patients, 58%) had positive tests, especially for heterozygous factor V Leiden (N=39; 64%) and the heterozygous prothrombin 20210A mutation (N=13; 22%).CONCLUSIONSThis report represents the largest number of pregnant women with a history of VTE participating in a RCT to date, and the future results are very likely to impact current clinical practice and consensus guidelines. Reassuringly, our enrolment rate shows that recruitment of pregnant women with a history of VTE is feasible. With the current enrolment rate we expect to include the last patient, reaching the event-driven sample size of approximately a 1000 patients, by the end of 2019. Hence, the outcome results can be expected in 2020.SPONSORSHIP AND FINANCIAL SUPPORTAn unrestricted grant is provided by Aspen Pharma to the Academic Medical Center in Amsterdam (the Netherlands), who is the sponsor of the Highlow study. In France, where CHU de Saint Etienne is the sponsor, a grant was acquired from the French Ministry of Health (PHRC national 2014). [Display omitted] [Display omitted] DisclosuresBuchmüller:French Ministry of Health: Research Funding. Chauleur:Sanofi: Honoraria; French Ministry of Health: Research Funding. Ní Áinle:Actelion UK: Research Funding. Verhamme:Boehringer Ingelheim: Honoraria, Research Funding; Bayer-Healthcare: Honoraria, Research Funding; Pfizer: Honoraria; Sanofi-Aventis: Honoraria, Research Funding; LeoPharma: Research Funding; Daiichi-Sankyo: Honoraria. Décousus:French Ministry of Health: Research Funding.

A Retrospective Study of Venous Thromboembolism in Acute Leukemia Patients during Prolonged Hospital Stay. the Princess Margaret Cancer Centre Experience

▪BackgroundThe role of thromboprophylaxis in solid organ malignancies is well established. Hematologic malignancies can also be associated with a considerable risk of thromboembolic complications. The incidence of these events is variable and is influenced by multiple factors. Limited data are available regarding the incidence of venous thromboembolism (VTE) in hospitalized acute leukemia (AL) patients. The management of symptomatic VTE in patients with AL can be challenging due to the increased risk of thrombocytopenia-related bleeding.MethodsThe Discharge summary Database (DAD) was used to extract post-admitted PE and DVT volumes in AL patients admitted to Princess Margaret Cancer Centre from 2007-2016. ICD-10-CA diagnosis codes for acute leukemia, and both PE and DVT events, were used. Only patients diagnosed with VTE at least 48 hours post-admission were included to restrict the cohort to patients that developed VTE during their admission.ResultsWe analyzed a total of 10,041 patients that were admitted to Princess Margaret Cancer Centre during the 2007-2016 period. (Table 1) Of these, 7759 had a solid tumor diagnosis (271 VTE events, 3.4%) and 2282 patients had AL (1675 AML, 464 ALL, 144 APL). The AL patients (AML, ALL, APL) admitted to our Centre for chemotherapy or for the management of complications were further evaluated to determine VTE incidence and to evaluate its management in this setting. As of September 2012, patients with solid tumors treated at our Centre received standard thromboprophylaxis as part of an institutional in-patient (VTE) prophylaxis policy (IPP) that reduced the incidence of VTE from 4.8% (219/4520) to 1.6% (3239/52) before and after the policy was initiated, respectively. AL patients are not given prophylactic anticoagulation. 37 AL patients (22 AML, 10 ALL, and 5 APL; overall incidence 1.6%) developed symptomatic VTE (DVT only 23, PE only 8, DVT + PE 6). VTE was reported as central venous catheter related in 12/37 patients (32.4%). PE was detected in all cases by CT-PE. Median age of VTE patients was 53 years (range 32-77), with a median hospital stay of 35 days (range 2-144). Chemotherapy was given to 26 of the 37 patients that developed VTE, with 20 receiving initial induction chemotherapy. 17/37 (46%) patients had PLT<50.000/mm3 at VTE diagnosis. Full dose low molecular weight heparin with platelet transfusion support was used to treat 35/37 patients with acute VTE during the first month of treatment. 2/37 did not receive anticoagulation due to ongoing active bleeding. None of the treated patients experienced major bleeding.ConclusionsIn our experience, the incidence of VTE in AL patients during prolonged hospital stay is relatively low, raising questions about the need for routine VTE prophylaxis in this group. The relatively increased risk of VTE in AL patients receiving chemotherapy (particularly, induction chemotherapy), should prompt particular scrutiny in symptomatic patients. [Display omitted] DisclosuresSchuh:Amgen: Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schimmer:Novartis: Honoraria.

Clinical Outcome of 127 Cases of Splanchnic Venous Thrombosis: Benefit of Anticoagulant Therapy

Background: Splanchnic venous thrombosis (SVT) encompasses thrombosis in the mesenteric, splenic or portal veins (with or without hepatic veins involvement). Little is known about appropriate therapeutic interventions and long-term clinical outcome of SVT patients. Aim of this study was to identify the correct management of SVT and encourage a multidisciplinary approach by a team composed of hematologists, hepatologists, and infectivologists.Methods:We analyzed clinical, laboratory, therapeutic and outcome data of 127 patients with SVT that were recruited from 2000 to 2016. In patients with no active bleeding, anticoagulation treatment was started as soon as possible, according to platelet count. We administered intermediate or full therapeutic dose low-molecular-weight heparin (LMWH) and early initiation of vitamin-K antagonist (VKA; INR range 2-3 or 1.8-2.5 in patients with high bleeding risk) for a platelet count >50.000/μl, only half or prophylactic dose of LMWH for a platelet count >30.000 and < 50.000/μl and no treatment for a platelet count <30.000/μl. Indefinite duration treatment was used for patients with persistent or permanent risk (i.e. cirrhosis, active solid cancer and hematological cancer). Moreover, an appropriate prophylaxis with beta-blockers and endoscopic therapies were applied in cirrhotic SVT. The quality of VKA treatment was assessed by the time in therapeutic range (TTR). The number of vascular complications was expressed as incidence rate, calculated by the number of events per 100 patients-year of observation. The Kaplan-Meier method was performed to estimate the time to reach vessel recanalization. Cox regression analysis was used to identify independent predictors of vascular events or recanalization.Results: Overall, 127 patients were included (median age 58 years; 74% males). The median follow-up of all patients was 11 months (1-212). Portal vein thrombosis was the most common site of thrombosis (50%), followed by multiple venous involvement (37%). Liver cirrhosis and solid neoplasms were the common underlying disease (72% and 36% respectively) while myeloproliferative neoplasms were identified in 8 patients (6.2%). Eighty-nine patients (70%) had esophageal varices (grade >2 in 55 patients) and 81 (64%) had thrombocytopenia (mean 72.000/μl range 28.000/μl-148.000/μl). Ninety-nine patients (78%) were treated with anticoagulant therapy: 36% with intermediate or full dose of LMWH, 40% with half or prophylactic dose of LMWH and 24% with VKA (TTR 76%). During a median duration therapy of 7 months, the incidence rate of thrombotic events was 1.1 per 100 pt-y while the incidence rate of major bleeding was 1.6 per 100 pt-y. At univariate analysis, esophageal varices (p=0.030), renal failure (p=0.001) and liver cirrhosis (p=0.05) significantly increased the risk of bleeding events. Moreover VKA exposure was associated with a significantly lower risk of bleeding events compared to LMWH (p=0.042). Fifty-six patients (44%) obtained vessel recanalization and the probability of recanalization of the occluded vessels was 50% at 18 months. At univariate analysis, factors associated with a lack of recanalization included liver cirrhosis (p=0.004) and solid tumor (p=0.010). Only one death was attributed to fatal bleeding whereas 31 patients died for causes not related to anticoagulation (cirrhosis, cancer).Conclusions: Our study suggests the effectiveness of anticoagulant therapy (especially VKA), leading to thrombus recanalization in 44% of patients with SVT. Notably, the anticoagulant treatment was associated with a very low bleeding incidence also in patients with major risk factors for bleeding (i.e. liver cirrhosis, cancer or esophageal varices). Treatment algorithm and therapeutic decisions were taken as a multidisciplinary team, able to adapt the individual approach and avoid fatal complications. DisclosuresOffidani:Janssen: Honoraria; Celgene: Honoraria, Research Funding.

Anticoagulation Treatment with Low Molecular-Weight Heparin for Portal Vein Thrombosis in Liver Cirrhosis: Efficacy and Risk of Hemorrhagic Complications

▪Introduction: Portal vein thrombosis (PVT) is a well-known complication caused by disturbed portal flows and hemostatic imbalances in liver cirrhosis (LC). Low molecular-weight heparin (LMWH) can be used as a treatment of PVT, but knowledge the about efficacy and safety of LMWH for LC patients remains limited. The aim of this study is therefore to investigate the clinical outcomes of cirrhotic patients with PVT treated with LMWH.Method: From September of 2013 to December of 2015, LC patients who had PVT were treated with therapeutic doses of LMWH, dalteparin or enoxaparin for six months. Patients with severely decompensated LC, a history of major bleeding in the last six months, and/or impaired renal function were excluded.Results: Ninety patients were enrolled. The median age was 63.5 years (range 38-65), and male patients numbered 66 (73.3%). The most common cause of LC was hepatitis B virus infection (55 patients, 61.1%), followed by alcohol abuse (12 patients, 13.3%). Fifty-eight patients (64.4%) had hepatocellular carcinoma. Half of the patients had Child-Pugh class A cirrhosis, and 41 patients (45.6%) had class B cirrhosis. Thirty patients had thrombocytopenia with platelet counts less than 50,000/mm3. All patients had thrombus in the main trunk or in branches of the portal vein. Splenic vein involvement was confirmed in four patients, and 25 patients had superior mesenteric vein thrombus. PVT was newly discovered in 30 patients (33.3%), previously established but recently progressed was found in 43 (47.8%), and chronic but stable thrombus was noted in 17 (18.9%). The median time from the initial diagnosis of PVT to the start of anticoagulation therapy was 8.7 months (range: 0-125.9 months). Dalteparin was prescribed to 81 patients (90.0%) and enoxaparin to 9 (10.0%). The median duration of treatment was 5.8 months (range: 1-34.6 months). The overall rate of recanalization was 58.9%. Complete recanalization was reported in 16 patients (17.8%) and partial recanalization in 37 (41.1%). Patients with a favorable Child-Pugh class and recently diagnosed thrombus showed significantly better responses (Table 1). Concomitant hepatocellular carcinoma had no effect on the recanalization rate. In the patients who responded to anticoagulation therapy, the post-treatment laboratory findings including serum bilirubin and albumin were slightly improved compared to the pre-treatment state. At the time of the analysis, 48 patients (53.3%) had finished six months of the initial LMWH treatment as scheduled, while treatments for five patients were ongoing. The relapse rate of PVT was 56.6%, and the median time from the cessation of anticoagulation to relapse was 4.2 months (range: 1.4-7.0 months). Eight patients (8.9%) suspended their use of LMWH due to adverse events. The most common adverse event was bleeding, which was reported in 13 patients (14.4%). A history of variceal bleeding was a significant risk factor for hemorrhagic complications. Patients denoted as Child-Pugh Classes B or C showed a higher incidence rate compared to those designated as Class A. Two patients died due to fatal bleeding events, which were in these cases intractable duodenal variceal bleeding and intracranial hemorrhage.Conclusion: Anticoagulation therapy using LMWH for PVT in LC is effective, with a recanalization rate of 59.6%. Advanced LC and a delayed start of anticoagulation since the initial diagnosis of PVT disrupted the recanalization effect of LMWH. Long-term maintenance of anticoagulation should be considered owing to the high recurrence rates, but much care is necessary with regard to hemorrhagic complications in patients with a past history of variceal bleeding. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.