Low Molecular Weight Heparin Therapy Research Articles

Effect of prolonged fasting and low molecular weight heparin or warfarin therapies on 2-deoxy-2-[18F]-fluoro-D-glucose PET cardiac uptake

BackgroundWhether anticoagulants other than unfractionated heparin are able to suppress cardiac PET uptake of 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) is unknown. MethodsOne-hundred-seventy-four patients without history and clinical evidence of cardiac dysfunction and/or coronary heart disease underwent a 18F-FDG PET/CT study. All patients were studied with a >12-hours fasting and divided into 2 groups: group-1 without anticoagulant therapy (n:75); group-2 patients on low molecular weight heparin (n:60) or warfarin therapy (n:39). Cardiac 18F-FDG uptake was estimated qualitatively using a 4-point scale and semiquantitatively as total LV glycolysis (LVG) and metabolic volume (MV), drawing isocontour volume of interest (VOI) including the whole LV. ResultsQualitatively, LV 18-FDG uptake was scored 0 or 1, indicating a good suppression, in 10/75 (13%) patients of group-1 and 77/99 (78%) of group-2 (p < .001). Semiquantitatively, patients of group-1 showed higher values of 18-FDG uptake than patients of group-2, assessed as LVG (802,649 ± 468,442 vs 198,989 ± 261,439, p < .0001) or MV (219 ± 77 vs 57 ± 48 cm3, p < .0001). Subanalysis for anticoagulant drugs showed similar results. ConclusionsProlonged fasting combined to anticoagulants other than unfractionated heparin is able to minimize glucose cardiac metabolism. Our data confirm previous observation on the possibility to influence the metabolic pattern of the heart before the PET scan and broadens the spectrum of pharmacological options.

Quality of life in cancer patients undergoing anticoagulant treatment with LMWH for venous thromboembolism: the QUAVITEC study on behalf of the Groupe Francophone Thrombose et Cancer (GFTC).

BackgroundClinical guidelines recommend at least 3-months low molecular weight heparin (LMWH) treatment for established venous thromboembolism (VTE) in cancer patients. However, no study has analyzed the impact of 3–6 months of LMWH therapy on quality-of-life (QoL) in cancer patients.ResultsAmong 400 cancer patients included at M0, 88.8% received long-term LMWH. Using a random-effects linear regression model with time as covariate, QoL scores in the MOS SF-36 (Global HRQoL, 1.3-fold per month [95% confidence interval (CI) 0.81–1.79], p < 0.0001) and EORTC QLQ-C30 (global health status/qol, 2.25-fold per month [95% CI 1.63–2.88]; p < 0.0001) questionnaires significantly improved over the 6-month study period in patients treated with LMWH, while VEINES-QOL scores did not change. In the MOS SF-36 and EORTC QLQ-C30, the following factors were associated with change in QoL: symptomatic VTE, cancer dissemination and histological type. Factors pertaining to reduced mobility were also identified as significant predictors of QoL outcomes, including being bedridden in the MOS SF-36 and ECOG score ≥ 2 in the EORTC QLQ-C30. Presence of acute infection and not undergoing anti-angiogenic therapy were additional factors associated with QoL improvement in the EORTC QLQ-C30.MethodsQUAVITEC, a prospective, longitudinal, multicenter study, recruited all consecutive eligible adult cancer patients with objectively confirmed VTE between February 2011 and 2012. Patients were asked to answer three QoL questionnaires at anticoagulant treatment initiation (M0) and at 3 (M3) and 6 (M6)-month follow-ups.ConclusionQUAVITEC is the first study to show that QoL was improved in cancer patients receiving long-term LMWH treatment for established VTE.

Subcutaneous Administration of Low-Molecular-Weight Heparin to Horses Inhibits Ex Vivo Equine Herpesvirus Type 1-Induced Platelet Activation.

Equine herpesvirus type 1 (EHV-1) is a major cause of infectious respiratory disease, abortion and neurologic disease. Thrombosis in placental and spinal vessels and subsequent ischemic injury in EHV-1-infected horses manifests clinically as abortion and myeloencephalopathy. We have previously shown that addition of heparin anticoagulants to equine platelet-rich plasma (PRP) can abolish ex vivo EHV-1-induced platelet activation. The goal of this study was to test whether platelets isolated from horses treated with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) were resistant to ex vivo EHV-1-induced activation. In a masked, block-randomized placebo-controlled cross-over trial, 9 healthy adult horses received 4 subcutaneous injections at q. 12 h intervals of one of the following treatments: UFH (100 U/kg loading dose, 3 maintenance doses of 80 U/kg), 2 doses of LMWH (enoxaparin) 80 U/kg 24 h apart with saline at the intervening 12 h intervals, or 4 doses of saline. Blood samples were collected before treatment and after 36 h, 40 h (4 h after the last injection) and 60 h (24 h after the last injection). Two strains of EHV-1, Ab4 and RacL11, were added to PRP ex vivo and platelet membrane expression of P selectin was measured as a marker of platelet activation. Drug concentrations were monitored in a Factor Xa inhibition (anti-Xa) bioassay. We found that LMWH, but not UFH, inhibited platelet activation induced by low concentrations (1 × 106 plaque forming units/mL) of both EHV-1 strains at 40 h. At this time point, all horses had anti-Xa activities above 0.1 U/ml (range 0.15–0.48 U/ml) with LMWH, but not UFH. By 60 h, a platelet inhibitory effect was no longer detected and anti-Xa activity had decreased (range 0.03 to 0.07 U/ml) in LMWH-treated horses. Neither heparin inhibited platelet activation induced by high concentrations (5 × 106 plaque forming units/mL) of the RacL11 strain. We found substantial between horse variability in EHV-1-induced platelet activation at baseline and after treatment. Minor injection site reactions developed in horses given either heparin. These results suggest that LMWH therapy may prevent thrombotic sequelae of EHV-1, however further evaluation of dosage regimens is required.

Heparin-induced thrombocytopenia complicating extracorporeal membrane oxygenation support in pediatric patients: review of the literature and alternative anticoagulants.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic, immune-mediated complication of unfractionated heparin (UFH) and low molecular weight heparin therapy. HIT is characterized by moderate thrombocytopenia 5-10 days after initial heparin exposure, detection of platelet-activating anti-platelet factor 4/heparin antibodies and an increased risk of venous and arterial thrombosis. Extracorporeal membrane oxygenation (ECMO) is a form of mechanical circulatory support used in critically ill patients with respiratory or cardiac failure. Systemic anticoagulation is used to alleviate the thrombotic complications that may occur when blood is exposed to artificial surfaces within the ECMO circuit. Therefore, when HIT complicates patients on ECMO support, it is associated with a high thrombotic morbidity and mortality. The following article reviews the current knowledge in pediatric HIT, especially in ECMO patients, and the alternative anticoagulation options in the presence of HIT.

The Cost of Unfractionated and Low-Molecular Weight Heparin Therapy in the Management of Unstable Coronary Syndromes

ABSTRACT Objectives: To determine the direct costs involved in the administration of intravenous (IV) unfractionated heparin (UFH) compared with the projected costs of subcutaneous (SC) low molecular weight heparin (LMWH), dalteparin, in the management of acute coronary syndromes (unstable angina or acute myocardial infarction) from a hospital perspective. Methods: A 9-week prospective time-motion study was conducted in a 9-bed coronary care unit (CCU) of a Canadian university-affiliated hospital. Direct costs (expressed in 1998 Canadian dollars) including all drug, labour, supply and equipment costs associated with the preparation, administration, and monitoring of IV UFH were calculated. Throughout the duration of therapy, the number and types of heparin-related activities and the time spent completing these activities were self-recorded by 25 CCU nurses for 116 consecutive patients with acute coronary syndromes requiring IV UFH. The final labour cost was determined by multiplying the mean hourly nursing wage by the mean times recorded during the time-motion study. The projected costs from use of SC dalteparin for this indication were also estimated. Results: IV UFH was associated with a drug cost of $4.19 per day plus nursing time ($7.28 ± 0.32), supplies ($4.13) and laboratory monitoring ($10.09 ± 0.49) for a total daily cost of $25.68 ± 0.81. The projected cost of dalteparin SC was quite similar at $28.82 ± 0.47 per day consisting mainly of drug acquisition ($26.56 ± 0.47) with a small component for administration ($2.26). Conclusions: The administration of IV UFH for the management of acute coronary syndromes involves a number of activities and consumption of resources beyond the price of drugs alone, and overall the daily costs are similar to using a SC LMWH regimen. The decision to use a LMWH for acute coronarv syndromes therefore should be based on the further consideration of clinical outcomes rather than focusing on drug acquisition cost. RESUME Objectifs : Determiner les cout directs engages dans l’administration intraveineuse (I.V.) d’heparine non fractionnee (HNF) comparativement a ceux projetes dans l’administration sous-cutanee (S.-C.) d’heparine de faible poids moleculaire (HFPM), la dalteparine, dans le traitement des syndromes coronariens instables (angine instable ou infarctus du myocarde aigu) d’un point de vue hospitalier. Methode : Une etude prospective temps-mouvements de neuf semaines a ete menee dans une unite de soins coronariens (USC) de neuf lits d’un centre hospitalier canadien affilie a une universite. Les couts directs (exprimes en dollars canadiens de 1998) comprenant ceux de tous les medicaments, de la main d’oeuvre, des fournitures et des equipements associes a la preparation, a l’administration, et au suivi de l’administration IV HNF ont ete calcules. Pendant toute la duree du traitement, le nombre et les types d’activites liees a l’administration d’heparine et le temps passe a accomplir ces activites ont ete inscrits par 25 infirmieres de l’USC pour 116 patients consecutifs presentant des syndromes coronariens instables necessitant l’administration IV HNF. Le cout final de la main d’ouevre a ete determine en multipliant le salaire horaire moyen d’une infirmiere par les temps moyens d’une infirmiere par les temps moyens inscrits au cours de cette etude temps-mouvements. Les couts projetes de l’utilisation de la dalteparine sous-cutanee dans ces cas ont aussi ete evalues. Resultats : L’administration IV HNF a ete associee a un cout de 4,19 $ par jour pour le medicament, plus la main d’oeuvre du personnel infirmier (7,28 ± 0,32 $), les fournitures (4,13 $) et le suivi du laboratoire (10,09 ± 0,49 $), pour un total quatidien de 25,68 ± 0,81 $. Le cout projete de l’administration de la dalteparine S.-C. etait tres semblable, soit 28,82 ± 0,47 $ par jour, et consistait principalement en cout d’acquisition du medicament (26,56 ± 0,47 $) avec une faible partie pour l’administration (2,26 $). Conclusions: L’administration IV HNF dans le traitement des syndromes coronariens instables implique un certain nombre d’activites et la consommation de ressources en-deca du prix du medicament seul, et les couts globaux quotidiens sont semblables a ceux de l’utilisation du traitement S.-C. HFPM. La decision d’utiliser une HFPM pour les syndromes coronariens instables devrait par consequent etre fondee sur une evaluation plus poussee des resultats cliniques plutot que sur le cout d’acquisition du medicament.

ClotAssist: A program to treat cancer-associated thrombosis in an outpatient pharmacy setting.

Stable cancer patients diagnosed with a pulmonary embolus or deep vein thrombosis are commonly referred to the emergency department for management. This practice strains an already overburdened emergency department and is associated with long wait times and poor disease/injection education for patients. This pilot study sought to determine if stable cancer patients with newly diagnosed cancer-associated thrombosis could be effectively managed by community-based pharmacists who followed an evidence-based protocol to prescribe and initiate low-molecular weight heparin therapy. We hypothesized that this novel care pathway could provide faster patient care with more comprehensive disease education, self-injection training, and follow-up. Fifty-five patients with various cancers, including gastroesophageal, urogenital, breast, brain, and lung were enrolled into this pilot study. We observed that this alternative first-dose treatment pathway provided safe and effective treatment of venous thromboembolism combined with excellent patient satisfaction. Following their interaction with the pharmacist, patients felt confident about their ability to self-inject and about their venous thromboembolism management overall. No occurrences of bleeding or other side-effects were observed. This pilot study demonstrates that community-based pharmacists are capable of delivering complex care services in the outpatient environment, particularly in the management of venous thromboembolism.

BSH Guideline: management of thrombotic and haemostatic issues in paediatric malignancy.

BSH Guideline: management of thrombotic and haemostatic issues in paediatric malignancy.

Anticoagulation for the initial treatment of venous thromboembolism in people with cancer.

Compared with people without cancer, people with cancer who receive anticoagulant treatment for venous thromboembolism (VTE) are more likely to develop recurrent VTE. To compare the efficacy and safety of three types of parenteral anticoagulants (i.e. fixed-dose low molecular weight heparin (LMWH), adjusted-dose unfractionated heparin (UFH), and fondaparinux) for the initial treatment of VTE in people with cancer. A comprehensive search included a major electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) (2018, Issue 1), MEDLINE (via Ovid) and Embase (via Ovid); handsearching of conference proceedings; checking of references of included studies; use of the 'related citation' feature in PubMed; and a search for ongoing studies. This update of the systematic review was based on the findings of a literature search conducted on 14 January 2018. Randomized controlled trials (RCTs) assessing the benefits and harms of LMWH, UFH, and fondaparinux in people with cancer and objectively confirmed VTE. Using a standardized form, we extracted data in duplicate on study design, participants, interventions outcomes of interest, and risk of bias. Outcomes of interested included all-cause mortality, symptomatic VTE, major bleeding, minor bleeding, postphlebitic syndrome, quality of life, and thrombocytopenia. We assessed the certainty of evidence for each outcome using the GRADE approach. Of 15440 identified citations, 7387 unique citations, 15 RCTs fulfilled the eligibility criteria. These trials enrolled 1615 participants with cancer and VTE: 13 compared LMWH with UFH enrolling 1025 participants, one compared fondaparinux with UFH and LMWH enrolling 477 participants, and one compared dalteparin with tinzaparin enrolling 113 participants. The meta-analysis of mortality at three months included 418 participants from five studies and that of recurrent VTE included 422 participants from 3 studies. The findings showed that LMWH likely decreases mortality at three months compared to UFH (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.40 to 1.10; risk difference (RD) 57 fewer per 1000, 95% CI 101 fewer to 17 more; moderate certainty evidence), but did not rule out a clinically significant increase or decrease in VTE recurrence (RR 0.69, 95% CI 0.27 to 1.76; RD 30 fewer per 1000, 95% CI 70 fewer to 73 more; moderate certainty evidence).The study comparing fondaparinux with heparin (UFH or LMWH) did not exclude a beneficial or detrimental effect of fondaparinux on mortality at three months (RR 1.25, 95% CI 0.86 to 1.81; RD 43 more per 1000, 95% CI 24 fewer to 139 more; moderate certainty evidence), recurrent VTE (RR 0.93, 95% CI 0.56 to 1.54; RD 8 fewer per 1000, 95% CI 52 fewer to 63 more; moderate certainty evidence), major bleeding (RR 0.82, 95% CI 0.40 to 1.66; RD 12 fewer per 1000, 95% CI 40 fewer to 44 more; moderate certainty evidence), or minor bleeding (RR 1.53, 95% CI 0.88 to 2.66; RD 42 more per 1000, 95% CI 10 fewer to 132 more; moderate certainty evidence)The study comparing dalteparin with tinzaparin did not exclude a beneficial or detrimental effect of dalteparin on mortality (RR 0.86, 95% CI 0.43 to 1.73; RD 33 fewer per 1000, 95% CI 135 fewer to 173 more; low certainty evidence), recurrent VTE (RR 0.44, 95% CI 0.09 to 2.16; RD 47 fewer per 1000, 95% CI 77 fewer to 98 more; low certainty evidence), major bleeding (RR 2.19, 95% CI 0.20 to 23.42; RD 20 more per 1000, 95% CI 14 fewer to 380 more; low certainty evidence), or minor bleeding (RR 0.82, 95% CI 0.30 to 2.21; RD 24 fewer per 1000, 95% CI 95 fewer to 164 more; low certainty evidence). LMWH is possibly superior to UFH in the initial treatment of VTE in people with cancer. Additional trials focusing on patient-important outcomes will further inform the questions addressed in this review. The decision for a person with cancer to start LMWH therapy should balance the benefits and harms and consider the person's values and preferences.

Management of cancer-associated venous thromboembolism – a case-based practical approach

In patients with solid tumours or haematological malignancies, venous thromboembolism (VTE) is a leading cause of death and significantly contributes to morbidity and healthcare resource utilization. Current practice guidelines recommend long-term anticoagulation with low-molecular-weight heparin (LMWH) as the treatment of choice for cancer-associated VTE, based on clinical trial data showing an overall improved safety and efficacy profile of LMWH compared to vitamin K antagonists. However, several open questions remain, e. g. with regard to the intensity and duration of LMWH therapy; moreover, recent real-world evidence indicates that adherence to parenteral anticoagulation with LMWH over the course of treatment is poor in clinical practice. In this regard, the direct oral factor Xa or thrombin inhibitors (DOACs) have emerged as potential alternatives in the management of patients with cancer-associated VTE, albeit findings from randomized controlled studies with a direct head-to-head comparison of DOACs with LMWH, the current standard of care, are still lacking. Based on the case of a lymphoma patient experiencing symptomatic pulmonary embolism during immunochemotherapy, this article aims at both highlighting the current state-of-the-art approach to cancer-associated VTE and pointing out some of the unresolved, controversial issues clinicians have to face when taking care of haematology and oncology patients with already established or with high risk of developing VTE. These issues include the management of patients with incidental pulmonary embolism or thrombocytopenia, the use of DOACs, and the initiation of pharmacological thromboprophylaxis in non-surgical cancer patients.

Higher Adherence to Treatment With Low-Molecular-Weight-Heparin Nadroparin Than Enoxaparin Because of Side Effects in Cancer-Associated Venous Thromboembolism.

Current guidelines recommend low-molecular-weight-heparins (LMWH) monotherapy for 3 to 6 months as first-line treatment for cancer-associated venous thromboembolism (VTE). In clinical practice, enoxaparin and nadroparin are common agents used. However, differences in therapy adherence between these LMWHs have never been reported. Therefore, our aim was to compare adherence to enoxaparin and nadroparin in patients with cancer-associated VTE. Consecutive patients with active cancer and objectively confirmed VTE, treated at a Dutch or a Spanish hospital, were followed during LMWH therapy with a maximum of 180 days. Cumulative incidences of discontinuation of both LMWHs were estimated and compared according to the Kaplan-Meier method, applying a competing risk analysis to correct for mortality. A total of 366 patients were analyzed during LMWH treatment, of whom 284 patients (78%) were treated with enoxaparin and 82 (22%) with nadroparin. The cumulative incidence of discontinuation of enoxaparin and nadroparin treatment because of side effects was 30% (95% confidence interval [CI] 24–36) and 8.8% (95% CI 1.1–15), respectively. Competing risk analysis revealed a higher number of patients discontinuing enoxaparin due to side effects (adjusted hazard ratio [HR]: 2.8; 95% CI 1.06–7.2). Pain at the injection site was the most common reason of discontinuation in patients using enoxaparin, occurring in 32 patients, while it occurred in 1 patient using nadroparin (adjusted HR: 4.0; 95% CI 0.52–31). This analysis reveals that enoxaparin was associated with a higher risk of discontinuation because of side effects compared to nadroparin. However, given the nature of the patient groups, these findings should be followed by future studies.

Angiogenic Factor Profiles in Pregnant Women With a History of Early-Onset Severe Preeclampsia Receiving Low-Molecular-Weight Heparin Prophylaxis.

To evaluate whether daily low-molecular-weight (LMW) heparin prophylaxis during pregnancy alters profile of circulating angiogenic factors that have been linked with the pathogenesis of preeclampsia and fetal growth restriction. This is a planned ancillary study of the Heparin-Preeclampsia trial, a randomized trial in pregnant women with a history of severe early-onset preeclampsia (less than 34 weeks of gestation). In the parent study, all women were treated with aspirin and then randomized to receive LMW heparin or aspirin alone. In this study, we measured serum levels of circulating angiogenic factors (soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin by immunoassay) at the following gestational windows: 10-13 6/7 weeks, 14-17 6/7 weeks, 18-21 6/7 weeks, 22-25 6/7 weeks, 26-29 6/7 weeks, 30-33 6/7 weeks, and 34-37 6/7 weeks. Samples were available from 185 patients: LMW heparin+aspirin (n=92) and aspirin alone (n=93). The two groups had comparable baseline characteristics and had similar adverse composite outcomes (35/92 [38.0%] compared with 36/93 [38.7%]; P=.92). There were no significant differences in serum levels of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin in the participants who received LMW heparin and aspirin compared with those who received aspirin alone regardless of gestational age period. Finally, women who developed an adverse composite outcome at less than 34 weeks of gestation demonstrated significant alterations in serum angiogenic profile as early as 10-13 6/7 weeks that was most dramatic 6-8 weeks preceding delivery. Prophylactic LMW heparin therapy when beginning from before 14 weeks of gestation with aspirin during pregnancy is not associated with an improved angiogenic profile. This may provide a molecular explanation for the lack of clinical benefit noted in recent trials. ClinicalTrials.gov, NCT00986765.

Evaluation and management of acute and chronic portal vein thrombosis in patients with cirrhosis.

Evaluation and management of acute and chronic portal vein thrombosis in patients with cirrhosis.

Safe Use of Low–Molecular-weight Heparin in Pediatric Acute Lymphoblastic Leukemia and Lymphoma Around Lumbar Punctures

Children with acute lymphoblastic leukemia or lymphoma (ALL) undergo multiple lumbar punctures (LPs) and frequently require low-molecular-weight heparin (LMWH) for thromboembolic complications. We evaluated if withholding LMWH 24 hours before and after LPs prevented bleeding complications. Children (n=133) with ALL from who were: (1) treated at St. Jude Children's Research Hospital, (2) received LMWH (2×/day of ~1 mg/kg) between January 2004 until December 2012, and (3) underwent a LP were analyzed. Spinal hematoma was defined as a clinical suspicion leading to diagnostic imaging. Traumatic LP was defined as ≥10 red blood cells per microliter of cerebrospinal fluid. In 1708 LPs, no hematomas occurred. For each child treated with LMWH, the probability of experiencing a spinal hematoma during the entire ALL treatment course was 0% (95% confidence interval [CI], 0.0%-2.7%), and in each LP, assuming no intrapatient correlation, the probability of spinal hematoma was 0% (95% CI, 0.0%-0.2%). Traumatic LPs were more common when performed when children were not receiving LMWH therapy (odds ratio [OR], 1.5; 95% CI, 1.1-2.2) which may be explained by clinician optimization of known risk factors for traumatic cerebrospinal fluid before the procedures. Withholding LMWH for 24 hours before and after LPs in children being treated for ALL is safe.

Prognostic importance of central thrombus in hemodynamically stable patients with pulmonary embolism

The association between mortality and localization of central thrombus in hemodynamically stable patients with pulmonary embolism (PE) is unclear. Sufficient data are not available to help clinicians to select between low molecular weight heparin (LMWH), unfractionated heparin (UFH) and thrombolytics for the management of central thrombus. The present study aims to investigate whether central thrombus in the pulmonary artery affects 30-day mortality rate, and to compare the outcomes of different treatment approaches in patients with central thrombus. This multi-central, prospective, observational study included 874 hemodynamically stable patients with PE confirmed by multidetector computed tomography scan. The localization of the emboli was evaluated and categorized as central (saddle or at least one main pulmonary artery), lobar or distal. The primary study outcome was 30-day all-cause mortality. Localization of the emboli was central in 319 (36.5%) patients, lobar in 264 (30.2%) and distal in 291 (33.2%) patients. Seventy-four (8.5%) patients died during the 30-day follow-up period. All-cause mortality rate was 11.9%, 6.8% and 6.2% in patients with central, lobar, and distal emboli, respectively (p < 0.001). Multivariate analysis did not show that hemodynamically stable central thrombus was an independent predictor of mortality. Additionally, mortality rate was not significantly different between UFH, LMWH and thrombolytic therapy groups. The present study showed that central thrombus was not an independent predictor of mortality in hemodynamically stable PE patients. LMWH and UFH were similarly effective in the treatment of this patient group.

Correlation between activated partial thromboplastin time and anti-Xa activity in patients who received low-molecular weight heparin as anticoagulation for haemodialysis.

Plasma anti-Xa activity, the recommended test to monitor low-molecular weight heparin (LMWH) therapy, is not readily available in many laboratories. In our clinical trials on the use of LMWH as anticoagulation for haemodialysis, a consistent prolongation of APTT in addition to the elevated anti-Xa activity was observed in the patients after LMWH administration. Hence, the paired anti-Xa activity and APTT data were re-analyzed. The APTT ratio, which was the proportional change in APTT from the baseline value after LMWH administration, was found to have a strong correlation with anti-Xa activity (coefficient of determination, R 2 = 0.72, P < 0.001). In the receiver operating characteristic analysis, the APTT ratio was also found to be an excellent predictor of therapeutic anti-Xa activity ≧0.5 IU/mL (area under curve = 0.93, P < 0.001). The sensitivity was 88% and the specificity was 83.3% when an APTT ratio ≧1.4 was used as the cut point to predict the achievement of therapeutic anti-Xa activity. Our results illustrated that APTT is a potentially useful screening test to assess the degree of anticoagulation achieved by LMWH during haemodialysis, if the testing for plasma anti-Xa activity is not available.

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.

OP 56 Dalteparin promotes fetal and placental growth in the reduced uterine perfusion pressure model of preeclampsia

Introduction Severe early-onset preeclampsia is caused by defects in placentation and subsequent placental dysfunction, often resulting in an imbalance of circulating angiogenic molecules including sFlt1 and PlGF that mediate many manifestations of the disease. Low-molecular-weight heparins (LMWHs) such as Dalteparin may prevent early severe preeclampsia although recent randomized clinical trials showed no benefit for overall disease prevention. Examining the effects of LMWH in an animal model will provide valuable insights into the potential impact of LMWH therapy in severe preeclampsia. Objective Investigate the effects of Dalteparin in the reduced uterine perfusion pressure (RUPP) model of preeclampsia. Methods The RUPP model of preeclampsia was induced in the pregnant rat by using silver clips to restrict blood perfusion into the uteroplacental circulation beginning gestation day (GD) 14. By GD19 the rats exhibited features of preeclampsia including new-onset hypertension, angiogenic imbalance, intrauterine growth restriction, and fetal loss. Daily subcutaneous injections of low-dose Dalteparin (saline in control RUPP animals) commenced on GD15 until GD19, when blood pressure was measured via carotid catheterization in the anaesthetized animal prior to sacrifice. Values are reported as mean ± SEM. Results Compared to sham-operated animals (n = 6), RUPP rats (n = 6) displayed significantly elevated mean arterial blood pressure (MAP; 85 ± 5 vs 102 ± 2 mmHg), greater fetal resorption (0 ± 0 vs 61 ± 8%), and lower average placental (0.56 ± 0.02 vs 0.50 ± 0.01 g) and fetal (2.56 ± 0.08 vs 2.15 ± 0.04 g) weights. Daily low-dose Dalteparin (n = 8) did not decrease MAP in RUPP rats (105 ± 3 mmHg); however, treatment improved placental (0.56 ± 0.02 g) and fetal (2.49 ± 0.04 g) weights. No effect of Dalteparin on fetal loss was observed (56 ± 7%). Conclusion Although Dalteparin did not ameliorate the elevated blood pressure in RUPP animals, treatment improved placental and fetal growth, which are important aspects in the management of severe preeclampsia. Early administration of LMWH in a subset of patients at high risk of early-onset, placenta-driven severe preeclampsia may support placental growth and prevent extreme preterm delivery due to severe dysfunction.

A STUDY ON THE EFFECT OF LOW MOLECULAR WEIGHT ON POTASSIUM HOMEOSTASIS IN PATIENTS ADMINISTERED HEPARIN FOR THROMBOPROPHYLAXIS IN A TERTIARY CARE HOSPITAL

Objective: Low molecular weight heparin (LMWH) is an indirect thrombin inhibitor used clinically as an anticoagulant for thromboprophylaxis of patients at risk of deep vein thrombosis. The study was done to assess the magnitude of rise in serum potassium after administration of low molecular weight heparin comparing enoxaparin with dalteparin and to evaluate the frequency of clinically significant hyperkalemia in the population studied.Methods: The study was done as a prospective non-randomized observational study in a population of 32 patients started on heparin for thromboprophylaxis for deep venous thrombosis, pulmonary thromboembolism or stroke.Results: A statistically significant elevation in serum potassium was seen in patients treated with LMWH (p = 0.007). The magnitude of rise in potassium was significantly higher in enoxaparin (p = 0.008) than the dalteparin group (p = 0.447). A clinically relevant hyperkalemia of&gt;5 mEq/l was seen in 25% of the population studied. Other important associations detected from the study were that the advancing age and increasing dose could be potential risk factors contributory to an accentuated rise in serum potassium which may culminate in clinically significant hyperkalemia.Conclusion: The study has highlighted that the likelihood of rise in potassium levels during LMWH therapy necessitates monitoring of serum potassium.

Low-Molecular-Weight Heparin Versus Vitamin K Antagonists for the Treatment of Cancer-Associated Thrombosis: A Cost-Effectiveness Analysis

Abstract Introduction Cancer-associated venous thromboembolism (VTE) is primarily treated with low-molecular weight heparin (LMWH), a strategy based on studies showing it to be superior to the vitamin K antagonist (VKA) warfarin for preventing VTE recurrence. Subsequent analyses suggest that the magnitude of this benefit might be less than previously determined. Neither patient-focused measures of utility nor the costs of each strategy have been evaluated in the current treatment era. Methods This is a cost-effectiveness analysis of VKA and LMWH for the treatment of cancer-associated thrombosis through use of a microsimulation model of outcomes for competing anticoagulation management strategies from a 2014 United States societal perspective. Results LMWH therapy added 0.27 QALYs relative to VKA treatment with an ICER of $217,007. One-way sensitivity analysis evaluating the utility of LMWH revealed that VKA was always the preferred strategy at a willingness to pay (WTP) threshold of $100,000 per QALY. Limitations include that the model incorporates a low VKA time in therapeutic range (TTR) and that the TTR in some centers may be higher thereby increasing the cost-effectiveness of the VKA strategy. Utilities for anticoagulation strategies were not derived from cancer patients, and preference is known to vary depending on how anticoagulation method is integrated with cancer treatment. Conclusions Our findings suggest that compared to LMWH, warfarin is a more cost-effective strategy to treat cancer-associated VTE. Although LMWH is associated with a modest increase in life expectancy, this increase comes at significant cost.

Effect of dalteparin administration on thrombin generation kinetics in healthy dogs.

Dalteparin is used to prevent thrombotic complications in dogs. Measurement of anti-factor Xa (anti-FXa) activity is currently used for monitoring therapy, but remains a nonfunctional test. The calibrated automated thrombogram (CAT) could be a suitable approach for functional monitoring. We hypothesized that the CAT will detect decreased endogenous thrombin potential (ETP) in healthy dogs receiving dalteparin. Twenty-four healthy adult Beagles were randomly allocated to 4 equal groups. A single subcutaneous (SC) dose of 50 U/kg, 100 U/kg, or 150 U/kg of dalteparin was given. Platelet-poor plasma (PPP) was collected over a 24-hour period and evaluated by thrombin generation (TG) via CAT, anti-FXa activity, and APTT. Analysis was performed with a repeated-measures general linear mixed model, and the treated groups were compared to a placebo group. Time, dose, and time-dose interaction significantly affected ETP (P < .0001 for all effects), peak (P < .0001 for all effects), rate index (P < .0006 for all effects), and anti-FXa activity (P < .0001 for all effects). No significant time trend was detected in the control group. Dogs receiving the 100 U/kg dalteparin SC injection showed the most homogeneous response of ETP inhibition among treated groups. The % inhibition of ETP from baseline increased nonlinearly as a function of anti-FXa activity (r2 = .8186). The CAT assay can be employed to measure the effects of dalteparin at different doses in healthy dogs, showing sensitivity to time- and dose-dependent changes in ETP and other TG variables. Further investigation of the CAT as a tool for monitoring low molecular weight heparin therapy in dogs is warranted.