Low Molecular Weight Heparin Dalteparin Research Articles

Blocking inhibition of prothrombinase by tissue factor pathway inhibitor alpha: a procoagulant property of heparins.

Unfractionated heparin (UFH) has procoagulant activity in antithrombin/heparin cofactor II (HCII)-depleted plasma. UFH prevents tissue factor pathway inhibitor alpha (TFPIα) from inhibiting the procoagulant enzyme complex, prothrombinase, providing a possible mechanism for its procoagulant activity. The procoagulant potential of UFH and various low molecular weight heparins (LMWHs) were characterized for TFPIα dependence, using thrombin generation assays performed with antithrombin/HCII-depleted plasma. UFH, the LMWHs enoxaparin and dalteparin, and the low anticoagulant LMWH 2-O, 3-O desulphated heparin (ODSH) all promoted thrombin generation, but fondaparinux did not, and this activity was blocked by a TFPIα antibody. UFH, enoxaparin, and dalteparin were anticoagulant in reactions containing 1-2% normal plasma. In prothrombinase activity assays, UFH, enoxaparin, dalteparin and ODSH blocked prothrombinase inhibition by TFPIα, while again fondaparinux did not. In both the plasma and purified assays, LMWHs displayed greater procoagulant potential than UFH, even when normalized to saccharide concentration. These biochemical data reveal that UFH and LMWHs, but not fondaparinux, block prothrombinase inhibition by TFPIα, thereby producing their paradoxical procoagulant activity observed in the absence of antithrombin/HCII. The findings may help to understand the complex pathophysiology and treatment of patients that are simultaneously bleeding and clotting, such as those with disseminated intravascular coagulation.

Clinical Practice Patterns of Anti-Xa Monitoring During Low Molecular Weight Heparin Therapy

Introduction: Therapeutic low molecular weight heparin (LMWH) regimens were developed empirically based on patient weight and renal function without the need for laboratory monitoring. The role of anti-Xa monitoring for patients receiving LMWH has yet to be fully established and is routinely performed only in high risk patients. At our institution, guidelines for monitoring LMWH recommend drawing anti-Xa levels for patients with chronic kidney disease or those with obesity requiring long-term therapy. The purpose of this analysis was to evaluate compliance with institutional guidelines for monitoring anti-Xa levels for patients receiving LMWH, including indication for anti-Xa monitoring, timing of anti-Xa level in relation to drug administration, and follow up actions of providers in response to abnormal anti-Xa levels.Methods: We conducted a retrospective chart review of adult patients who received therapeutic LMWH (enoxaparin or dalteparin) and were ordered for an anti-Xa level between September 1, 2014 and July 1, 2015. Patients were excluded if they were ordered for an anti-Xa level while on a prophylactic dose of LMWH or while on a non-LMWH factor Xa inhibitor. Data collected included patient demographics, LMWH dose and indication, ordering service, presence of a Hematology consult, reason for anti-Xa monitoring, timing of the level after the previous LMWH dose, and provider response to the level.Results: One hundred patients met inclusion criteria, 99 of whom received enoxaparin. Venous thromboembolism was the most common reason for LMWH therapy (85%) followed by atrial fibrillation (11%). The most frequent doses of enoxaparin administered were 1 mg/kg every 12 hours (52%), 1 mg/kg every 24 hours (22%) and 1.5 mg/kg every 24 hours (21%). The most frequently specified indications for anti-Xa monitoring were renal dysfunction and acute kidney injury (30%), followed by abnormal body mass index (13%); no indication was specified by the prescriber or pharmacist in 36% of cases. Of the 100 anti-Xa levels in the study, 65 were drawn at the correct time (3-5 hours after the previous dose of enoxaparin); of the 35 drawn at an incorrect time, 33 had levels measured more than 5 hours after the previous enoxaparin dose. Fifty-four of the initial anti-Xa levels were not within the therapeutic range for the dosing interval of LMWH; of these, follow up action was taken for only 21 patients (39%), most frequently resulting in a dose increase or decrease.Conclusions: In clinical practice, the use of anti-Xa monitoring is inconsistent and commonly done without a documented need. The majority of anti-Xa levels at our institution are drawn at the appropriate time after the previous dose of LMWH, but action is generally not taken in response to non-therapeutic levels. Additional guidance on the use of LMWH monitoring is needed. DisclosuresNo relevant conflicts of interest to declare.

Competing Risk Analysis for Evaluation of Dalteparin Versus Unfractionated Heparin for Venous Thromboembolism in Medical-Surgical Critically Ill Patients.

Failure to recognize the presence of competing risk or to account for it may result in misleading conclusions. We aimed to perform a competing risk analysis to assess the efficacy of the low molecular weight heparin dalteparin versus unfractionated heparin (UFH) in venous thromboembolism (VTE) in medical-surgical critically ill patients, taking death as a competing risk.This was a secondary analysis of a prospective randomized study of the Prophylaxis for Thromboembolism in Critical Care Trial (PROTECT) database. A total of 3746 medical-surgical critically ill patients from 67 intensive care units (ICUs) in 6 countries receiving either subcutaneous UFH 5000 IU twice daily (n = 1873) or dalteparin 5000 IU once daily plus once-daily placebo (n = 1873) were included for analysis.A total of 205 incident proximal leg deep vein thromboses (PLDVT) were reported during follow-up, among which 96 were in the dalteparin group and 109 were in the UFH group. No significant treatment effect of dalteparin on PLDVT compared with UFH was observed in either the competing risk analysis or standard survival analysis (also known as cause-specific analysis) using multivariable models adjusted for APACHE II score, history of VTE, need for vasopressors, and end-stage renal disease: sub-hazard ratio (SHR) = 0.92, 95% confidence interval (CI): 0.70-1.21, P-value = 0.56 for the competing risk analysis; hazard ratio (HR) = 0.92, 95% CI: 0.68-1.23, P-value = 0.57 for cause-specific analysis. Dalteparin was associated with a significant reduction in risk of pulmonary embolism (PE): SHR = 0.54, 95% CI: 0.31-0.94, P-value = 0.02 for the competing risk analysis; HR = 0.51, 95% CI: 0.30-0.88, P-value = 0.01 for the cause-specific analysis. Two additional sensitivity analyses using the treatment variable as a time-dependent covariate and using as-treated and per-protocol approaches demonstrated similar findings.This competing risk analysis yields no significant treatment effect on PLDVT but a superior effect of dalteparin on PE compared with UFH in medical-surgical critically ill patients. The findings from the competing risk method are in accordance with results from the cause-specific analysis.clinicaltrials.gov Identifier: NCT00182143.

Opposing effects of low molecular weight heparins on the release of inflammatory cytokines from peripheral blood mononuclear cells of asthmatics.

BackgroundT-cell-mediated inflammatory cytokines, such as interleukin (IL)-4, IL-5, IL-13 and tumor necrosis factor-alpha (TNF-α), play an important role in the initiation and progression of inflammatory airways diseases. Low-molecular-weight heparins (LMWHs), widely used anticoagulants, possess anti-inflammatory properties making them potential treatment options for inflammatory diseases, including asthma. In the current study, we investigated the modulating effects of two LMWHs (enoxaparin and dalteparin) on the release of cytokines from stimulated peripheral blood mononuclear cells (PBMCs) of asthmatic subjects to identify the specific components responsible for the effects.MethodsPBMCs from asthmatic subjects (consist of ~75% of T-cells) were isolated from blood taken from ten asthmatic subjects. The PBMCs were pre-treated in the presence or absence of different concentrations of LMWHs, and were then stimulated by phytohaemagglutinin for the release of IL-4, IL-5, IL-13 and TNF-α. LMWHs were completely or selectively desulfated and their anticoagulant effect, as well as the ability to modulate cytokine release, was determined. LMWHs were chromatographically fractionated and each fraction was tested for molecular weight determination along with an assessment of anticoagulant potency and effect on cytokine release.ResultsEnoxaparin inhibited cytokine release by more than 48%, whereas dalteparin increased their release by more than 25%. The observed anti-inflammatory effects of enoxaparin were independent of their anticoagulant activities. Smaller fractions, in particular dp4 (four saccharide units), were responsible for the inhibitory effect of enoxaparin. Whereas, the larger fractions, in particular dp22 (twenty two saccharide units), were associated with the stimulatory effect of dalteparin.ConclusionEnoxaparin and dalteparin demonstrated opposing effects on inflammatory markers. These observed effects could be due to the presence of structurally different components in the two LMWHs arising from different methods of depolymerisation. This study provides a platform for further studies investigating the usefulness of enoxaparin in various inflammatory diseases.

Cost-effectiveness of Dalteparin vs Unfractionated Heparin for the Prevention of Venous Thromboembolism in Critically Ill Patients

Venous thromboembolism (VTE) is a common complication of acute illness, and its prevention is a ubiquitous aspect of inpatient care. A multicenter blinded, randomized trial compared the effectiveness of the most common pharmocoprevention strategies, unfractionated heparin (UFH) and the low-molecular-weight heparin (LMWH) dalteparin, finding no difference in the primary end point of leg deep-vein thrombosis but a reduced rate of pulmonary embolus and heparin-induced thrombocytopenia among critically ill medical-surgical patients who received dalteparin. To evaluate the comparative cost-effectiveness of LMWH vs UFH for prophylaxis against VTE in critically ill patients. Prospective economic evaluation concurrent with the Prophylaxis for Thromboembolism in Critical Care Randomized Trial (May 2006 to June 2010). The economic evaluation adopted a health care payer perspective and in-hospital time horizon; derived baseline characteristics and probabilities of intensive care unit and in-hospital events; and measured costs among 2344 patients in 23 centers in 5 countries and applied these costs to measured resource use and effects of all enrolled patients. Costs, effects, incremental cost-effectiveness of LMWH vs UFH during the period of hospitalization, and sensitivity analyses across cost ranges. Hospital costs per patient were $39,508 (interquartile range [IQR], $24,676 to $71,431) for 1862 patients who received LMWH compared with $40,805 (IQR, $24,393 to $76,139) for 1862 patients who received UFH (incremental cost, -$1297 [IQR, -$4398 to $1404]; P = .41). In 78% of simulations, a strategy using LMWH was most effective and least costly. In sensitivity analyses, a strategy using LMWH remained least costly unless the drug acquisition cost of dalteparin increased from $8 to $179 per dose and was consistent among higher- and lower-spending health care systems. There was no threshold at which lowering the acquisition cost of UFH favored prophylaxis with UFH. From a health care payer perspective, the use of the LMWH dalteparin for VTE prophylaxis among critically ill medical-surgical patients was more effective and had similar or lower costs than the use of UFH. These findings were driven by lower rates of pulmonary embolus and heparin-induced thrombocytopenia and corresponding lower overall use of resources with LMWH.

Affinity capillary electrophoresis for the determination of binding affinities for low molecular weight heparins and antithrombin‐III

The anticoagulant properties of heparin stem in part from high-affinity binding to antithrombin-III (AT-III) inducing a 300-fold increase in its inhibitory activity against the coagulation protease factor Xa. The minimal structural requirements for AT-III binding are contained in the rare heparin pentasaccharide sequence containing a 3,6-O-sulfated N-sulfoglucosamine residue. ACE is used in this work to measure the relative AT-III binding affinities of the low molecular weight heparins (LWMHs) dalteparin, enoxaparin, and tinzaparin and the synthetic pentasaccharide drug fondaparinux (Arixtra). Determination of the AT-III binding affinities of the LWMHs is complicated by their inherent structural heterogeneity and polydispersity. The fractional composition of 3-O-sulfo-N-sulfoglucosamine residues was determined for each drug substance using 2D NMR and used in the interpretation of the ACE results.

CP-055 Effect of rivaroxaban on wound healing after elective tibial osteotomy

BackgroundAfter elective tibial osteotomy patients are considered at high risk of venous thromboembolism (VTE) due to prolonged immobilisation. Routine pharmacological thromboprophylaxis for these patients is widely adopted in clinical practice...

Identification of pro- and anti-proliferative oligosaccharides of heparins

Heparins, unfractionated heparin (UFH) and low molecular weight heparins (LMWHs), are heterogeneous mixtures of anticoagulant and non-anticoagulant oligosaccharides. In addition to their well-known anticoagulant effect, heparins have shown to mediate a wide range of non-anticoagulant effects, including the modulation of cellular growth. However, contradictory results have been reported with regard to their effects on cellular proliferation, with some studies suggesting anti-proliferative while others indicating pro-proliferative effects. This study investigated the proliferation of human colonic epithelial cancer cells in the presence of UFH and LMWHs (enoxaparin and dalteparin). In our experimental setting, all heparins caused a dose-dependent reduction in cellular growth, which correlated well with the induction of cell cycle arrest in the G₁ phase and which was not associated with significant changes in cell viability. The effects on cellular proliferation of 14 different oligosaccharides of enoxaparin obtained through ion-exchange chromatography were also assessed. Surprisingly, only two oligosaccharides showed distinctive anti-proliferative effects while the majority of oligosaccharides actually stimulated proliferation. Interestingly, the smallest oligosaccharide devoid of any anticoagulant activity showed the strongest anti-proliferative effect. Notably, heparins are currently standardised only according to their anticoagulant activity but not based on other non-anticoagulant properties. Our results indicate that slight differences in the composition of heparins' non-anticoagulant oligosaccharides, due to different origins of material and preparation methods, have the potential to cause diverse effects and highlight the need for additional characterisation of non-anticoagulant activities.

Heparin thromboprophylaxis in critically ill patients: Is it really changing outcome?

Heparin thromboprophylaxis in critically ill patients: Is it really changing outcome?

The effect of small-molecular-weight heparin added to chemotherapy on survival in small-cell lung cancer - A retrospective analysis.

Aims and Background: Small cell lung cancer (SCLC) is a chemotherapy-responsive tumor and associated with alterations in the coagulation system. Addition of low-molecular-weight heparin (LMWH) to combination chemotherapy (CT) had resulted in increase in survival. The present retrospective trial was designed to determine whether the duration of dalteparin usage has an effect on progression and survival. Materials and Methods: The medical records of 67 patients with SCLC who were given cisplatin-etoposide and concomitant LMWH (dalteparin) was evaluated retrospectively. Results: Median follow-up of patients was 11.3 months. Outcome: 10.6% complete response, 3.0% good partial response, 36.4% partial response, 10.6% stable disease, and 39.4% progressive disease. Side-effects were seen in 40.3% of the patients. Median dalteparin duration was 6,1 months. According the duration of dalteparin patients were grouped in three: who took dalteparin less than 4 months (Group A), 4-6 months (Group B) and more than 6 months (Group C). Mean overall survival (OS) in Group A was 6.5 months, in Group B 11.8 months, and Group C 14.6 months. Mean OS in Group B and C were statistically significantly (P < 0.001) longer than Group A, between Group B and C there was not any significant difference (P = 0.037). Mean progression free survival (PFS) was 9 months. Conclusions: The CT plus LMWH minimum 4 months long is well-tolerable, and may improve PFS and OS in patients with SCLC. For treatment of patients with SCLC CT plus LMWH may be considered as effective future-therapy, and further multi-centre randomised prospective clinical trials must be done to determine the new standard treatment approach for SCLC.

Structural features of glycol-split low-molecular-weight heparins and their heparin lyase generated fragments

Periodate oxidation followed by borohydride reduction converts the well-known antithrombotics heparin and low-molecular-weight heparins (LMWHs) into their "glycol-split" (gs) derivatives of the "reduced oxyheparin" (RO) type, some of which are currently being developed as potential anti-cancer and anti-inflammatory drugs. Whereas the structure of gs-heparins has been recently studied, details of the more complex and more bioavailable gs-LMWHs have not been yet reported. We obtained RO derivatives of the three most common LMWHs (tinzaparin, enoxaparin, and dalteparin) and studied their structures by two-dimensional nuclear magnetic resonance spectroscopy and ion-pair reversed-phase high-performance liquid chromatography coupled with electrospray ionization mass spectrometry. The liquid chromatography-mass spectrometry (LC-MS) analysis was extended to their heparinase-generated oligosaccharides. The combined NMR/LC-MS analysis of RO-LMWHs provided evidence for glycol-splitting-induced transformations mainly involving internal nonsulfated glucuronic and iduronic acid residues (including partial hydrolysis with formation of "remnants") and for the hydrolysis of the gs uronic acid residues when formed at the non-reducing ends (mainly, in RO-dalteparin). Evidence for minor modifications, such as ring contraction of some dalteparin internal aminosugar residues, was also obtained. Unexpectedly, the N-sulfated 1,6-anhydromannosamine residues at the enoxaparin reducing end were found to be susceptible to the periodate oxidation. In addition, in tinzaparin and enoxaparin, the borohydride reduction converts the hemiacetalic aminosugars at the reducing end to alditols. Typical LC-MS signatures of RO-derivatives of individual LMWH both before and after digestion with heparinases included oligosaccharides generated from the original antithrombin-binding and "linkage" regions.

Use Of Fondaparinux For Venous Thromboembolism Prophylaxis In Critically Ill Adult Patients With Moderate Renal Insufficiency

Introduction Fondaparinux, a selective activated Factor Xa inhibitor, is a parenteral anticoagulant primarily excreted by the kidneys. Renal insufficiency (RI), commonly encountered in the critically ill, has been shown to portend an increased risk of bleeding than in normal healthy adults. In comparison to the low molecular weight heparin dalteparin, fondaparinux has been shown to be superior for the prevention of post-surgical venous thromboembolism (VTE), however an increased rate of nonfatal bleeding has been observed. Recently, data has emerged supporting empiric dose reductions in patients with moderate RI, defined as a creatinine clearance (CrCl) between 30 and 50 mL/min. Overall, the data supporting appropriate use of fondaparinux in patients with RI is lacking. This retrospective, single center study describes our experience using prophylactic fondaparinux in critically ill patients with moderate RI. Methods We report our experience utilizing fondaparinux in a mixed medical and surgical, critically ill adult population with moderate RI. The site examined was UF Health; an 852-bed sized tertiary care hospital in Gainesville, Florida between 2006 and 2012. Moderate RI was defined as a CrCl between 30 and 50 mL/min calculated by the Cockcroft/Gault equation. Only patients treated with fondaparinux for prophylaxis of VTE were included, patients treated for other indications were excluded. Doses, dose frequency and dose adjustments were documented. If patients had anti-Xa level monitoring these values were recorded. Timing of anti-Xa levels drawn with respect to fondaparinux dosing was also noted. The primary end point of the study was the rate of clinically significant bleeding events in patients receiving at least 72 hours of fondaparinux. Clinically significant bleeding was defined as transfusion of at least two units of packed red blood cells within 48 hours of a documented bleeding event or the workup of bleeding with endoscopy or imaging. Bleeding events were screened by ICD-9 codes and validated via chart review, incidence of VTE was also noted. Results Sixty-fourpatients met inclusion criteria between October 2006 and November 2012. Two patients (3.1%) experienced clinically significant bleeding events as per our definition, both in the form of gastrointestinal bleeding. Empiric dose reductions occurred in 8 (12.5%) patients, this occurred in the form of every other day administration or dose reduction using fondaparinux 1.25mg daily. Nine (14%) patients were monitored with anti-Xa levels, none of these patients encountered bleeding events. The median anti-Xa level was 0.5 mcg/mL, which is in the target prophylactic range for in our lab. The median time interval after last dose of fondaparinux to anti-Xa level measurement was 4 hours. Seven (10.9%) patients had VTE diagnoses prior to the initiation of prophylactic fondaparinux. No patients suffered a VTE event after treatment with prophylactic fondaparinux in our data set. Conclusion We report a cohort of patients with moderate RI receiving fondaparinux for the prevention of VTE. The incidence of clinically significant bleeding was 3.1%. The risk of VTE was low, no patients suffered from a VTE after treatment with fondaparinux in our data set. The rate of bleeding is slightly higher compared to patients with normal renal function. Our experience over this 6 year period supports the notion that RI portends an increased risk of bleeding with the use of fondaparinux. Further prospective studies are needed to determine the safety and efficacy of empiric fondaparinux dose reductions in patients with RI and end stage renal disease. Anti-Xa monitoring may help reduce the risk of bleeding in this patient population by identifying those patients in whom a dose reduction may be beneficial. Disclosures: No relevant conflicts of interest to declare.

Low-molecular-weight heparin for anti-coagulation after left ventricular assist device implantation

Anti-coagulation is required in patients with left ventricular assist devices (LVADs). We evaluated the feasibility of low-molecular-weight heparin (LMWH) for initiation of anti-coagulation and transitioning to oral anti-coagulation after LVAD implantation. This single-center study included 78 consecutive patients who underwent either Thoratec HeartMate II LVAD (n = 27) or HeartWare ventricular assist device (HVAD, n = 51) implantation. The LMWHs enoxaparin (n = 50) and dalteparin (n = 28) were used. LMWH was started within 24 hours post-operatively in 79.5% of patients. No anti-coagulation was given before starting LMWH therapy. LMWH activity was monitored by determination of anti-factor Xa levels in plasma. The majority of patients (80.7%) had peak anti-Xa activity within the defined range of efficacy of 0.2 to 0.4 IU/ml by the second day of treatment. Mean effective peak anti-Xa activity was 0.28 ± 0.06 IU/ml. Mean duration of anti-coagulation with LMWH was 25.8 ± 18 days. Ischemic strokes were observed in 3 patients (3.8%), with a total of 4 events. Three events occurred while on LMWH, and 1 event occurred during follow-up on oral anti-coagulation. There was 1 fatal stroke. No pump thrombus was observed. Major bleeding was observed in 5 patients (6.4%), with a total of 6 events. Gastrointestinal bleeding was the most common complication (n = 3). There were no fatal bleeding events. LMWH in the setting of LVAD shows rapid and constant biologic efficacy. Anti-coagulation with LMWH appears feasible after LVAD implantation. These findings support further evaluation of LMWH as an alternative to unfractionated heparin in this patient cohort.

Effects of low molecular weight heparin on clot rate and activated clotting time: an in vitro study

Background Due to lack of point-of-care testing, the use of low-molecular-weight heparin (LMWH) therapy in some special patients is restricted. This study was designed to explore the effects of LMWH on clot rate (CR) and activated clotting time (ACT), and to search for an appropriate method for bedside monitoring of anticoagulant activity of LMWH. Methods Thirty-two healthy volunteers were selected from the staff of Beijing Tongren Hospital. CR and ACT were measured with different reagents (glass beads, diatomite, kaolin and magnetic bar) on blood samples spiked with increasing concentrations of LMWH (dalteparin, 0.2–1.8 IU/ml). Correlations between concentrations of LMWH and values of CR and ACT were analysed based on the data obtained and regression analysis was performed to establish a regression equation. Results With the increase in doses of dalteparin, CR values reduced gradually. The values of CR of four reagents (glass beads, diatomite, kaolin and magnetic bar) were 20.4–4.5 IU/min, 27.4–6.9 IU/min, 27.5–7.9 IU/min and 7.8–0.1 IU/min respectively and an linear relationship was observed between the CR values and dalteparin concentrations (P&lt;0.05). The values of ACT were 173–615 seconds, 130–270 seconds, 123–226 seconds, 337–1411 seconds respectively, which showed a linear regression between the ACT values and dalteparin concentrations (P&lt;0.01). Differences in slope of the regression curves of ACT were observed with all the reagents tested (glass beads 248.2 s/IU, diatomite 74.8 s/IU, kaolin 58.2 s/IU and magnetic bar 1112.2 s/IU, P&lt;0.01). While the minimum concentration of dalteparin was 0.2 IU/ml, 0.4 IU/ml, 1.4 IU/ml and 0.2 IU/ml separately, the ACT values of the four coagulants (glass beads, diatomite, kaolin and magnetic bar) were beyond the normal limit and showed a noticeable increase respectively (P&lt;0.01). Conclusions This study showed that there was an excellent linear relationship between the CR and ACT values and dalteparin concentrations for all the four reagents (glass beads, diatomite, kaolin and magnetic bar) in vitro. The sensitivity of different coagulation reagents to LMWH different. Choosing a suitable reagent, both CR and ACT were possible to be used as a convenient bedside test for LMWH.

Use of viscoelastic coagulation testing to monitor low molecular weight heparin administration to healthy horses

To evaluate the utility of thromboelastography (TEG) and Sonoclot analyses to monitor the effects of low molecular weight heparin (LMWH) administration to healthy horses. Randomized crossover study. Large animal veterinary teaching hospital. Six adult mixed breed healthy mares. LMWH (dalteparin) was administered (50 U/kg subcutaneously) either every 12 or 24 h for 3 consecutive days. Blood samples were collected before LMWH administration and then at selected time points for analysis. Thromboelastography derived R-time (R), K-time (K), angle (ANG), and maximum amplitude (MA), and Sonoclot activated clot time (ACT), clot rate (CR), and platelet function (PF) were measured in whole blood 30 min after sample collection. Change (Δ) and percentage change (%Δ) from baseline of each TEG and Sonoclot variable were subsequently calculated. Anti-factor Xa activity and activated partial thromboplastin time (aPTT) were assayed in harvested plasma. The association between anti-factor Xa activity and TEG and Sonoclot (measured and calculated) variables was assessed by calculating correlation coefficients and multiple regression analysis. The ability of measured and calculated TEG and Sonoclot variables to predict when anti-factor Xa activity fell below suggested thromboprophylactic levels was assessed using receiver operating characteristic curve analysis. The correlation between aPTT and anti-factor Xa activity was weak (r = 0.343). Changes in TEG and Sonoclot variables following LMWH administration were consistent with hypocoagulation. All measured and calculated TEG variables were significantly correlated with anti-factor Xa activity. Sonoclot ACT, ΔACT, CR, ΔCR, and %ΔCR were also significantly correlated with anti-factor Xa activity. TEG ΔR and %ΔR best predicted anti-factor Xa activity below the suggested thromboprophylactic level. Although correlations were modest, serial measurement of TEG variables may be used to monitor LMWH therapy in horses; however, further research is required in sick horses.

The Cost-Effectiveness of Oral Direct Factor Xa Inhibitors Compared with Low-Molecular-Weight Heparin for the Prevention of Venous Thromboembolism Prophylaxis in Total Hip or Knee Replacement Surgery

Major orthopedic surgery is associated with a high risk of venous thromboembolism (VTE). Anticoagulants are recommended to prevent VTE, and recently an oral direct factor Xa inhibitor (FXaI) was approved for this indication. We compared the cost-effectiveness of FXaIs with low-molecular-weight heparin (LMWH) in patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery. A decision-tree model was developed to compare the cost-effectiveness of oral direct FXaIs (rivaroxaban, apixaban, and edoxaban) to subcutaneous LMWHs (enoxaparin and dalteparin), with separate models for THR and TKR. The analysis was conducted over a 180-day postoperative time horizon from the U.S. Medicare perspective. The model was developed using TreeAge Pro 2011 (TreeAge Software Inc., Williamstown, MA, USA). Efficacy and safety data (probabilities of distal and proximal deep vein thrombosis, symptomatic pulmonary embolism, and major bleeding) were derived from a systematic review and meta-analysis of phase II and III clinical trials. Costs and quality-adjusted life-years (QALYs) are reported. One-way and probabilistic sensitivity analyses were performed to evaluate parameter uncertainty. In the THR model, the average costs per patient for FXaIs and LMWHs were $18,762 and $18,897, respectively, and the QALYs were 0.938 and 0.932. In the TKR model, the average cost per patient for FXaIs and LMWHs were $18,804 and $18,991, respectively, and the QALYs were 0.935 and 0.931. In both models, FXaIs dominated LMWH (less costly and more efficacious). Neither model was sensitive to changes in any of the variables in the one-way sensitivity analyses. Probabilistic sensitivity analysis indicated that FXaIs were cost-effective in more than 99% of iterations in the THR population and in 98% of iterations in the TKR population assuming a willingness-to-pay threshold of $50,000/QALY. Oral direct FXaIs may be an economically dominant strategy compared with LMWHs for VTE prophylaxis in patients undergoing either THR or TKR surgery.

Pharmacodynamics of Multi‐Dose Low Molecular Weight Heparin in Healthy Horses

To compare the pharmacodynamics of once daily and twice daily administration of low molecular weight heparin (LMWH) administration in horses. Randomized cross over study. Adult mixed breed healthy mares (n = 6). LMWH (dalteparin) was administered (50 U/kg subcutaneously) either every 12 or 24 hours for 3 consecutive days. Anti-factor Xa activity was measured before and at select time points after LMWH administration. Packed cell volume (PCV), platelet count, partial thromboplastin time (PTT), and anti-thrombin (AT) activity were monitored throughout the study. No changes in PCV, platelet count, or AT activity were detected with either frequency of daily LMWH administration. Values for PTT increased throughout the study but never exceeded the normal reference interval. Anti-factor Xa activity was maintained within or above the suggested thromboprophylactic range (0.1-0.2 U/mL) when LMWH was administered twice daily, but fell below this range ≈ 16 hours after administration when given once daily. For both once and twice daily LMWH administration, the area under the curve was significantly greater after the last dose of LMWH when compared to the first dose. Administration of LMWH once or twice daily for 3 consecutive days appears to be safe in healthy adult horses. Anti-factor Xa activity was maintained within or above the suggested thromboprophylactic range for 24 hours with twice daily LMWH administration but not with once daily administration.

Bridging Anticoagulation in Patients Who Require Temporary Interruption of Warfarin for Elective Surger or Procedure - the BRIDGE Trial: Design, Rationale and Clinical Implications

Abstract 4327 Background:Low-molecular-weight heparin (LMWH) bridging, usually in treatment doses, may be used in patients with atrial fibrillation (AF) on chronic warfarin who require interruption for an invasive procedure or surgery to minimize the period of sub-therapeutic anticoagulation with the aim of reducing perioperative thromboembolism, as warfarin interruption and surgery may confer a prothrombotic state. However, the efficacy and safety of LMWH bridging therapy has not been tested in a rigorous and large randomized trial. We describe the design of the BRIDGE Trial, explain the rationale for the study population and bridging dose regimen, and discuss its implications for clinical practice. Hypothesis:No bridging is non-inferior to LMWH bridging for the prevention of arterial thromboembolism and is superior to bridging for perioperative bleeding. Design:BRIDGE is a NHLBI-funded randomized, multi-center, placebo-controlled trial assessing a standardized bridging protocol (NCT00786474). Population:3,626 adults with AF from at least 45 centers in the United States and Canada with ≥1 additional stroke risk factor who require interruption of warfarin for surgery/invasive procedure and do not have a prior stroke (within 12 weeks), major bleeding (within 6 weeks), severe renal insufficiency (CrCl <30 mL/min), thrombocytopenia (<100,000 × 109/L) or contraindication to perioperative LMWH. Intervention:Dalteparin, 100 IU/kg SC twice-daily, before and after surgery compared to SC placebo injections. Outcomes:1) primary outcomes: arterial thromboembolism (ischemic stroke, transient ischemic attack or systemic embolism) and major bleeding from perioperative Day −5 to Day +30; 2) secondary outcomes: acute coronary syndrome, venous thrombosis, minor bleeding. Analysis:Comparison of prespecified outcomes in LMWH and placebo groups. Summary:BRIDGE is an ongoing trial designed to definitively assess the efficacy and safety of LMWH bridging in patients with AF who require interruption of warfarin for an invasive procedure or surgery and aims to establish a standard-of-care for patients who require perioperative interruption of anticoagulants. Disclosures:Spyropoulos:sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Low molecular weight heparin dalteparin for bridging therapy. Douketis:sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, event adjudication; bristol meyer squibb: event adjudication; Pfizer: Speakers Bureau; boehringer-ingelheim: Membership on an entity's Board of Directors or advisory committees. Kaatz:Boehringer-Ingelheim: Consultancy, Research Funding, Speakers Bureau; Bristol Myer Squibb: Consultancy, Research Funding; Bayer: Research Funding; National Institute of Health: Research Funding; Canadian Institute of Health Research: Research Funding; Pfizer: Consultancy; Johnson and Johnson: Consultancy; Ortho-McNeil: Consultancy; GlaxoSmithKline: Speakers Bureau; AC Forum: Membership on an entity's Board of Directors or advisory committees; National Certification Board of Anticoagulation Providers: Membership on an entity's Board of Directors or advisory committees; National Blood Clot Alliance: Membership on an entity's Board of Directors or advisory committees. Ortel:Eisai: Research Funding; Instrumentation Laboratory: Consultancy; GSK: Research Funding.

Laboratory HIT Testing in Critically Ill Patients

Abstract 198▪FN2▪This icon denotes a clinically relevant abstract Introduction:Many critically ill patients are frequently suspected of having HIT because heparin exposure is nearly universal and up to 45% of medical-surgical ICU patients have a platelet count of less than 150 × 109. Methods:Our objectives were: (1) To estimate the incidence of suspected and objectively confirmed HIT; and (2) To evaluate whether a published clinical prediction rule (the 4T’s score) reliably rules out HIT in ‘low risk’ ICU patients. PROTECT was a multinational, concealed, stratified, randomized blinded trial enrolling medical-surgical critically ill patients to evaluate thromboprophylaxis with the low molecular weight heparin (LMWH) dalteparin 5,000U daily vs unfractionated heparin (UFH) 5,000 twice daily on the primary outcome of proximal leg deep vein thrombosis (DVT). Patients were evaluated for HIT and included in this HITEC Substudy if 1) their platelet count decreased to less than 50 × 109/L, 2) if there was an otherwise unexplained platelet count decrease to less than 50% of the patient’s baseline (defined as the value found on the first platelet count after ICU admission as long as the count is >100 × 109/L), or 3) if venous thrombosis occurred, and 4) if HIT was otherwise suspected. There were 2 laboratory components to HIT testing (local and central). For local real-time clinical care, HIT was evaluated and treated as per local practice. Centrally, blood samples were analyzed at the laboratory of Dr Ted Warkentin at McMaster University. The 4Ts Score was completed by Research Coordinators (RCs) and by central adjudication. We defined HIT as a clinical suspicion of HIT and a positive serotonin release assay (SRA). Results:The PROTECT trial enrolled 3746 patients of whom 763 patients (397 allocated to UFH and 366 to LMWH) met HITEC enrollment criteria; 151 because of an absolute platelet count of less than 50×109, 253 because of a fall in their platelet count of greater than 50% from the time of ICU admission and 534 because venous thrombosis developed and 128 because of a clinical suspicion of HIT (categories are not mutually exclusive). Of these 763 patients, 475 had a central or local laboratory HIT test performed and were adjudicated. HIT was present in 15/3746 patients enrolled in the PROTECT study (0.4%, 95% CI 0.2% to 0.7%), and 15/475 (3.2%) with local or central testing, while 432 patients with RC 4Ts scores were matched to an adjudicated outcome. Using the 4Ts score, RCs and central adjudication classified patients as low risk (4Ts score of 3 or less) in 71.1% and 86.3% of cases, respectively, moderate risk (score or 4 or 5) in 25.7% and 12.0% of cases, and high risk (score of 6 or more) in 3.2% and 1.7% of cases. There was a good correlation between a low pretest probability according to the RCs’ scores and the absence HIT (prevalence of adjudication confirmed HIT 1.6% (95% CI 0.5 to 3.7%).There was a moderate correlation between a low pretest probability according to central adjudication and the absence HIT (prevalence of adjudication confirmed HIT 2.6% (1.3 to 4.7%). Discussion:HIT occured in less than 1% of medical-surgical critically ill patients, and in 3% of patients who had at least one criterion to suspect HIT. We failed to confirm our pre-specified criteria for successful implementation of the 4T's score (that the upper boundary the 95% confidence interval about the proportion of patients with confirmed HIT and a low 4Ts score was less than 3%) and thus we conclude that use of the 4Ts score does not rule out the presence of platelet-activating antibodies in medical surgical critically ill patients with clinically suspected HIT; SRA testing is recommended. Funding:Canadian Institutes for Health Research and Heart and Stroke Foundation of Canada Disclosures:Crowther:CSL Behring: Consultancy; Leo Pharma: Consultancy, Research Funding; BI: Research Funding; Bayer: Research Funding; Pfizer: Consultancy, Research Funding; Octapharm: Consultancy; Artisan: Consultancy. Off Label Use: Dalteparin is not indicated for prolonged DVT prophylaxis in medical intensive care unit patients. Zytaruk:Pfizer: donated study drug dalteparin for PROTECT. Cook:Pfizer: donated study drug dalteparin for PROTECT. Warkentin:GTI Diagnostics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Pfizer Canada: Speakers Bureau; Sanofi-Aventis: Speakers Bureau; Informa: Patents & Royalties; Canyon Pharma: Consultancy, Speakers Bureau.

Dalteparin dose-dependently increases ROTEM® thrombelastography parameters only at supratherapeutic anti-factor Xa levels: An in vitro study

1. The low molecular weight heparin (LMWH) dalteparin is used, for example, to prevent primary venous thromboembolism in patients undergoing surgery or in medically ill patients. The anticoagulant activity of dalteparin can be monitored by measuring anti-factor Xa levels and activated partial thromboplastin time (aPTT); however, aPTT is an unreliable parameter in this case. The aim of the present in vitro study was to evaluate the thrombelastograph ROTEM(®) (Tem International, Munich, Germany) with respect to determining the anticoagulant activity of dalteparin at therapeutic and supratherapeutic plasma concentrations. 2. The ROTEM(®) parameters, namely coagulation time (CT), clot formation time (CFT) and maximum clot firmness (MCF), were measured using the reagents EXTEM and INTEM (Pentapharm, Munich, Germany) at increasing concentrations of dalteparin (0.01-10 μg/mL, which corresponded to anti-factor Xa levels of 1-1000 U/mL, respectively). 3. The mean CT measured using EXTEM was found to increase from 65.4 ± 27.9 s at baseline to 173.3 ± 112.2 s and 332.2 ± 200.7 s at drug concentrations of 1 and 10 μg/mL, respectively (P < 0.0001 for both). Moreover, the mean CFT value (EXTEM) increased from 97.7 ± 21.5 s at baseline to 187.6 ± 115.2 s (P = 0.0001) at a drug concentration of 10 μg/mL, which is greater than the therapeutic anti-factor Xa concentrations for LMWH. The results obtained when INTEM was used as the reagent were similar to those obtained using EXTEM. 4. In conclusion, the results indicate that the thrombelastograph ROTEM(®) can detect the anticoagulant effects of dalteparin only at supratherapeutic levels of anti-factor Xa.