Anti-factor Xa Activity Levels Research Articles

Novel fondaparinux protocol for anticoagulation therapy in adults with renal failure and suspected heparin-induced thrombocytopenia: a retrospective review of institutional protocol

IntroductionThe literature recommends against the use of fondaparinux in patients with kidney failure and dialysis as it may, with repeated dosing, accumulate and put patients at risk of bleeding. The management of patients with thrombosis in the presence of heparin-induced thrombocytopenia HIT requires the introduction of an alternative anticoagulant like bivalirudin or argatroban. When these drugs are not available, fondaparinux, remains the only alternative. In similar scenarios, there are few studies addressing how to administer it. MethodsWe developed a protocol for fondaparinux in patients with renal failure where pharmacokinetic parameters are altered, and levels changed only after hemodialysis or in cases of residual renal activity. Patients received a full first dose except for high risk of bleeding. We targeted a peak anti-factor Xa activity level of 0.6–1.3 units/ml and changed the subsequent dose accordingly. Furthermore, we monitored the patients for signs of bleeding, a drop in hemoglobin level, or clinical signs of thrombosis. DiscussionWe described 10 patients with kidney failure and suspected HIT taking fondaparinux. All the patients achieved therapeutic anti-factor Xa activity levels. However, one developed new-onset venous thromboembolism (VTE) despite therapeutic anti-factor Xa levels. Another patient experienced a bleeding episode. We believe that these two patients developed complications due to their medical conditions rather than the use of fondaparinux.ConclusionFondaparinux can be safely used in kidney failure using our protocol. However, despite its safety profile and relative success, this case series was small. More robust studies need to be conducted prior to drawing conclusions.

Efficacy and Safety of Two Different Enoxaparin Doses for Thromboprophylaxis in Non-critically Ill Patients: A Randomized Controlled Trial.

Recently, a few studies based on anti-factor Xa activity levels have propounded doubtful and sub-prophylactic levels by the usual dose of enoxaparin in surgical and critically ill patients. In this study, we assessed two doses of enoxaparin in adult non-critically ill patients. Patients were randomly assigned into two groups of intervention and control. While the intervention group received enoxaparin with a daily dose of 60 mg, the control group received enoxaparin 40 mg. Anti-factor Xa activity was measured based on the peak steady-state levels. The level of 0.2 to 0.4 IU/mL was considered as a prophylactic goal. All individuals were followed for bleeding or thromboembolic events during admission. The mean levels of anti-factor Xa were 0.29 ± 0.13 IU/mL in the control group (n = 31) and 0.44 ± 0.19 IU/mL in the intervention group (n = 29). More patients in the control group had an optimal level of anti-factor Xa compared to the patients in the intervention group (62.1% vs. 29%). No adverse outcomes were detected in any of the groups. Enoxaparin dose of 60 mg daily provided anti-factor Xa level higher than desired in most patients. In non-critically ill patients, the dose of 40 mg is the proper dose for thromboprophylaxis.

Association between anti F-Xa activity and plasma levels in patients with non valvular atrial fibrillation on apixaban

Apixaban, a Factor Xa inhibitor, has been shown to confer superior net clinical benefit compared to warfarin in the management of patients with non-valvular atrial fibrillation (NVAF). While warfarin effect can be easily monitored using INR measurements, assessment of anti-Factor Xa activity level is currently not readily available. Effects of direct oral anticoagulants have been shown to be related to their plasma levels.

Contemporary Reversal of Oral Anticoagulation in Intracerebral Hemorrhage.

Author(s): Bower, Matthew M; Sweidan, Alexander J; Shafie, Mohammad; Atallah, Steven; Groysman, Leonid I; Yu, Wengui

An anticoagulation protocol for use after congenital cardiac surgery

BackgroundPatients undergoing surgery for congenital heart disease are at high risk for bleeding as well as thrombosis in the postoperative period. The objective of the study was to describe the design and effects of implementing a standardized unfractionated heparin anticoagulation protocol for children after congenital heart surgery. MethodsWe created a tiered guideline for the postoperative management of bleeding and thrombosis. In patients treated with unfractionated heparin, anti-factor Xa activity level as well as activated partial thromboplastin time were used for dose titration. Clinical outcomes, including bleeding and thrombosis events, were prospectively collected for 5 months before and after protocol implementation and adjudicated as either minor, clinically relevant nonmajor, or major. ResultsAmong 792 surgical patients followed during the study period, a total of 203 patients (87 preimplementation, 116 postimplementation) were treated with therapeutic unfractionated heparin over a total of 1481 patient days. Of these, 28% were neonates and 35% were infants (29 days to 1 year), with a trend toward fewer neonates and lower Risk Adjustment for Congenital Heart Surgery (RACHS) scores after protocol implementation. Among 1321 time-matched pairs, activated partial thromboplastin time and antifactor Xa activity levels were poorly correlated (r2 = 0.33). Clinically relevant bleeding events, which required increased medical care, including blood transfusion, decreased after protocol implementation (4.14 vs 1.62 bleeding events per 100 patient-days; risk ratio, 0.39 [0.20-0.75]; P = .005), even after correcting for differences in age and RACHS scores (P = .006). This finding was primarily found after RACHS category 1 to 3 procedures (risk ratio, 0.27 [0.10-0.73]; P = .0099) and in noninfants (risk ratio, 0.25 [0.09-0.65]; P = .005). There were no significant differences in the incidences of major bleeding (P = .88) or any thrombosis (P = .55). ConclusionsThe use of a standardized anticoagulation protocol is feasible and might reduce the incidence of bleeding and thrombosis events in postcardiotomy patients.

Enoxaparin Population Pharmacokinetics in the First Year of Life.

Enoxaparin dosing requirements in the first year of life can be highly variable. Characterization of pharmacokinetics in this patient population can assist in dosing. Patients less than 1 year postnatal age who received enoxaparin and had an anti-factor Xa activity level drawn as inpatients were identified through the pharmacy database over a 5-year period. Patients on renal replacement therapy or with hyperbilirubinemia were excluded. Data collection included demographic variables, indication for enoxaparin, enoxaparin doses, anti-factor Xa activity levels, serum creatinine, hemoglobin, hematocrit, platelet count, and urine output over the previous 24 hours. Population pharmacokinetic analysis was performed with NONMEM. A total of 182 patients [male 50%, median 100 days postnatal age (range: 4-353 days)] met the study criteria. Patients received median 22 doses (range: 1-526) at a mean starting dose of 1.38 ± 0.43 mg/kg with median 5 (range: 1-56) anti-factor Xa activity levels measured. A 1-compartment proportional and additive error model best fits the data. Allometrically scaled weight significantly decreased the objective function value, as did serum creatinine on clearance, and postmenstrual age (PMA) on volume of distribution. When evaluated graphically, dosing based on PMA appeared to have less variability as compared to postnatal age-based dosing. Dosing of enoxaparin in infants younger than 1 year should incorporate PMA.

Population Pharmacokinetics of Enoxaparin in Pediatric Patients.

There are no studies evaluating the pharmacokinetics of enoxaparin in the hospitalized pediatric patient population. To characterize the pharmacokinetics of enoxaparin in pediatric patients. A retrospective review of inpatients 1 to 18 years of age admitted to our institution who received enoxaparin with anti-factor Xa activity level monitoring was performed. Demographic variables, enoxaparin dosing, and anti-factor Xa activity levels were collected. Population pharmacokinetic analysis was performed with bootstrap analysis. Simulation (n = 10 000) was performed to determine the percentage who achieved targeted anti-Xa levels at various doses. A total of 853 patients (male 52.1%, median age = 12.2 years; interquartile range [IQR] = 4.6-15.8 years) received a mean enoxaparin dose of 0.86 ± 0.31 mg/kg/dose. A median of 3 (IQR = 1-5) anti-factor Xa levels were sampled at 4.4 ± 1.3 hours after a dose, with a mean anti-factor Xa level of 0.52 ± 0.23 U/mL. A 1-compartment model best fit the data, and significant covariates included allometrically scaled weight, serum creatinine, and hematocrit on clearance, and platelets on volume of distribution. Simulations were run for patients both without and with reduced kidney function (creatinine clearance of ≤30 mL/min/1.73 m2). A dose of 1 mg/kg/dose every 12 hours had the highest probability (72.3%) of achieving an anti-Xa level within the target range (0.5-1 U/mL), whereas a dose reduction of ~30% achieved the same result in patients with reduced kidney function. Pediatric patients should initially be dosed at 1-mg/kg/dose subcutaneously every 12 hours for treatment of thromboembolism followed by anti-Xa activity monitoring. Dose reductions of ~30% for creatinine clearance ≤30 mL/min/1.73 m2 are required.

Strategies to Prevent and Manage Thrombotic Complications of Acute Lymphoblastic Leukemia in Children and Young People Vary Between Centers in the United Kingdom.

There is a lack of evidence-based guidance for the prevention and management of thrombosis in children and young people treated for acute lymphoblastic leukemia. To determine current UK practice, a survey was sent to 28 centers participating in the Medical Research Council UKALL 2011 trial. Marked variation in practice was noted. In total, 43% of centers defer central venous access device insertion until end of induction for treatment of low-risk disease. Central venous access devices are removed at the end of intensive blocks in 38% and end of treatment in 42%. Duration of anticoagulation for line-associated thrombosis is 6 weeks in 43% and 3 months in 33% and for cerebral sinovenous thrombosis is 3 months in 71% and 6 months in 24%. Platelet transfusion to maintain platelet count >50×10/L, in preference to interrupting therapeutic anticoagulation, is used by 50% for line-associated thrombosis and 73% for cerebral sinovenous thrombosis. Conformity of practice was seen in some areas. In total, 70% treat thrombosis with twice-daily low-molecular weight heparin and 86% monitor antifactor Xa activity levels. In total, 91% reexpose individuals to asparaginase following a thrombotic event. Given this variation in practice, in the absence of high-quality evidence, consensus guidelines may be helpful.

Non–weight-based enoxaparin dosing subtherapeutic in trauma patients

BackgroundWe report our experience dosing and monitoring enoxaparin with anti-factor Xa activity (anti-FXaA) levels for venous thromboembolism prophylaxis in trauma patients (TP). Materials and methodsTP receiving standard, non–weight-based dosed enoxaparin administered every 12 h for venous thromboembolism prophylaxis with peak anti-FXaA levels measured were prospectively monitored and evaluated and those whose first anti-FXaA levels ≥ or <0.2 IU/mL were compared. Anti-FXaA levels and enoxaparin dose (mg/kg actual body weight) were evaluated for correlation. ResultsOf the fifty-one TP included, initial anti-FXaA levels were <0.2 IU/mL in 37 (72.5%) whose dose was lower than those within target range (0.38 [0.32–0.42] mg/kg versus 0.45 [0.39–0.48] mg/kg, P = 0.003). Thirty-seven TP achieved anti-FXaA level ≥0.2 IU/mL (23 requiring dose increases) at a dose of 0.49 [0.44–0.54] mg/kg. Correlation between dose and anti-FXaA levels for the initial 51 anti-FXaA levels (r = 0.360, P = 0.009) and for all 103 anti-XaA levels (r = 0.556, P < 0.001) was noted. ConclusionsNon–weight-based enoxaparin dosing did not achieve target anti-FXaA levels in most TP. Higher anti-FXaA levels correlated with larger weight-based enoxaparin doses. Weight-based enoxaparin dosing (i.e., 0.5 mg/kg subcutaneously every 12 h) would better achieve target anti-FXaA levels.

Antithrombin Concentrate Use in Children Receiving Unfractionated Heparin for Acute Thrombosis

To characterize features of antithrombin concentrate (ATC) use in children receiving unfractionated heparin (UFH) therapy for acute thrombosis. All pediatric patients at Texas Children's Hospital who received ATC in the context of UFH therapy for acute thrombosis during February 2011 to May 2013 were analyzed. Fifty-one children received ATC during UFH therapy for acute thrombosis. Median age was 3 months (IQR 1 to 18 months). Clinical indications included venous (53%), arterial (37%), venous and arterial (6%), and intracardiac (4%) thrombosis. Median baseline antithrombin (AT) level was 61% and UFH dose was 26 U/kg/h. The median dose of ATC was 49.9 IU/kg (IQR 32.6 to 50.0 IU/kg). Although most patients (86%) did not undergo a change in UFH dose, there was a significant increase in both AT and anti-factor Xa level after the first dose of ATC (P < .001 for both). There was no correlation between ATC dose or increment in AT level above baseline and the achievement of targeted anticoagulation by anti-factor X activity level. Adverse bleeding events occurred in 10% of patients. There was a significant change in AT and anti-factor Xa activity level after a single dose of ATC despite little to no change in dose of UFH. ATC appears to facilitate anticoagulation with UFH in some children with acute thrombosis but the degree of response is variable and dependent on factors identified in this study. Bleeding and other theoretical risks must be carefully considered.

PKP-006 Evaluation of the predictive ability of different formulas to estimate renal function when enoxaparin is used

BackgroundExposure to enoxaparin is significantly increased in patients with severe renal impairment (creatinine clearance ClCr <30 mL/min). Thus, a dose adjustment is recommended for both the therapeutic and prophylactic dose...

New aspects on efficient anticoagulation and antiplatelet strategies in sheep

BackgroundAfter addressing fundamental questions in preclinical models in vitro or in small animals in vivo, the translation into large animal models has become a prerequisite before transferring new findings to human medicine. Especially in cardiovascular, orthopaedic and reconstructive surgery, the sheep is an important in vivo model for testing innovative therapies or medical devices prior to clinical application. For a wide variety of sheep model based research projects, an optimal anticoagulation and antiplatelet therapy is mandatory. However, no standardised scheme for this model has been developed so far. Thus the efficacy of antiplatelet (acetylsalicylic acid, clopidogrel, ticagrelor) and anticoagulant (sodium enoxaparin, dabigatran etexilate) strategies was evaluated through aggregometry, anti-factor Xa activity and plasma thrombin inhibitor levels in sheep of different ages.ResultsResponses to antiplatelet and anticoagulant drugs in different concentrations were studied in the sheep. First, a baseline for the measurement of platelet aggregation was assessed in 20 sheep. The effectiveness of 225 mg clopidogrel twice daily (bid) in 2/5 sheep and 150 mg bid in 3/5 lambs could be demonstrated, while clopidogrel and its metabolite carboxylic acid were detected in every plasma sample. High dose ticagrelor (375 mg bid) resulted in sufficient inhibition of platelet aggregation in 1/5 sheep, while acetylsalicylic acid did not show any antiplatelet effect. Therapeutic anti-factor Xa levels were achieved with age-dependent dosages of sodium enoxaparin (sheep 3 mg/kg bid, lambs 5 mg/kg bid). Administration of dabigatran etexilate resulted in plasma concentrations similar to human ranges in 2/5 sheep, despite receiving quadruple dosages (600 mg bid).ConclusionHigh dosages of clopidogrel inhibited platelet aggregation merely in a low number of sheep despite sufficient absorption. Ticagrelor and acetylsalicylic acid cannot be recommended for platelet inhibition in sheep. Efficient anticoagulation can be ensured using sodium enoxaparin rather than dabigatran etexilate in age-dependent dosages. The findings of this study significantly contribute to the improvement of a safe and reliable prophylaxis for thromboembolic events in sheep. Applying these results in future translational experimental studies may help to avoid early dropouts due to thromboembolic events and associated unnecessary high animal numbers.

Intentional low-molecular-weight heparin overdose

The reversal of low-molecular-weight heparins, particularly at supratherapeutic levels, remains challenging. The paucity of literature available to guide the treatment of these patients makes their management difficult for primary care providers, surgeons, and subspecialists alike. We report the case of a 34-year-old woman, who intentionally overdosed on enoxaparin (Lovenox) in a suicide attempt. Her initial antifactor Xa activity level was 8.3 IU/ml, the highest level reported in the literature to date. She was initially managed conservatively, however, within 24 h of admission she developed evidence of acute blood loss. Protamine sulfate and three doses of recombinant activated factor VII (rFVIIa) were administered in an effort to control bleeding. We report the effects of these measures and review the literature to date. Our study is one of the first to graph in-vivo antifactor Xa activity levels and to suggest a drug half-life of approximately 25 h.

Fluctuations in anti-factor Xa levels with therapeutic enoxaparin anticoagulation in pregnancy

The objective of the study was to evaluate anti-factor Xa levels with therapeutic enoxaparin anticoagulation in pregnancy. A total of 15 pregnant subjects on therapeutic doses of enoxaparin (1 mg/kg +/-20% subcutaneously (s.c.) twice daily (b.i.d.)) were enrolled prospectively in this cross-sectional pilot project. Three blood levels for anti-factor Xa activity were examined: before the enoxaparin dose (trough), 3- to 4-h later (peak) and 8-h later. Anti-factor Xa activity level between 0.5 and 1.2 U/ml was considered therapeutic. Mean anti-factor Xa activity levels were: trough 0.45+/-0.18, peak 0.9+/-0.25 and 8-h after dose 0.72+/-0.23 U/ml. All peak levels were therapeutic; 20% (3/15) of the 8 h and 73% (11/15) of the trough levels were sub-therapeutic. Trough and 8-h post-dose anti-factor Xa activity levels were sub-therapeutic in a substantial number of patients receiving a b.i.d. regimen of therapeutic enoxaparin.

Validation of Pharmacokinetic {PK} Simulation for Fondaparinux (FPX) Dosing by FPX-Specific Anti-Factor Xa Assay in Elderly Cancer Patients with Severe Renal Dysfunction

Background: Fondaparinux (FPX) is a synthetic pentasaccharide inhibitor of factor Xa indicated for prophylaxis and treatment of venous thromboembolism (VTE). It has an 18 hr half-life (T 1/2), thus is suitable for once-daily dosing, but is cleared by the kidney and not recommended for patients with SRD (creatinine clearance (CrCl) <30 mL/min) in whom drug accumulation could increase bleeding risk. No published clinical trials have evaluated the use of FPX in this population. However, in a pharmacokinetic simulation, serum FPX concentrations in such patients receiving FPX for VTE prophylaxis every other day were predicted to be similar to those in patients with mild renal impairment on daily dosing. Validation of this dosing regimen with an automated assay that determines anti-factor Xa activity levels using FPX calibrators could make this versatile drug accessible to many hypercoagulable patients with severe renal dysfunctionMethods: A retrospective analysis of institutional pharmacokinetic protocol outcomes was conducted in a small population of elderly cancer patients with chronic or acute-on- chronic SRD (CrCl < 30ml/min for >72 hrs) who received subcutaneous FPX 2.5 mg every 48 hrs for VTE prophylaxis. Peak and trough levels were determined at 3 hours post-dose and 1hr pre-dose respectively, for at least 3 doses. FPX levels were assayed with FPX-specific calibrators.Descriptive data appear in Table 1.PtAgeSexRaceDHeight (cm)Weight (kg)Creatinine (mg/dL)CrCl (ml/min)Peak (mcg/mL)Trough (mcg/mL)171FWBladder CA167.671.92.7180.520.15286MBLung CA166.476.21.7280.470.14367MWGiloma180.375.03.2240.270.12483MWBladder CA175.390.01.9290.330.08575MWProstate CA16774.55.4110.60.11662MWLymphoma17261.53.1220.280.03759FBUterine CA160115.04.8100.370.1853MBMultiple myeloma177.857.06.0100.270.2Results: Eight patients were included in this study with mean age of 69.5 ± 11.5 years and creatinine clearance of 19 ± 7.9 mL/min. The mean peak FPX concentration was 0.39 ± 0.13 mcg/mL, in the lower target range for prophylaxis efficacy (0.39–0.50 mcg/mL) and mean trough concentration, thought to be an indicator of drug accumulation, 0.12 ± 0.05 mcg/mL (target range: 0.14–0.19 mcg/mL). No major bleeding or VTE events were noted during FPX administration.Conclusion: A pharmacokinetic simulation permitting extrapolation of FPX dosing for VTE prophylaxis in patients with severe renal dysfunction from data in patients with mild dysfunction has been shown to be valid in a small population of sick elderly cancer patients by PK monitoring using a FPX -specific anti-Factor Xa assay, showing no drug accumulation over at least three doses (144 hrs) [cyl1] and the drug clinically safe as dosed.

Do we need thrombin generation assays for monitoring anticoagulation?

Thromb Haemost 2008; 100: 179–180 Protamine sulphate neutralizes the anticoagulant effect of unfractionated heparin (UFH), and this effect can easily be demonstrated by a variety of assay systems, including the traditional activated partial thromboplastin time (aPTT), as well as anti-factor Xa assays, or thrombin generation tests such as the Calibrated Automated Thrombogram (CAT) (1). Protamine also neutralizes the anticoagulant effect of low-molecular-weight heparins (LMWH), but to a lesser and variable extent (2). In this issue of Thrombosis and Haemostasis Gatt et al. (3) compared the effect of protamin sulphate and other drugs on the effect of UFH, LMWH, danaparoid and fondaparinux on aPTT, anti-factor Xa-level, and a thrombin generation test. Reversal of anticoagulation is an interesting model for testing the performance of monitoring assays for anticoagulant drugs. One important finding of the present paper by Gatt et al. is that protamine has little effect on apparent anti-factor Xa-activity levels of LMWH, but a considerable effect on the CAT results. This suggests that the success of protamine administration cannot be monitored by measuring anti-factor Xa activity.This is in some contrast to other investigations showing that anti-factor Xa activity of LMWH is affected by protamine (4, 5). Finally, protamine has no effect on the anticoagulant effect of danaparoid and fondaparinux, and this was evident in both anti-factor Xa-activity and CAT assays. Reversal of danaparoid and fondaparinux, and the conventional LMWH is seldom necessary, but these drugs display a considerably prolonged half-life in patients with impaired renal function and severe bleeding may occur if the dose is not adjusted appropriately (6). Monitoring of the anticoagulant effect in patients with impaired renal function and in critically ill patients in general is essential for prevention of bleeding complications, and an assay system that gives a more global image of haemostatic function than an anti-factor Xa assay might be advantageous (7). Recombinant factor VIIa (rFVIIa, NovoSeven®) has been suggested for treatment of patients with severe anticoagulant-induced bleeding (8), and several case reports have been published on the use of rFVIIa in bleeding fondaparinux-treated patients (9, 10). As shown by Gatt et al. (3), the anti-factor Xa levels are not influenced by rFVIIa, whereas the CAT results reflect the procoagulant effect of rFVIIa. FEIBA® is an alternative to rFVIIa in the treatment of haemophilia patients with inhibitors, and may also be helpful in anticoagulant-induced bleeding. In the present experiments of Gatt et al., FEIBA acted quite similar to rFVIIa, although rFVIIa seemed to be more efficient. Another interesting result is that fresh frozen plasma reduces the anti-factor Xa-activity of UFH, LMWH, danaparoid, and fondaparinux, but has little effect on the anticoagulant effect measured by CAT. The main effect of fresh frozen plasma is dilution, and it might be that the threshold concentration of the anticoagulants for an effect on the assay systems is different. Additional experiments might be needed to determine the threshold concentration of LMWH, danaparoid and fondaparinux for the CAT. From the present results, and experiments by other investigators it seems that thrombin generation tests more reliably reflect the anticoagulant effect of these drugs (11). Anticoagulant drugs delay clot formation and traditional methods for the monitoring of anticoagulation are based precisely on this effect.After addition of an activator, clot formation occurs when only about 5% of the prothrombin has been activated to form thrombin. There are many theories why additional thrombin is formed after clot formation.The additional thrombin may not only improve clot stability by activating factor XIII and TAFI, induce cellular invasion or activation of endothelial cells adjacent to the clot in vivo, but also serves to induce the anticoagulant protein C-dependent feedback control of thrombin generation. Thrombin generation assays not only detect delayed thrombin generation (leading to a prolonged clotting time), but also reduced thrombin activity (leading to changes in structural and functional properties of the clot). Both may be relevant for the therapeutic effect of anticoagulant drugs. The results of Gatt et al. (3) indicate that the CAT may be a prototype for global coagulation assays used for monitoring of anticoagulant therapy. New anticoagulants are entering the scene and one of the major advantages of these drugs is the reliable anticoagulant effect with little intraand inter-individual varia-

Unfractionated heparin infusion for thromboprophylaxis in highest risk gastric bypass surgery.

Patients undergoing gastric bypass for obesity are at risk for postoperative venous thromboembolic complications. Per our routine, these patients receive unfractionated heparin (UFH) per a previously described, blood volume-based, subcutaneous prophylactic UFH protocol. However, some patients have additional risk factors for thromboembolism, and we consider these patients to be at highest risk. To increase the predictability and reliable achievement of prophylactic anti-factor Xa levels for these patients at highest risk, we developed a prophylactic UFH continuous intravenous infusion protocol. An UFH prophylactic protocol was developed in which the initial UFH loading dose and infusion rate were determined, based on patient blood volume and age. The target prophylactic anti-factor Xa activity range was 0.15-0.20 units/mL. 19 patients were admitted to the hospital the day before gastric bypass surgery. A prophylactic UFH infusion was initiated, and anti-factor Xa levels were checked and adjusted per protocol. The patients underwent surgery the following day and the UFH infusion was continued intra-operatively. No patients were diagnosed with a deep venous thromboembolism. 2 patients experienced peri-operative hemorrhagic complications in spite of anti-factor Xa activity levels in, or only slightly above, the targeted range. Both patients recovered without further complications. For highest risk gastric bypass patients, an UFH prophylactic continuous infusion protocol was effective in preventing postoperative thromboembolic events. Hemorrhagic complications were easily managed and did not result in long-term sequelae.

A Comparative, Double-blind, Randomised Trial of a New Second Generation LMWH (Bemiparin) and UFH in the Prevention of Post-operative Venous Thromboembolism

A randomised, prospective, double-blind trial was performed, to compare the safety and efficacy of a new low-molecular-weight heparin (LMWH) Bemiparin and standard unfractionated heparin (UFH), for the prophylaxis of postoperative venous thromboembolism. 300 patients scheduled to undergo elective hip arthroplasty were included. The principal outcome measures were the incidence of thromboembolic events and bleeding complications. 149 patients received 3,500 anti-Xa IU of bemiparin plus a placebo injection daily and 149 patients received 5,000 IU of UFH twice a day. The two groups were similar with respect to factors likely to affect the risk of developing post-operative venous thromboembolism (VTE) and risk of bleeding events. During the post-operative period, 34 patients developed VTE complications; 9 (7.2%) in the bemiparin group and 25 (18.7%) in the UFH group. VTE in the two groups was statistically significant (OR of 2.96; 95% CI 1.32-6.62 and p = 0.01). There were no significant differences in the frequency of bleeding complications: major bleeding requiring discontinuation of prophylaxis, (OR 1.21; 95% CI 0.36-4.05; p = 1.00), the measured median operative blood loss (p = 0.77) or the median postoperative drain loss (p = 0.97), and the number of patients who developed wound haematoma (OR 0.87; 95% CI 0.31-2.46; p = 1.00). A comparison of coagulation parameters on the preoperative day with post-operative day 2 +/- 1, day 6 +/- 1 and day of discharge showed a significantly higher AT concentration, anti-factor Xa activity and TFPI levels in the bemiparin group when compared with UFH. This study demonstrates that bemiparin, in a single daily subcutaneous dose of 3,500 anti-Xa IU in high risk patients undergoing hip arthroplasty is more effective than UFH administered twice daily at a dose of 5,000 IU in the prevention of postoperative VTE. Both agents are equally safe.

Changes in the pharmacokinetics of the low-molecular-weight heparin enoxaparin sodium during pregnancy

Objective: We sought to evaluate the pharmacokinetics of subcutaneously administered enoxaparin sodium during and after pregnancy. Study Design: Daily subcutaneous injections of enoxaparin sodium (40 mg) were administered to 13 pregnant women. On 3 separate occasions, once early in pregnancy (12-15 weeks), once late in pregnancy (30-33 weeks), and once in the nonpregnant state (6-8 weeks post partum), serial blood samples were collected, and plasma was analyzed for antifactor Xa activity. Analysis of variance was used for statistical analysis. P < .05 was significant. Results: The time to maximum concentration and the mean residence time in pregnancy compared with the postpartum state were not significantly different. During early and late pregnancy, maximum concentration and the last measurable anti–factor Xa activity level were lower than in the nonpregnant state ( P < .05). The area under the plasma activity–versus–time curve was significantly lower in pregnancy than in the postpartum state ( P < .05). Conclusion: The pharmacokinetics of enoxaparin sodium are significantly different during pregnancy than in the same women when nonpregnant. The observed difference is likely because of increased renal clearance of enoxaparin during pregnancy. This finding has significant implications for appropriate dosing of enoxaparin in pregnancy. (Am J Obstet Gynecol 1999;181:1113-7.)