Comparison of efficacy of nadroparin and fondaparinux sodium for prevention of deep vein thromboembolism in lower extremities after total hip arthroplasty and total knee arthroplasty: a retrospective study of 592 patients.

OBJECTIVES: To compare the efficacy of nadroparin and fondaparinux sodium for prevention of deep vein thromboembolism (DVT) in lower extremities after total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: A total of 592 patients were enrolled in the study. Clinical data of patients who underwent total hip arthroplasty (THA) and total knee arthroplasty (TKA) in our hospital from December 2021 to September 2022 were retrospectively collected, which mainly included patients' general information, surgery-related information, and DVT-related information. The patients were categorized into the nadroparin group(n = 278) and the fondaparinux sodium group(n = 314) according to the types of anticoagulants used. Anticoagulant therapy began 12-24 h after operation and continued until discharge. DVT prevalence between two groups was compared. The Statistical Package for Social Sciences (SPSS) software version 25 (SPSS, Armonk, NY, USA) was used for statistical analysis. RESULTS: The prevalence of DVT in the nadroparin group and the fondaparinux sodium group was 8.3% (23/278) and 15.0% (47/314), respectively(p = 0.012). Statistical analysis showed that nadroparin group showed a lower prevalence of thrombosis than fondaparinux group (OR = 1.952, P = 0.012). Subgroup analyses showed that nadroparin group had a lower prevalence of DVT than fondaparinux group in some special patients groups such as female patients (OR = 2.258, P = 0.007), patients who are 65-79 years old (OR = 2.796, P = 0.004), patients with hypertension (OR = 2.237, P = 0.042), patients who underwent TKA (OR = 2.091, P = 0.011), and patients who underwent combined spinal-epidural anesthesia (OR = 2.490, P = 0.003) (P < 0.05). CONCLUSION: Nadroparin may have an advantage over fondaparinux sodium in preventing DVT in lower extremities after THA and TKA.

Large variation in anti-factor Xa levels with nadroparin as thromboprophylaxis in COVID-19 and non-COVID-19 critically ill patients.

PURPOSE: Critically ill COVID-19 and non-COVID-19 patients receive thromboprophylaxis with the LMWH nadroparin. Whether a standard dosage is adequate in attaining the target anti-FXa levels (0.20-0.50 IU/ml) in these groups is unknown. METHODS: This study was a prospective, observational study in the ICU of a large general teaching hospital in the Netherlands. COVID-19 and non-COVID-19 patients admitted to the ICU who received LMWH in a prophylactic dosage of 2850 IU, 5700 IU or 11400 IU subcutaneously were eligible for the study. Anti-FXa levels were determined 4 h after administration. Relevant laboratory parameters, prespecified co-variates and clinical data were extracted from the electronic health record system. The primary goal was to evaluate anti-FXa levels in critically ill patients on a prophylactic dosage of nadroparin. The second goal was to investigate whether covariates had an influence on anti-FXa levels. RESULTS: A total of 62 patients were included in the analysis. In the COVID-19 group and non-COVID-19 group, 29 (96%) and 12 patients (38%) reached anti-FXa levels above 0.20 IU/ml, respectively. In the non-COVID-19 group, 63% of the patients had anti-FXA levels below the target range. When adjusted for nadroparin dosage a significant relation was found between body weight and the anti-FXa level (p = 0.013). CONCLUSION: A standard nadroparin dosage of 2850 IU sc in the critically ill patient is not sufficient to attain target anti-FXa levels in the majority of the studied patient group. We suggest a standard higher dosage in combination with body-weight dependent dosing as it leads to better exposure to nadroparin. CLINICAL TRIALS REGISTRATION: Retrospectively registered, ClinicalTrials.gov ID NTC 05926518 g, date of registration 06/01/23, unique ID 2020/1725.

Is the current therapeutic dosage of nadroparin adequate for neonates and infants under 8 months with thromboembolic disease? a population pharmacokinetic study from a national children's medical center.

Objectives: Nadroparin, a low-molecular-weight-heparin is commonly used off-label in neonates and infants for thromboembolic events prevention. However, the recommended dosing regimen often fails to achieve therapeutic target ranges. This study aimed to develop a population pharmacokinetic (PK) model of nadroparin to determine an appropriate dosing regimen for neonates and infants less than 8 months. Methods: A retrospective chart review was conducted on patients treated with nadroparin at Children's Hospital of Fudan University between July 2021 and December 2023. A population PK model was developed using anti-Xa levels, and its predictive performance was evaluated internally. Monte Carlo simulations were performed to design an initial dosing schedule targeting anti-Xa levels between 0.5 and 1 IU/mL. Results: A total of 40 neonates and infants aged less than 8 months with gestational age ranging from 25 to 41 weeks treated with nadroparin were enrolled in the study for analysis. A one-compartment PK model with first order absorption and elimination was adequately fitted to the data. Creatinine clearance was identified as a significant factor contributing to inter-individual variability in clearance. The typical population parameter estimates of clearance, distribution volume and absorption rate in this population were 0.211 L/h, 1.55 L and 0.495 h-1, respectively. Our findings suggest that current therapeutic doses of nadroparin (150-200 IU/kg q12 h) may result in subtherapeutic exposure, thus higher doses might be required. Conclusion: The present study offers the first estimation of PK parameters for nadroparin in preterm or term neonates and infants less than 8 months utilizing the model. Our findings have potential implications for recommending initial personalized dosages, particularly among patient populations exhibiting similar characteristics.

Effect of conventional hemodialysis on the apixaban plasma concentration.

PURPOSE: Apixaban is a factor Xa inhibitor used in patients undergoing hemodialysis treatment. The objective of this study is to investigate the effect of hemodialysis on apixaban plasma concentrations. METHODS: This observational study is on patients treated with apixaban 2.5 mg twice daily on conventional hemodialysis with standard low-molecular-weight heparin (LMWH) anticoagulation (nadroparin 3800-7600 IU). Plasma blood samples were collected before starting dialysis (t1), 2 h after starting dialysis (t2), and directly after dialysis (t3). Apixaban concentration was measured before and after dialysis. Anti-Xa activity was measured for all three samples. RESULTS: A significant difference was observed between the apixaban concentration before and after dialysis (mean before dialysis 141.03 ng/mL; mean after dialysis 102.71 ng/mL; p = 0.003). Nonetheless, both apixaban plasma concentrations and anti-Xa levels remained within the reference range. Anti-Xa levels had a strong correlation with the apixaban concentrations (r = 0.935, p = 0.000). Thus, anti-Xa activity might be used as a surrogate for apixaban plasma concentration. CONCLUSION: There seems to be no need for dose adjustments of apixaban; co-administration of LMWH next to apixaban might also be unnecessary.

The effect of renal impairment and obesity on anti-Xa peak and trough levels in patients receiving therapeutic doses of nadroparin: a comparison with control patients.

PURPOSE: Anti-Xa peak level monitoring is recommended during LMWH treatment in renal impairment or obesity. The trough level has been proposed as marker for bleeding. We studied the influence of renal impairment and obesity on anti-Xa levels. METHODS: Peak and trough levels were collected during therapeutic nadroparin treatment in patients with renal impairment, obese patients, and controls. 27 patients (n = 68 samples) were evaluated and combined with published data (n = 319 samples from 35 patients) using population pharmacokinetic (popPK) modelling. RESULTS: Median peak level was 0.44 and 0.95 IU/mL in renal impairment with and without dose reduction and 0.60 and 0.43 IU/mL in obesity and controls, respectively. Trough levels were < 0.5 IU/mL in all patients with renal impairment with dose reduction and in 5/6 control patients. In the popPK model, total body weight and eGFR were covariates for clearance and lean body weight for distribution volume. Model-based evaluations demonstrated peak levels below the therapeutic window in controls and increased levels in renal impairment. Dose reductions resulted in a different effect on peak and trough levels. Obese patients (BMI up to 32 kg/m2) had similar levels upon weight-based dosing. CONCLUSION: In renal impairment, anti-Xa peak levels after dose reduction are comparable to those in controls. Weight-based dosing is suitable for obese patients. Aiming for peak levels between 0.6 and 1.0 IU/mL in these patients would result in overexposure compared to controls. Considering the association of trough levels and bleeding risk and our findings, trough monitoring seems to be a suitable parameter to identify nadroparin accumulation.

The right time to measure anti-Xa activity in critical illness: pharmacokinetics of therapeutic dose nadroparin.

Background: Peak anti-Xa activity of low-molecular-weight heparin nadroparin is measured 3 to 5 hours after subcutaneous injection. In critically ill patients, physiological changes and medical therapies may result in peak activities before or after this interval, possibly impacting dosing. Objectives: The primary objective was to determine the percentage of critically ill patients with adequately estimated peak activities drawn 3 to 5 hours after subcutaneous administration of a therapeutic dose of nadroparin. Adequate was defined as a peak activity of ≥80% of the actual peak anti-Xa activity. If ≥80% of patients had adequately estimated peak activities in the 3- to 5-hour interval, measurement in this interval was regarded as acceptable. The secondary objective was to determine the pharmacokinetic profile of nadroparin. Methods: In this single-center, prospective study, we evaluated anti-Xa activities in patients admitted to a general intensive care unit. After ≥4 equal doses of nadroparin, anti-Xa activity was measured according to a 12- to 24-hour sampling scheme. Results: In 25 patients, anti-Xa activities drawn between 3 and 5 hours after administration ranged 80% to 100% of the actual peak activity. Compared to the threshold level of an adequate estimation in at least 20 patients (≥80%), measuring anti-Xa activities in the 3- to 5-hour interval is an acceptable method (1-tailed binomial test; P < .02). We found a large interindividual variability for nadroparin exposure (mean ± SD area-under-the-curve0-12h, 10.3 ± 4.8 IU·h/mL) and delayed elimination (t1/2 range, 4.0-120.9 hours) despite adequate renal function. Conclusion: In critically ill patients, measuring anti-Xa activity in a 3- to 5-hour interval after subcutaneous injection of therapeutic nadroparin is an acceptable method to estimate the actual peak anti-Xa activity.

Effects of Routine Antithrombotic-Adjusted Dose of Rivaroxaban and Nadroparin Calcium on Tendon Healing of Rats: An Experimental Study.

Introduction Achilles tendon injury necessitates thromboembolism prophylaxis after repair. This study aimed to investigate the effects of antithrombotic-adjusted prophylactic doses of nadroparin calcium and rivaroxaban on Achilles tendon healing. Materials and Methods Twenty-four young adult male Wistar Albino type rats were randomly divided into three groups. All rats underwent a full-thickness surgical incision of the Achilles tendon, followed by primary repair. After the procedure, group 1 was determined as the control group and received no medication. Group 2 received 2.03 mg/kg rivaroxaban daily via gastric lavage once daily, and group 3 was given subcutaneous 114 IU AXa nadroparin calcium once daily for 28 days. After euthanization, the degrees of inflammation, neovascularization, fibroblastic activity, and collagen fiber sequencing were examined and scored for histopathological evaluation. The Statistical Package for Social Science (SPSS) version 21.0 for Windows software (SPSS, Inc., Chicago, Illinois, United States) was used for all statistical analyses. The number of inflammatory cells, capillary vessels, and fibroblasts, which met the parametric tests' assumptions, were compared between three independent groups by one-way analysis of variance. The significance level was set at p- value < 0.05. Results Histological examination of the group 1 sample showed the presence of inflammatory cells, an increase in the number of fibroblasts, and sequencing of collagen fibers scattered. The presence of inflammatory cells, remarkable increases in the number of fibroblasts, the presence of mature collagen fibers, and regular sequencing of collagen fibers regular were shown in groups 2 and 3. There were statistically significant differences between the groups regarding the number of inflammatory cells and fibroblasts. In group 2, the number of inflammatory cells was lower than in groups 1 and 3. Elsewhere, the number of fibroblasts was higher in group 1 compared than in groups 2 and 3. Conclusion Both rivaroxaban and nadroparin calcium in their daily dosage have a beneficial effect on Achilles tendon healing.

Low-Molecular-Weight Heparins (LMWH) and Synthetic Factor X Inhibitors Can Impair the Osseointegration Process of a Titanium Implant in an Interventional Animal Study.

Background and objectives: Cementless total hip arthroplasty is a common surgical procedure and perioperative thromboprophylaxis is used to prevent deep vein thrombosis or pulmonary embolism. Osseointegration is important for long-term implant survival, and there is no research on the effect of different thromboprophylaxis agents on the process of osseointegration. Materials and Methods: Seventy rats were allocated as follows: Group I (control group), Group II (enoxaparin), Group III (nadroparin), and Group IV (fondaparinux). Ovariectomy was performed on all subjects, followed by the introduction of an intramedullary titanium implant into the femur. Thromboprophylaxis was administered accordingly to each treatment group for 35 days postoperatively. Results: Group I had statistically significantly lower anti-Xa levels compared to treatment groups. Micro-CT analysis showed that nadroparin had lower values compared to control in bone volume (0.12 vs. 0.21, p = 0.01) and percent bone volume (1.46 vs. 1.93, p = 0.047). The pull-out test showed statistically significant differences between the control group (8.81 N) compared to enoxaparin, nadroparin, and fondaparinux groups (4.53 N, 4 N and 4.07 N, respectively). Nadroparin had a lower histological cortical bone tissue and a higher width of fibrous tissue (27.49 µm and 86.9 µm) at the peri-implant area, compared to control (43.2 µm and 39.2 µm), enoxaparin (39.6 µm and 24 µm), and fondaparinux (36.2 µm and 32.7 µm). Conclusions: Short-term administration of enoxaparin, nadroparin, and fondaparinux can reduce the osseointegration of titanium implants, with nadroparin having the most negative effect. These results show that enoxaparin and fondaparinux are preferred to be administered due to a lesser negative impact on the initial implant fixation.

Sequential Therapy of Nadroparin and Rivaroxaban in the Initial Treatment of Patients With Acute Pulmonary Embolism.

Background: Sequential low molecular weight heparin (LMWH) plus warfarin, LMWH plus edoxaban, and LMWH plus dabigatran regimens have already shown efficacy and safety in the treatment of acute pulmonary embolism (PE). The efficacy and safety of sequential LMWH plus rivaroxaban regimen in the treatment of acute PE have been understudied. Methods: A retrospective study was performed to explore the efficacy and safety of sequential therapy regimens of subcutaneous LMWH (nadroparin 86 IU/kg every 12 h for a week) followed by oral rivaroxaban (20 mg once daily for 3 months) for the management of patients with established acute PE without hemodynamic instability, compared with those of nadroparin plus dabigatran and nadroparin plus warfarin. Results: The number of patients with total resolution of PE were 238 (80.1%), 220 (78.0%), and 166 (62.6%), in the nadroparin + rivaroxaban, nadroparin + dabigatra, and nadroparin + warfarin groups, respectively. (p = 0.001) The prevalence of DVT at the 3-month follow-up visit was 18 (6.1%), 14 (5.0%), and 11 (4.2%), in the aforementioned three groups, respectively. (p = 0.559) The NT-proBNP level (pg/ml) at the 3-month follow-up visit was 122.5 (97.4-158.9), 131.7 (102.2-166.3), and 357.8 (275.4-433.2) in the three groups, respectively. (p = 0.001) The D-dimer level (ng/ml) at the 3-month follow-up visit was 387.3 (310.9-465.2), 432.5 (382.4-489.6), and 854.0 (721.5-993.7) in the three groups, respectively (p < 0.001). The number of patients with major bleeding events was 3(0.9%), 6(1.8%), and 18 (5.5%) in the three groups, respectively (p < 0.001). Conclusion: The regimen of sequential subcutaneous nadroparin at body-weight adjusted dose for a week followed by oral rivaroxaban at a dose of 20 mg once daily for 3 months is effective and safe in the initial treatment of patients with acute pulmonary embolism.

Rare complication of nadroparin injections: Skin necrosis and heparin-induced thrombocytopenia syndrome.

We described a rare case of nadroparin-induced skin necrosis with thrombocytopenia. LMWH therapy is used in thrombosis prophylaxis, it is important to recognize that skin necrosis can be a part of HIT early in its course and change heparin or LMWH to non-heparin anticoagulants such as direct thrombin III inhibitors or anti-Xa anticoagulants.

Tinzaparin vs. Nadroparin Safety and Efficacy in Neurosurgery.

BACKGROUND: An outbreak of African swine fever (ASF) in China in 2020 has led to an unprecedented shortage of nadroparin. Most patients, especially those kept in hospital for surgery, are currently treated with prophylactic anticoagulation (AC). In search of alternatives for nadroparin (fraxiparine), we found no sufficient data on alternatives for neurosurgical patients, such as tinzaparin of European origin. We compared nadroparin and tinzaparin concerning adverse events (bleeding versus thromboembolic events) in neurosurgical patients. METHODS: Between 2012 and 2018, 517 neurosurgical patients with benign and malignant brain tumors as well as 297 patients with subarachnoid hemorrhage (SAH) were treated in the Department of Neurosurgery, University Hospital Leipzig, receiving prophylactic anticoagulation within 48 h. In 2015, prophylactic anticoagulation was switched from nadroparin to tinzaparin throughout the university hospital. In a retrospective manner, the frequency and occurrence of adverse events (rebleeding and thromboembolic events) in connection with the substance used were analyzed. Statistical analysis was performed using Fisher's exact test and the chi-squared test. RESULTS: Rebleeding rates were similar in both nadroparin and tinzaparin cohorts in patients being treated for meningioma, glioma, and SAH combined (8.8% vs. 10.3%). Accordingly, the rates of overall thromboembolic events were not significantly different (5.5% vs. 4.3%). The severity of rebleeding did not vary. There was no significant difference among subgroups when compared for deep vein thrombosis (DVT) or pulmonary embolism (PE). CONCLUSION: In this retrospective study, tinzaparin seems to be a safe alternative to nadroparin for AC in patients undergoing brain tumor surgery or suffering from SAH.

Effectiveness and Safety of Nadroparin Therapy in Preterm and Term Neonates with Venous Thromboembolism.

INTRODUCTION: Optimal neonatal nadroparin dosages to treat venous thromboembolism (VTE) are unknown. OBJECTIVE: To evaluate therapeutic nadroparin dosages to reach therapeutic target ranges (TTR: 0.5-1.0 International Unit (IU)/mL) and the effectiveness and safety of nadroparin in neonatal VTE. METHODS: Retrospective study including neonates with VTE on nadroparin in a tertiary center between 2007 and 2018. Two groups were distinguished: neonates before (group 1) and after (group 2) switch to higher starting dosages in 2014. RESULTS: Sixty-one neonates (44 preterm, 17 term) with 64 VTEs were included. TTR was reached in 32/64 (50%) VTEs (group 1: 35.7%; group 2: 61.1%). Median nadroparin dosage to reach TTR was 197 (97.9-330.3) IU/kg/12 h. No therapy-related deaths occurred. Recurrent VTE developed in 6 (9.8%) neonates. Complete clot resolution was observed in 31/41 (75.6%) VTEs. TTR was reached in 58.1% VTEs with complete clot resolution. No major bleeding occurred. Non-major clinically relevant bleedings occurred in 3/64 (4.7%) VTEs, consisting of large hematomas due to the use of subcutaneous catheters. CONCLUSIONS: High nadroparin dosages are needed to reach TTR in neonates, which seem to be safe. Clot resolution may occur without reaching TTR. Subcutaneous catheters may cause important bleeding complications.

Arterial Versus Venous Port Site Administration of Nadroparin for Preventing Thrombosis of Extracorporeal Blood Circuits in Patients Receiving Hemodiafiltration Treatment.

INTRODUCTION: Administration of low-molecular-weight heparins (LMWHs) is necessary for preventing extracorporeal circuit thrombosis during hemodialysis. A substantial amount of LMWH is removed with online hemodiafiltration (OL-HDF) when administered through the inlet site of the extracorporeal circuit. Consequently, administration of LMWH at the outlet site appears to be more efficient. In this study we aimed to compare the effects of nadroparin calcium (NAD) administered through the outlet versus the inlet port site in postdilution OL-HDF and assess the NAD dose reduction. METHODS: Forty-nine hemodialysis patients were included in 3 consecutive 6-week studies as follows: phase I, inlet port line; phase II, outlet port line; and phase III, outlet port line with reduced dose. We evaluated clotting in the hemodialyzer and venous bubble trap, the dialysis dose (K t/V), and substitution volume. RESULTS: Thirty four percent, 63%, and 66% were categorized as "white" during phases I, II, and III, respectively. During phases I, II, and III, 75%, 93%, and 95% of the venous bubble traps were "clean," and 9%, 0.6%, and 0.4% of the dialyzers clotted, respectively. Average NAD dose was 0.43 ml during phase I and 0.3 ml during phase II. During phase III, the LMWH dose was reduced by 33% to 50% in 15 patients. In phase III, Kt/V improved from 1.64 to 1.75 and substitution volume increased from 20.18 to 21.96 L. CONCLUSIONS: When using OL-HDF, a single administration of NAD at the outlet port line allows for a significant dose reduction and was associated with improved dialysis performance.

[Comparison of hemostatic effect and safety in primary unilateral total hip arthroplasty receiving different anticoagulants after anti-fibrinolysis with tranexamic acid].

OBJECTIVE: To compare the hemostatic effect and safety in primary unilateral total hip arthroplasty (THA) receiving nadroparin calcium, enoxaparin sodium, rivaroxaban, or apixaban after anti-fibrinolysis with tranexamic acid (TXA) and explore the best anticoagulant. METHODS: A retrospective analysis was conducted on 184 patients who underwent the primary unilateral THA between January 2014 and December 2018, administrated 15 mg/kg TXA before surgery and received nadroparin calcium, enoxaparin sodium, rivaroxaban, or apixaban. The patients were divided into four groups based on the different anticoagulants: 46 patients received nadroparin calcium; 45 patients received enoxaparin sodium; 47 patients received rivaroxaban; the other 46 patients received apixaban. There was no significant difference in age, gender, body mass, body mass index, the types of hip joint diseases, complications, anesthesia mode, operation time, and preoperative laboratory indexes (hemoglobin, hematocrit, platelet, prothrombin time, activated partial prothrombin time, blood volume) ( P>0.05). Perioperative blood data (total blood loss, hidden blood loss, dominant blood loss, postoperative drainage volume, maximum loss of hemoglobin, and blood transfusion rate) and complications (incision, bleeding, and thrombosis) were recorded and compared between groups. RESULTS: There was no significant difference in total blood loss, hidden blood loss, dominant blood loss, postoperative drainage volume, maximum loss of hemoglobin, and blood transfusion rate between groups ( P>0.05). The comparison of postoperative complications showed that 1 case (2.1%) of redness and swelling of incision occurred in the rivaroxaban group, and 1 case (2.2%) of the other 3 groups each had poor incision healing. No incision infection, fat liquefaction, or other incision complications occurred in the 4 groups. There was no significant difference in incision complication between groups ( P>0.05). There were 2 cases (4.3%) bleeding events (1 case of right inguinal hematoma and 1 case of subcutaneous ecchymosis in front of left leg) in the nadroparin calcium group, while no bleeding event occurred in the other 3 groups, which had no significant difference in bleeding complication between groups ( χ 2=5.612, P=0.132). There was 1 case (2.2%) of intermuscular vein thrombosis of the lower extremity in the nadroparin calcium group and no case in the other 3 groups, which had no significant difference between groups ( χ 2=2.789, P=0.425). Neither deep venous thrombosis nor pulmonary embolism occurred in any group. CONCLUSION: No significant difference in the hemostatic effect and incidences of complications for patients underwent primary unilateral THA receiving nadroparin calcium, enoxaparin sodium, rivaroxaban, or apixaban after anti-fibrinolysis with TXA. One of the four anticoagulants can be selected to prevent thrombosis after anti-fibrinolysis with TXA, which has certain safety.

Low molecular weight heparins and their clinical applications.

Heparin is an anticoagulant medication that was discovered in 1917 and used in clinic since 1935. Low molecular weight heparins (LMWHs) represent a refined use of heparin as anticoagulant medications that were developed in 1980s. LMWHs are obtained by cleaving heparin with different chemical or enzymatic methods. Eight chemically distinct and officially approved LMWHs are Bemiparin, Certoparin, Dalteparin, Enoxaparin, Nadroparin, Parnaparin, Reviparin, and Tinzaparin. LMWHs are mainly used for preventing blood clots, for treating deep vein thrombosis and pulmonary embolism, and for treating myocardial infarction. LMWHs have advantages over heparin in that they can be used at home with good predictability, dose-dependent plasma levels, a long half-life, less bleeding for a given antithrombotic even, smaller risk of osteoporosis in long-term use, and smaller risk of heparin-induced thrombocytopenia and thrombosis, a potential side effect of heparin. However, heparin is reversible with protamine sulfate while LMWHs have no antidote. Moreover, LMWHs have less of an effect on inhibiting thrombin activity than heparin. Furthermore, patients with end-stage renal diseases have to use heparin because LMWHs are dependent on functioning kidney for their clearance but heparin is primarily cleared in the liver. We will review the recent progress made on the clinically approved and under clinical trialed LMWHs and their potential medical applications. In particular, we will provide an update on the chemical characteristics and clinical use of different branded LMWHs. In addition, the potential clinical applications of LMWHs in other therapeutic area will also be discussed.

Qualitative and quantitative analysis of 2, 5-anhydro-d-mannitol in low molecular weight heparins with high performance anion exchange chromatography hyphenated quadrupole time of flight mass spectrometry.

Low molecular weight heparins (LMWHs), derived from unfractionated heparin (UFH) by chemical or enzymatic degradation, have lower side effects than that of heparin. Enoxaparin, nadroparin, and dalteparin are the most widely used LMWHs. Nadroparin and dalteparin are prepared through nitrous acid degradation followed by a subsequent reduction process, in which specific residue, 2,5-anhydro-d-mannitol (An-Man), is formed at the reducing terminals of generated sugar chains. However, few practicable analytical method was available to analyze An-Man qualitatively and quantitatively. In this work, a HPAEC-PAD-MS method was developed to analyze monosaccharides in heparin and LMWHs, especially An-Man. An ion suppressor is set up between HPAEC and MS to remove the nonvolatile salts from HPAEC and make the elute compatible to MS. Various monosaccharides were separated well with HPAEC. Online MS and MS/MS confirmed all sugar residues in the hydrolysates of heparin samples. The specific residue, An-Man, was only observed in the hydrolysates of LMWHs prepared with nitrous acid degradation and reduction. In addition, major glucosamine and minor arabinose/galactose were observed in all heparin samples. The amounts of these sugar residues were quantitated with PAD, simultaneously. The ratio of glucosamine to An-Man could be used to calculate the molecular weight of LMWHs. The calculated values are comparable to the value measured with size-exclusion chromatography-multiple angle laser scattering detection. Higher the ratio of glucosamine to An-Man higher the molecular weight. The HPAEC-PAD-MS platform is an accurate, precise and efficient way to identify LMWHs by determination of An-Man. It is also an alternative method to detect the MWs of LMWHs having An-Man for quality control purposes.

Strong ion difference and CVVH: Different response during nadroparin versus citrate anticoagulation.

PURPOSE: To determine the effect on strong ion difference of citrate as an anticoagulant during continuous veno-venous hemofiltration (CVVH). MATERIALS AND METHODS: ICU patients with renal failure and CVVH were included. Patients were treated with either nadroparin (N) or sodium citrate (C) as an anticoagulant. Strong ion difference (SID) apparent (SIDa) and SID effective (SIDe) and strong ion gap (SIG) were calculated at t = 0 and t = 24 h. Citrate concentration was measured in the citrate treated patients. RESULTS: Ten patients with N and nine with C were included. In both groups the SIDa did not change significantly. SIG decreased significantly with N (11.4 ±â€¯4.2 to 4.0 ±â€¯3.1 meq/l; p = 0.005) but not with C (9.3 ±â€¯1.9 to 8.1 ±â€¯2.4 meq/l; p = 0.097). The decrease was significantly greater for N compared to C; p = 0.014. This is reflected by the SIDe which increased significantly (p = 0.022) more from 24.7 ±â€¯4.5 to 32.9 ±â€¯3.9 (p = 0.005) for N and from 26.3 ±â€¯5.8 to 29.6 ±â€¯1.6 for C (p = 0.058). CONCLUSION: Citrate anticoagulation results in a persistently high SIG during CVVH compared to nadroparin. This is associated with the presence of unmeasured anions such as citrate in the systemic circulation.

Rivaroxaban versus nadroparin for preventing deep venous thrombosis after total hip arthroplasty following femoral neck fractures: A retrospective comparative study.

Objective This study was performed to evaluate the efficacy of rivaroxaban versus nadroparin for preventing deep venous thrombosis (DVT) in elderly patients with osteoporosis undergoing initial total hip arthroplasty (THA) for femoral neck fractures. Methods Prospectively maintained databases were reviewed to retrospectively compare elderly patients with osteoporosis who underwent initial THA for femoral neck fractures from 2007 to 2015. The patients received peroral rivaroxaban at 10 mg/day for 2 weeks or subcutaneous injections of nadroparin at 0.3 mL/day for 2 weeks until the primary analysis cut-off date. The time to first on-study DVT was the primary endpoint. Results In total, 399 patients were included (rivaroxaban group: n=200; mean age, 70.20 ± 9.16 years and nadroparin group: n = 199; mean age, 69.90 ± 8.87 years), with a mean 3-year follow-up. The time to first on-study DVT was significantly longer in the rivaroxaban than nadroparin group (12 and 5 days, respectively). The incidence of DVT within the 2-week follow-up was significantly higher in the nadroparin than rivaroxaban group (6.8% and 19.7%, respectively), but this difference was no longer present at the final follow-up. Conclusion Rivaroxaban was associated with a significant reduction in the occurrence of first on-study DVT compared with nadroparin.

The Effect of Obesity on Anti-Xa Concentrations in Bariatric Patients.

BACKGROUND: Morbidly obese patients are at increased risk to develop venous thromboembolism (VTE), especially after bariatric surgery. Adequate postoperative thrombosis prophylaxis is of utmost importance. It is assumed that morbidly obese patients need higher doses of low molecular weight heparin (LMWH) compared to normal-weight patients; however, current guidelines based on relative efficacy in obese populations are lacking. OBJECTIVES: First, we will evaluate the relationship between body weight descriptors and anti-Xa activity prospectively. Second, we will determine the dose-linearity of LMWH in morbidly obese patients. SETTING: This study was performed in a general hospital specialized in bariatric surgery. METHODS: Patients were scheduled for a Roux-en-Y gastric bypass with a total bodyweight (TBW) of ≥ 140 kg. Patients (n = 50, 64% female) received a daily postoperative dose of 5700 IU of nadroparin for 4 weeks. Anti-Xa activity was determined 4 h after the last nadroparin administration. To determine the dose linearity, anti-Xa was determined following a preoperative dose of 2850 IU nadroparin in another 50 patients (52%). RESULTS: TBW of the complete group was 148.5 ± 12.6 kg. Mean anti-Xa activity following 5700 IU nadroparin was 0.19 ± 0.07 IU/mL. Of all patients, 32% had anti-Xa levels below the prophylactic range. Anti-Xa activity inversely correlated with TBW (correlation coefficient - 0.410) and lean body weight (LBW; correlation coefficient - 0.447); 67% of patients with a LBW ≥ 80 kg had insufficient anti-Xa activity concentrations. No VTE events occurred. CONCLUSIONS: In morbidly obese patients, a postoperative dose of 5700 IU of nadroparin resulted in subprophylactic exposure in a significant proportion of patients. Especially in patients with LBW ≥ 80 kg, a higher dose may potentially be required to reach adequate prophylactic anti-Xa levels.