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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., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

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/m 2 ) 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., (© 2023. The Author(s).)

Background and Objective: The risk of thrombotic complications in critical patients with COVID-19 remains extremely high, and multicenter trials failed to prove a survival benefit of escalated doses of low-molecular-weight heparins (nadroparin calcium) in this group. The aim of this study was to develop a pharmacokinetic model of nadroparin according to different stages of COVID-19 severity., Methods: Blood samples were obtained from 43 patients with COVID-19 who received nadroparin and were treated with conventional oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation. We recorded clinical, biochemical, and hemodynamic variables during 72 h of treatment. The analyzed data comprised 782 serum nadroparin concentrations and 219 anti-Xa levels. We conducted population nonlinear mixed-effects modeling (NONMEM) and performed Monte Carlo simulations of the probability of target attainment for reaching 0.2-0.5 IU/mL anti-Xa levels in study groups., Results: We successfully developed a one-compartment model to describe the population pharmacokinetics of nadroparin in different stages of COVID-19. The absorption rate constant of nadroparin was 3.8 and 3.2 times lower, concentration clearance was 2.22 and 2.93 times higher, and anti-Xa clearance was 0.87 and 1.1 times higher in mechanically ventilated patients and the extracorporeal membrane oxygenation group compared with patients treated with conventional oxygen, respectively. The newly developed model indicated that 5.900 IU of nadroparin given subcutaneously twice daily in the mechanically ventilated patients led to a similar probability of target attainment of 90% as 5.900 IU of subcutaneous nadroparin given once daily in the group supplemented with conventional oxygen., Conclusions: Different nadroparin dosing is required for patients undergoing mechanical ventilation and extracorporeal membrane oxygenation to achieve the same targets as those for non-critically ill patients., Clinical Trial Registration: ClinicalTrials.gov identifier no. NCT05621915., (© 2023. The Author(s).)

Background and Objective: Low-molecular-weight heparins are routinely administered to patients in the intensive care unit to prevent venous thromboembolisms. There is considerable evidence that low-molecular-weight heparin doses should be personalised based on anti-Xa levels, but pharmacokinetic data in intensive care unit patients are lacking. This study aimed to characterise the pharmacokinetics and associated variability of the low-molecular-weight heparin nadroparin in critically ill patients., Methods: Critically ill adult patients who were admitted to the intensive care unit and received nadroparin for prophylaxis of venous thromboembolism were included in a study. Population pharmacokinetic analysis was performed by means of parametric non-linear mixed-effects modelling (NONMEM)., Results: A total of 30 patients were enrolled with 12 patients undergoing continuous veno-venous hemodialysis and 18 patients not undergoing continuous veno-venous hemodialysis. Very high variability in pharmacokinetics was observed with an inter-individual variability in the volume of distribution of 63.7% (95% confidence interval 46.5-90.6), clearance of 166% (95% confidence interval 84.7-280) and relative bioavailability of 40.2% (95% confidence interval 29.5-52.6). We found that standard doses of 2850 IE and 5700 IE of nadroparin resulted in sub-prophylactic exposure in critically ill patients., Conclusions: Low exposure and highly variable pharmacokinetics of nadroparin were observed in intensive care unit patients treated with a prophylactic dose. It can be debated whether nadroparin is currently dosed optimally in intensive care unit patients and our findings encourage the investigation of higher and tailored dosing of nadroparin in the critically ill., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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.

Introduction: The optimal nadroparin dose in patients undergoing hemodialysis is difficult to determine in clinical practice. Anti-Xa levels ≥ 0.4 IU/mL and < 2.0 IU/mL are suggested to prevent thrombus formation within the extracorporeal circuit whilst minimizing bleeding risk. We aimed to characterize the variability in the association between dose and anti-Xa levels, identify patient and dialysis characteristics that explained this variability, and optimize nadroparin dosing based on the identified characteristics., Methods: Anti-Xa samples were collected in patients who received intravenous nadroparin as thromboprophylaxis during routine dialysis sessions. A population pharmacodynamic model was developed using non-linear mixed-effects modelling. The percentage of patients ≥ 0.4 IU/mL (efficacy) and < 2.0 IU/mL (safety) was simulated for different doses, patient and dialysis characteristics., Results: Patients (n = 137) were predominantly receiving standard hemodialysis (84.7% vs. hemodiafiltration 15.3%) and had a mean bodyweight of 76.3 kg (± 16.9). Lean body mass (LBM), mode of dialysis, and dialyzer partially explained between-subject variability in anti-Xa levels. Patients on hemodiafiltration and those receiving hemodialysis with a high LBM (≥ 80 kg) had a low probability (< 29%) of anti-Xa levels ≥ 0.4 IU/mL during the entire dialysis session. All patients, except hemodialysis patients with a low LBM (< 50 kg), had a high probability (> 70%) of peak anti-Xa levels < 2.0 IU/mL., Conclusion: Mainly patients receiving hemodiafiltration and those receiving hemodialysis with a high LBM can benefit from a higher nadroparin dose than currently used in clinical practice, while having anti-Xa levels < 2.0 IU/mL., (© 2022. The Author(s).)

Background: Low molecular weight heparins (LMWH) are recommended for thromboprophylaxis in ICU patients but often fail to reach adequate peak anti-Xa activity., Objective: To compare the pharmacokinetic profiles of intravenous (IV) versus subcutaneous (SC) route of administration of LMWH., Method: This was a prospective, monocentric, randomized trial. Patients were randomized to the IV route of administration with a 4-h infusion of nadroparin 3800 IU or to the SC route of administration. Randomization was stratified according to the need for vasopressor or not. Anti-Xa activity was measured at baseline, and at 1, 2, 4, 6, 8, 12 and 24 h after the administration was started., Results: Sixty patients were included, of whom 30 were randomized to the IV group and 30 to the SC route. Pharmacokinetic profiles were significantly different. Mean peak anti-Xa activity was 0.38 IU/ml in the IV group vs 0.20 IU/ml in the SC group (p < 0.001). Trough values and AUC (0-24 h) were similar in both groups. Pharmacokinetic profiles were similar whether patients received vasopressors or not., Conclusions: The IV route of administration with a 4-h infusion lead to a significantly higher peak anti-Xa activity without affecting trough value or the AUC (0-24 h). Whether the IV administration of LMWH might improve the efficacy of thromboprophylaxis requires further research., Registration: ClinicalTrials.gov, NCT04982055, retrospectively registered 08 July 2021, https://clinicaltrials.gov/ct2/show/NCT04982055?cond=NCT04982055&draw=2&rank=1., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Celiac crisis (CC) is a rare life-threatening course of celiac disease, observed mainly in children. In adults, CK can be the first manifestation of the disease and, very rarely, a relapse that occurs in patients who do not follow the gluten-free diet (AGD). Triggers can be stress, surgery, childbirth, etc. A clinical observation of CC developed in a 49-year-old patient with previously established latent celiac disease with subtotal villous atrophy, stage Marsh III C is presented. The patient did not comply with AHD. After severe angina, she developed anorexia, diarrhea, emaciation, coagulopathy, bilateral pulmonary embolism, infarction pneumonia, and enterogenic sepsis. As a result of intensive therapy with prednisolone, Fraxiparine, antibiotics, fresh frozen plasma and strict adherence to hypertension, remission of the disease was achieved.

Objectives: For the non-vitamin-K oral anticoagulants, data on bleeding when used for 42 days as thromboprophylaxis after total knee arthroplasty (TKA) are scarce. This pilot study assessed feasibility of a multicentre randomised clinical trial to evaluate major and clinically relevant non-major bleeding during 42-day use of dabigatran, nadroparin and rivaroxaban after TKA., Patients and Methods: In 70 weeks, between July 2012 and November 2013, 198 TKA patients were screened for eligibility in the Martini Hospital (Groningen, the Netherlands). Patients were randomly assigned to dabigatran (n=45), nadroparin (n=45) or rivaroxaban (n=48). The primary outcome was the combined endpoint of major bleeding and clinically relevant non-major bleeding. Secondary endpoints of this study were the occurrence of clinical venous thromboembolism (VTE) (pulmonary embolism or deep venous thrombosis), compliance, duration of hospital stay, rehospitalisation, adverse events and Knee Injury and Osteoarthritis Outcome Score (KOOS)., Results: The primary outcome was observed in 33.3% (95% CI 20.0% to 49.0%), 24.4% (95% CI 12.9% to 39.5%) and 27.1% (95% CI 15.3% to 41.8%) of patients who received dabigatran, nadroparin or rivaroxaban, respectively (p=0.67). Major bleeding was found in two patients who received nadroparin (p=0.21). Clinically relevant non-major bleeding was observed in 33.3% (95% CI 20.0% to 49.0%), 22.2% (95% CI 11.2% to 37.1%) and 27.1% (95% CI 15.3% to 41.8%) for dabigatran, nadroparin and rivaroxaban, respectively (p=0.51). Wound haematoma was the most observed bleeding event. VTE was found in one patient who received dabigatran (p=0.65). The presurgery and postsurgery KOOS qQuestionnaires were available for 32 (71%), 35 (77%) and 35 (73%) patients for dabigatran, nadroparin and rivaroxaban, respectively. KOOS was highly variable, and no significant difference between treatment groups in mean improvement was observed., Conclusions: A multicentre clinical trial may be feasible. However, investments will be substantial. No differences in major and clinically relevant non-major bleeding events were found between dabigatran, nadroparin and rivaroxaban during 42 days after TKA. KOOS may not be suitable to detect functional loss due to bleeding., Trial Registration Number: NCT01431456., Competing Interests: Competing interests: MvH reports grants from Bayer and personal fees from Boehringer Ingelheim during the conduct of the study. Other authors have nothing to report., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Extracorporeal membrane oxygenation (ECMO) requires constant management of coagulation. Whereas unfractionated heparin remains the anticoagulant of choice, experienced centers report high bleeding rates. Biocompatibility of the extracorporeal circuit enables management of anticoagulation with subcutaneous low-molecular-weight heparins only. The aim of this study was to evaluate the safety and feasibility of anticoagulation with subcutaneous nadroparin compared with unfractionated heparin during respiratory ECMO in patients. We assessed for thrombotic complications and number of bleeding and life-threatening bleeding events. Additionally, we evaluated the change in resistance to flow in the oxygenator and the number of transfused blood products. Nadroparin and unfractionated heparin were comparable in terms of number of bleeding (34 vs. 53%; p = 0.12), life-threatening bleeding (2.8 vs. 9.3%; p = 0.26) events, and daily red blood cell transfusion rates (0.79 units/patient/day vs. 0.71 units/patient/day in nadroparin group; p = 0.87) during respiratory ECMO. The relative change in resistance to flow in the oxygenator was similar between groups (8.03 vs. 11.6%; p = 0.27). Nadroparin seemed equivalent to unfractionated heparin in the number of thrombotic and hemorrhagic events as well as in the daily red blood cell transfusion rates during venovenus-ECMO., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © 2020 by the ASAIO.)

Background: In patients who undergo curative treatment for oesophageal cancer, risk estimates of venous thromboembolism (VTE), arterial thromboembolism and bleeding are needed to guide decisions about thromboprophylaxis., Methods: This was a single-centre, retrospective cohort study of patients with stage I-III oesophageal cancer who received neoadjuvant chemoradiation followed by oesophagectomy. The outcomes VTE, arterial thromboembolism, major bleeding, clinically relevant non-major bleeding and mortality were analysed for four consecutive cancer treatment stages (from diagnosis to neoadjuvant chemoradiotherapy, during neoadjuvant treatment, 30-day postoperative period, and up to 6 months after postoperative period)., Results: Some 511 patients were included. The 2-year survival rate was 67·3 (95 per cent c.i. 63·2 to 71·7) per cent. During the 2-year follow-up, 50 patients (9·8 per cent) developed VTE, 20 (3·9 per cent) arterial thromboembolism, 21 (4·1 per cent) major bleeding and 30 (5·9 per cent) clinically relevant non-major bleeding. The risk of these events was substantial at all treatment stages. Despite 30-day postoperative thromboprophylaxis, 17 patients (3·3 per cent) developed VTE after surgery. Patients with VTE had worse survival (time-varying hazard ratio 1·81, 95 per cent c.i. 1·25 to 2·64). Most bleeding events occurred around the time of medical intervention, and approximately one-half during concomitant use of prophylactic or therapeutic anticoagulation., Conclusion: Patients with oesophageal cancer undergoing neoadjuvant chemoradiotherapy and surgery are at substantial risk of thromboembolic and bleeding events throughout all stages of treatment. Survival is worse in patients with thromboembolic events during follow-up., (© 2020 The Authors. British Journal of Surgery published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Background:  Both compression stockings and low molecular weight heparin (LMWH) are used for the prevention of post-operative venous thromboembolism (VTE) in cerebellopontine angle (CPA) tumour excisions., Objective:  In an attempt to optimise the prophylactic treatment in these patients, we compared LMWH (nadroparin) plus compression stockings to nadroparin as single therapy., Methods:  Patients undergoing CPA tumour excision in the period between January 2014 and November 2015 received nadroparin as a single therapy. Patients treated since November 2015 received, in addition to this therapy, peri-operative compression stockings as VTE prophylaxis due to a change in protocol. VTE was defined as symptomatic deep vein thrombosis or pulmonary embolism and was confirmed via radiological imaging or autopsy., Results:  A total of 146 consecutive patients were reviewed. Treatment groups were comparable with respect to demographics and risk factors. Six of the 60 patients (10.0%; 95% confidence interval [CI] 3.8-20.5) receiving nadroparin single therapy developed symptomatic VTE. One out of 86 patients (1.2%; 95% CI 0-6.3) treated with combination therapy developed VTE ( p  = 0.019) with a risk difference of 8.8% (95% CI 1.43-19.0). In comparison to combination therapy, nadroparin single therapy showed a relative risk of 8.6 (95% CI 1.1-69.6)., Conclusion:  Adding compression stockings to peri-operative nadroparin, as a prophylactic strategy for thromboembolic complications in patients undergoing surgical intervention for CPA tumours, was associated with a significant reduction in the occurrence of VTE., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Placental structural abnormalities and dysfunction in those with gestational diabetes mellitus (GDM) can lead to increased placental permeability, which is in turn related to a poorer maternal and fetal prognosis. The present study sought to assess whether increased placental permeability in rats with GDM was accompanied by alterations in tight junction (TJ) factors and to evaluate the impact of low molecular weight heparin (LMWH) on these factors. The present study was conducted using pregnant female rats that were randomized into control, GDM and GDM + LMWH groups. Diabetes was induced via intraperitoneal administration of streptozotocin to rats in the GDM and GDM + LMWH groups, whereas rats in the GDM + LMWH group received daily subcutaneous LMWH starting on day 5 of pregnancy. On gestational day 16, all rats were sacrificed and Evans Blue (EB) assay was used to gauge vascular permeability based on EB dye leakage. Transmission electron microscopy was further used to assess TJ structures, and the TJ proteins zonular occludens‑1 (ZO‑1) and occludin (OCLN) were assessed using immunohistochemistry and western blotting. Blood samples were obtained from the abdominal aorta for ELISA measurements of advanced glycation end products (AGEs) concentrations, and placental receptor for AGEs (RAGE) and vascular endothelial growth factor (VEGF) expression was assessed using reverse transcription‑quantitative PCR. In addition, western blotting was used to measure placental NF‑κB. Compared with in the control group, EB leakage was markedly increased in GDM group rats; this was associated with reduced ZO‑1 and OCLN expression. Conversely, LMWH attenuated this increase in placental permeability in rats with GDM and also mediated a partial recovery of ZO‑1 and OCLN expression. Blood glucose and serum AGEs concentrations did not differ between the GDM and GDM + LMWH groups. Furthermore, LMWH treatment resulted in decreases in RAGE and VEGF mRNA expression levels, which were upregulated in the GDM group, whereas it had the opposite effect on the expression of NF‑κB. In conclusion, GDM was associated with increased placental permeability and this may be linked with changes in TJs. LMWH intervention mediated protection against this GDM‑associated shift in placental permeability via the RAGE/NF‑κB pathway.

Background: Retrospective studies suggest that low molecular weight heparin may delay the development of metastasis in patients with resected NSCLC., Methods: Multicentre phase 3 study with patients with completely resected NSCLC who were randomised after surgery to receive chemotherapy with or without nadroparin. The main exclusion criteria were R1/2 and wedge/segmental resection. FDG-PET was required. The primary endpoint was recurrence-free survival (RFS)., Results: Among 235 registered patients, 202 were randomised (nadroparin: n = 100; control n = 102). Slow accrual enabled a decrease in the number of patients needed from 600 to 202, providing 80% power to compare RFS with 94 events (α = 0.05; 2-sided). There were no differences in bleeding events between the two groups. The median RFS was 65.2 months (95% CI, 36-NA) in the nadroparin arm and 37.7 months (95% CI, 22.7-NA) in the control arm (HR 0.77 (95% CI, 0.53-1.13, P = 0.19). FDG-PET SUVmax ≥10 predicted a greater likelihood of recurrence in the first year (HR 0.48, 95% CI 0.22-0.9, P = 0.05)., Conclusions: Adjuvant nadroparin did not improve RFS in patients with resected NSCLC. In this study, a high SUVmax predicted a greater likelihood of recurrence in the first year., Clinical Trial Registration: Netherlands Trial registry: NTR1250/1217.

Background: Postpancreatectomy haemorrhage (PPH) and venous thromboembolism (VTE) are serious complications following pancreatic surgery. The aim was to assess the timing, occurrence and predictors of PPH and VTE., Methods: Elective pancreatic resections undertaken in a single university hospital between November 2013 and September 2017 were assessed. Three intervals were reviewed, each with a different routine regimen of nadroparin: 2850 units once daily (single dose) administered in hospital only, or 5700 units once daily (double dose) or 2850 units twice daily (split dose) administered in hospital and continued for 6 weeks after surgery. Clinically relevant PPH (CR-PPH) was classified according to International Study Group of Pancreatic Surgery criteria. VTE was defined according to a number of key diagnostic criteria within 6 weeks of surgery. Cox regression analyses were performed to test the hypotheses that the double-dose group would experience more PPH than the other two groups, the single-dose group would experience more VTE than the other two groups, and the split-dose group would experience the fewest adverse events (PPH or VTE)., Results: In total, 240 patients were included, 80 per group. The double-dose group experienced significantly more CR-PPH (hazard ratio (HR) 2·14, 95 per cent c.i. 1·16 to 3·94; P = 0·015). More relaparotomies due to CR-PPH were performed in the double-dose group (16 versus 3·8 per cent; P = 0·002). The single-dose group did not experience more VTE (HR 1·41, 0·43 to 4·62; P = 0·570). The split dose was not associated with fewer adverse events (HR 0·77, 0·41 to 1·46; P = 0·422). Double-dose low molecular weight heparin (LMWH), high BMI and pancreatic fistula were independent predictors of CR-PPH., Conclusion: A double dose of LMWH prophylaxis continued for 6 weeks after pancreatic resection was associated with a twofold higher rate of CR-PPH, resulting in four times more relaparotomies. Patients receiving a single daily dose of LMWH in hospital only did not experience a higher rate of VTE., (© 2019 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Essentials Management of patients with calf deep vein thrombosis remains controversial. We conducted a post-hoc analysis of a placebo controlled LMWH randomized clinical trial. Pain was assessed using visual analogue scale at inclusion, one and six weeks. There was no difference in pain control between the two arms. SUMMARY: Background The optimal management of distal deep vein thrombosis (DVT) is highly debated. The only available placebo-controlled trial suggested the absence of clear benefit of anticoagulation. Many physicians feel that, beyond preventing thromboembolic complications, anticoagulation with low-molecular-weight heparin (LMWH) has the potential to improve pain control. Objectives To analyze whether LMWHs decrease pain in patients with distal deep vein thrombosis. Patients and methods Two-hundred and fifty-two patients included in a multicenter, placebo-controlled, randomized clinical trial of LMWH in patients with acute distal DVT and who were asked to rate their pain at inclusion and at each medical visit, using a visual analogue pain scale (VAS). Results One hundred and thirty patients were randomized in the therapeutic nadroparin arm and 122 patients were randomized in the placebo arm. Mean VAS values were 4.6 (standard deviation [SD] 2.5) at inclusion, 2.1 (SD 2.0) at 1 week and 0.4 (SD 1.2) at 6 weeks. We calculated the individual variation in VAS between inclusion and 1 week in patients in whom VAS was available at the two study time-points. There was no difference in the mean VAS reduction between patients treated with therapeutic nadroparin (n = 106) and with placebo (n = 109): -2.6 (SD 2.4) vs. -2.3 (SD 2.0) after 1 week and -4.4 (SD 2.8) vs. -4.0 (SD 2.4) after 6 weeks, respectively. The use of compression stockings was associated with a reduction in pain. Conclusion These data suggests that LMWH use does not improve pain control as compared with placebo in patients with acute distal DVT., (© 2019 International Society on Thrombosis and Haemostasis.)

Background: Morbidly obese patients are at high risk for developing venous thromboembolism (VTE). The aim of this study was to evaluate the effect of a new VTE prophylaxis protocol (low dosage, low-molecular-weight heparin [LMWH]) with a pneumatic compression device (PCD) in patients undergoing bariatric surgery., Materials and Methods: Between November 2015 and December 2017, 368 patients underwent surgery due to obesity. The patients received 0.2 ml of nadroparin (Fraxiparine, GlaxoSmithKline) 12 h before the operation. A PCD (Kendall SCD Compression System) was applied to the patient during the operation and left on the patient during the subsequent 24 h. Nadroparin 0.4 ml was started subcutaneously after the PCD was removed from the patient and the same dosage of nadroparin was given daily for 15 days following the bariatric operation. Ambulation within 2 h of surgery was encouraged and was performed frequently., Results: A total of 368 patients underwent laparoscopic bariatric surgery. The median age was 34.1 years (range, 18-61), the median weight was 128 kg (range, 90-182), and the median body mass index (BMI) was 47.2 kg/m 2 (range, 36-72). No thrombotic events were observed postoperatively or at the 1-, 3-, and 6-month follow-up visits. Four bleedings occurred requiring transfusions. None of these patients required a re-laparotomy for hemorrhage control. The mortality rate was 0% at 30 and 90 days and during the hospitalization., Conclusion: Low dosage LMWH with PCD is very effective for VTE prophylaxis in bariatric surgery.

Thromboembolic complications are found in 2-3% of children with nephrotic syndrome (NS); this increased risk is caused by hypovolemia, hemoconcentration, increased number and activity of platelets, hyperfibrinogenemia and loss of coagulation inhibitors. Risk is even higher in case of additional factors e.g. congenital thrombophilia., Case Report: Girl with NS aged 17 11/12 years was admitted to hospital due to respiratory tract infection with cough and back pain. NS started 9 months earlier and she had two bouts of disease, and was treated only with prednisone (current dose - 60 mg/48h). On admission she was without any abnormalities on auscultation, with BP 111/65 mmHg, HR 80 bpm, satO2 99%. Lab results showed the increase of WBC 18.3×103/μL, D-dimers 23038 μg/L and proteinuria 900 mg/dL. Other values of examined parameters were in normal limits. Chest X-ray and ECG were also normal. Presumptive diagnosis of pulmonary embolism was made and the patient was given 1000IU of antithrombin III and nadroparine (2x90IU/kg/24h s.c.). In ECHO the occlusion of left pulmonary artery and preserved blood flow in right were revealed. In angioCT clot nearly filling lumen of left pulmonary artery, clot in intermediate part of right pulmonary artery, and focus of pulmonary infarction in 10th segment of left lung were found. Doppler USG of lower limb veins did not reveal thrombi or perforator vein incompetence. Treatment with nadroparine was continued, and rapid improvement of clinical condition and disappearance of pain and cough were observed. Mycophenolate mofetil was added, which resulted in subsidence of proteinuria. Rivaroxaban was used in prophylaxis of recurrences of thromboembolism. Tests for thrombophilia revealed factor V Leiden in patient., (© 2018 MEDPRESS.)

Background: Delayed cerebral ischemia (DCI) is one of the major causes of delayed morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH)., Objective: To evaluate the effect of high-dose nadroparin treatment following endovascular aneurysm treatment on the occurrence of DCI and clinical outcome., Methods: Medical records of 158 adult patients with an aSAH were retrospectively analyzed. Those patients treated endovascularly for their ruptured aneurysm were included in this study. They received either high-dose (twice daily 5700 AxaIE) or low-dose (once daily 2850 AxaIE) nadroparin treatment after occlusion of the aneurysm. Medical charts were reviewed and imaging was scored by 2 independent neuroradiologists. Data with respect to in-hospital complications, peri-procedural complications, discharge location, and mortality were collected., Results: Ninety-three patients had received high-dose nadroparin, and 65 patients prophylactic low-dose nadroparin. There was no significant difference in clinical DCI occurrence between patients treated with high-dose (34%) and low-dose (31%) nadroparin. More patients were discharged to home in patients who received high-dose nadroparin (40%) compared to low-dose (17%; odds ratio [OR] 3.13, 95% confidence interval [95% CI]: 1.36-7.24). Furthermore, mortality was lower in the high-dose group (5%) compared to the low-dose group (23%; OR 0.19, 95% CI: 0.07-0.55), also after adjusting for neurological status on admission (OR 0.21, 95% CI: 0.07-0.63)., Conclusion: Patients who were treated with high-dose nadroparin after endovascular treatment for aneurysmal SAH were more often discharged to home and showed lower mortality. High-dose nadroparin did not, however, show a decrease in the occurrence of clinical DCI after aSAH. A randomized controlled trial seems warranted.

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.

Background: The methodology of thromboprophylaxis post minimally invasive esophagectomy (MIE) is unclear. Thus, we compared the efficacy and safety of fondaparinux and nadroparin on the prophylaxis of venous thromboembolism (VTE) after MIE., Materials and Methods: We conducted a randomized, double-blind, treatment-controlled study. Consecutive patients undergoing MIE randomly received a single dose of either nadroparin 2850 AxaIU (Group H) or fondaparinux 2.5 mg (Group F) daily. We used ultrasonography to identify deep vein thrombosis (DVT) on postoperative day 7. The coagulation status was examined using thromboelastography (TEG) prior to and at 0, 24, 48, and 72 h after the operation. Bleeding events were recorded during anticoagulation therapy and analysis was performed on an intention-to-treat basis., Results: We randomly assigned the patients to Group H (n = 57) or Group F (n = 59). Symptomatic or asymptomatic DVT was identified in seven patients in Group H and one patient in Group F (12.28% vs. 1.69%, p = 0.031). Pulmonary embolism developed in one patient in Group H, and the VTE incidence was significantly lower in Group F than Group H (1.69% vs. 14.04%, RR: 0.121, 95% CI: 0.016-0.935, p = 0.016). TEG analysis showed a more inhibited coagulation profile of Group F compared with Group H reflected by the significantly prolonged R time at 48 h and 72 h after operation (6.8 ± 2.2 min vs. 8.4 ± 2.7 min, p = 0.005; 7.1 ± 1.6 min vs. 9.2 ± 3.7 min, p = 0.002). Bleeding events were not recorded in either group., Conclusions: Fondaparinux could provide similar efficacy and safety in postoperative thromboprophylaxis following MIE compared with nadroparin., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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.

Introduction: Procoagulant factors promote cancer progression and metastasis. Protein C is involved in hemostasis, inflammation and signal transduction, and has a protective effect on the endothelial barrier. In mice, administration of activated protein C reduced experimental metastasis. We assessed the association between protein C and mortality in patients with three types of cancer., Methods: The study population consisted of patients with advanced prostate, non-small cell lung or pancreatic cancer, who participated in the INPACT trial (NCT00312013). The trial evaluated the addition of nadroparin to chemotherapy in patients with advanced malignancy. Patients were divided into tertiles based on protein C at baseline. The association between protein C levels and mortality was evaluated with Cox proportional hazard models., Results: We analysed 477 patients (protein C tertiles: <97, 97-121 and ≥121%). Mean age was 65±9years; 390 (82%) were male; 191 patients (40%) had prostate cancer, 161 (34%) had lung cancer, and 125 (26%) pancreatic cancer. During a median follow-up of 10.4months, 291 patients (61%) died. Median protein C level was 107% (IQR 92-129). In the lowest tertile, 75 patients per 100 patient-years died, as compared to 60 and 54 in the middle and high tertile, respectively. Lower levels of protein C were associated with increased mortality (in tertiles: HR for trend 1.18, 95%CI 1.02-1.36, adjusted for age, sex and nadroparin use; as a continuous variable: HR 1.004, 95%CI 1.00-1.008, p=0.07)., Conclusion: Protein C seems inversely associated with mortality in patients with advanced prostate, lung and pancreatic cancer. Further research should validate protein C as a biomarker for mortality, and explore the effects of protein C on progression of cancer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aim: To improve the results of surgical treatment of benign prostatic hyperplasia., Materials and Methods: The study investigated the effectiveness of a comprehensive preoperative preparation of patients with benign prostatic hyperplasia. The clinical efficacy of traditional methods of preoperative preparation (compression bandaging of the lower extremities during surgery and in the postoperative period and Fraxiparine at a prophylactic dose) was compared with the same preoperative protocol used in combination with intravenous laser blood irradiation. The explored parameters included changes in clinical and laboratory coagulation indices and prostatic blood flow measured by Doppler sonography. The real time visualization was used to assess the effect of intravenous laser irradiation of blood on the morphofunctional state of platelets., Conclusion: The study findings showed a high effectiveness of intravenous laser blood irradiation in preoperative preparation of patients with benign prostatic hyperplasia. It was found to reduce the incidence of thrombotic events by 6% and hemorrhagic complications by 4.9% (p<0.05).

Background: The immobilisation of the lower leg is associated with deep vein thrombosis (DVT). However, thromboprophylaxis in patients with a below-knee plaster cast remains controversial. We examined the efficacy and safety of nadroparin and fondaparinux to ascertain the need for thromboprophylaxis in these patients., Methods: PROTECT was a randomised, controlled, single-blind, multicentre study that enrolled adults with an ankle or foot fracture who required immobilisation for a minimum of four weeks. The patients were randomly assigned (1:1:1) to a control group (no thromboprophylaxis) or to one of the intervention groups: daily subcutaneous self-injection of either nadroparin (2850 IE anti-Xa=0.3ml) or fondaparinux (2.5mg=0.5ml). A venous duplex sonography was performed after the removal of the cast or earlier if thrombosis was suspected. The primary outcome was the relative risk of developing DVT in the control group compared with that in both intervention groups. This trial is registered at ClinicalTrials.gov, number NCT00881088., Results: Between April 2009 and December 2015, 467 patients were enrolled and assigned to either the nadroparin group (n=154), the fondaparinux group (n=157), or the control group (n=156). A total of 273 patients (92, 92, and 94 patients, respectively) were analysed. The incidence of DVT in the nadroparin group was 2/92 (2.2%) compared with 11/94 (11.7%) in the control group, with a relative risk of 5.4 (95% CI 1.2-23.6; p=0.011). The incidence of DVT in the fondaparinux group was 1/92 (1.1%), yielding a relative risk of 10.8 (95% CI 1.4-80.7; p=0.003) compared with that in the control group. No major complications occurred in any group., Conclusion: Thromboprophylaxis with nadroparin or fondaparinux significantly reduces the risk of DVT in patients with an ankle or foot fracture who were treated in a below-knee cast without any major adverse events., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The comparative analysis data were presented, concerning the results of complex treatment of 28 patients, suffering ischemic-gangrenous form of the diabetic foot syndrome, developing on background of chronic ischemia of the lower extremities stage IV. In 14 patients (main group) a routine complex of the treatment measures was added by application of an active pressure (negative pressure wound therapy - NPWT) and a capicor preparation; 14 patients (the comparison group) were treated in accordance to routine scheme. In accordance to the comparative analysis data, in patients of the main group the wound surface sarea have kept reducing in twice more rapid, than in a comparison group, the wounds healing was achieved in 94% patients, duration of the patients’ stationary stay have reduced by (5.2 ± 1.4) days.

The aim of this study is to investigate thrombogenesis and the hypercoagulable changes in pregnant women affected by thrombophilia who received low-molecular-weight heparin (LWMH) prophylaxis. We included 21 pregnant women affected by thrombophilia treated with LWMH and 20 nontreated normal pregnant women as the control group. The sample group of thrombophilic pregnant women included different conditions (factor V Leiden mutation, protein C deficiency, protein S deficiency, antiphospholipid antibodies syndrome, and combined defects). Three blood samples were collected during pregnancy (i.e., at 16, 20, and 24 weeks) and tested for activated partial thromboplastin time and prothrombin fragment F1 + 2 (F1 + 2); anti-FXa activity was tested only in treated thrombophilic pregnant women. F1 + 2 levels progressively increased during pregnancy in both study groups. However, the F1 + 2 increase in women exposed to heparin prophylaxis was significantly lower than that in normal pregnant women in all 3 measurements carried out during gestation (p < 0.05); a statistically significant inverse correlation between F1 + 2 levels and anti-Xa activity (R = -0.8575, p < 0.05) was observed in treated women during pregnancy. Our findings suggest that F1 + 2 in addition to anti-Xa measurement could be used to adjust LWMH prophylaxis, at least in high-risk pregnant women., (© 2017 S. Karger AG, Basel.)

Background: The efficacy and safety of anticoagulant treatment is not established for patients with acute symptomatic deep vein thrombosis (DVT) of the calf. We aimed to assess whether therapeutic anticoagulation is superior to placebo in patients with symptomatic calf DVT., Methods: In this randomised, double-blind, placebo-controlled trial, we enrolled low-risk outpatients (without active cancer or previous venous thromboembolic disease) with a first acute symptomatic DVT in the calf from 23 university medical centres or community medical clinics in Canada, France, and Switzerland. We randomly assigned (1:1) patients to receive either the low-molecular-weight heparin nadroparin (171 UI/kg, subcutaneously, once a day) or placebo (saline 0·9%, subcutaneously, once a day) for 6 weeks (42 days). Central randomisation was done using a computer-generated randomisation list, stratified by study centre. Random allocation sequences of variable block size were centrally determined by an independent research clinical centre. Study staff, patients, and outcome assessors (central adjudication committee) were masked to group assignment. Numbered boxes of active drug or placebo were provided to pharmacies in identical packaging. All patients were prescribed compression stockings and followed up for 90 days. The primary efficacy outcome was a composite measure of extension of calf DVT to proximal veins, contralateral proximal DVT, and symptomatic pulmonary embolism at day 42 in the modified intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding at day 42. The trial was registered with ClinicalTrials.gov, number NCT00421538., Findings: Between Feb 1, 2008, and Nov 30, 2014, we screened 746 patients, enrolling 259 patients (50% of the prespecified sample size), before the trial steering committee terminated the trial because of expiry of study drug and slow recruitment. The intention-to-treat analysis population comprised 122 patients in the nadroparin group and 130 in the placebo group. There was no significant difference between the groups in the composite primary outcome, which occurred in four patients (3%) in the nadroparin group and in seven (5%) in the placebo group (risk difference -2·1%, 95% CI -7·8 to 3·5; p=0·54). Bleeding occurred in five patients (4%) in the nadroparin group and no patients in the placebo group (risk difference 4·1, 95% CI 0·4 to 9·2; p=0·0255). In the nadroparin group one patient died from metastatic pancreatic cancer and one patient was diagnosed with heparin-induced thrombocytopenia type 2., Interpretation: Nadroparin was not superior to placebo in reducing the risk of proximal extension or venous thromboembolic events in low-risk outpatients with symptomatic calf DVT, but did increase the risk of bleeding. Avoidance of systematic anticoagulation for calf DVT could have a substantial impact on individual patients and from a public health perspective., Funding: Swiss National Science Foundation, the Programme Hospitalier de Recherche Clinique in France, and the Canadian Institutes of Health Research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Anticoagulant thromboprophylaxis with low molecular weight heparin is widely used in nonsurgical settings. To obtain best estimates of the effects of nadroparin for the prevention of venous thromboembolism (VTE) in nonsurgical patients, we conducted a systematic review and meta-analysis. Data sources were Medline, Embase, and Cochrane Library supplemented with conference abstracts, without language restrictions. Selection criteria were randomized controlled trials with nadroparin at prophylactic dose in adult nonsurgical patients. Main efficacy outcomes were major VTE (the composite of symptomatic deep vein thrombosis, symptomatic pulmonary embolism, asymptomatic proximal deep vein thrombosis and VTE-related death) and symptomatic VTE. The main safety outcome was major bleeding. We expressed treatment effects as risk ratios. Ten studies (4 vs. placebo or no treatment, 4 vs. UFH, 1 vs. fondaparinux and 1 vs. warfarin) enrolling a total of 7658 patients were included. In comparison with placebo, nadroparin reduced major VTE by about one-half (RR 0.48, 95% CI 0.24-0.97) with a consistent effect on symptomatic VTE (RR 0.69, 95% CI 0.46-1.05) and no increase in major bleeding (RR 1.51, 95% CI 0.40-5.79). In comparison with other pharmacological prophylaxis, nadroparin was similarly efficacious for prevention of major VTE (RR 1.14, 95% CI 0.63-2.10) and symptomatic VTE (RR 1.10, 95% CI 0.51-2.35) and produced similar effects on major bleeding (RR 0.60, 95% CI 0.25-1.50). Five studies were open label, and for three of these the adjudication method was not described or not blinded. In nonsurgical populations at risk of VTE, nadroparin reduced VTE by about one half compared with placebo or no treatment and appeared similarly effective and safe as other prophylactic anticoagulants.

We report the case of a 16-year-old male patient who presented with a clavicular fracture that was conservatively treated with a redressment bandage. After a few days the patient developed deep vein thrombosis of the subclavian, axillary and brachial veins, which was successfully treated with nadroparin. Conservative treatment of clavicular fractures is a common procedure in modern traumatology. Continuous, close monitoring and knowledge of rare but severe complications are necessary to avoid further complications.

Background: Nephrotic syndrome confers an acquired prothrombotic phenotype due to the urinary loss of anticoagulant proteins.Patients with reactivation of nephrotic syndrome may develop thrombosis., Case Presentation: We report the case of a life-threatening cerebral venous thrombosis in a 13 year-old boy affected by a relapse of nephrotic syndrome during a P. aeruginosa otitis/mastoiditis. Due to the worsening general conditions and the severe neurological impairment, a course of systemic thrombolysis was successfully administered, followed by anticoagulant therapy. In the present case severe inherited thrombophilia (inherited dysfunctional protein S deficiency) was identified as an important additional risk factors for thrombosis., Conclusions: A careful evalutaion of risk factos for thrombosi during reactivation of nephrotic syndrome include measurement of plasma anticaogulant proteins. When low, antithrombotic prophylaxis with heparin should be considered to prevent thrombotic episodes.

Comparative results of treatment of thrombotic complications in the injured persons with combined trauma of trunk in two groups were adduced. The scheme of prophylax3 is and treatment of thrombotic complications was proposed; application of this scheme have permitted to reduce their rate in 5 times, from 54.5 to 11.2%.

Background: Low molecular weight heparins (LMWHs) are the cornerstone of the prevention of thromboembolic events in surgical patients. Recent clinical data suggest that LMWHs might improve survival of cancer patients, independent of their anticoagulant effect. The anti-cancer mechanism of LMWHs is incompletely understood, but may include effects on tumor angiogenesis. We assessed the effects of LMWHs on tumor angiogenesis and microcirculation in a mouse colorectal xenograft model using in vivo microscopy in window chambers., Methods: HT29 human colorectal cancers were implanted in dorsal skinfold window chambers in athymic mice. Animals (n = 8 per group) were treated with 200 IU of nadroparin, enoxaparin, or saline for 8 d. Repeated intravital fluorescence microscopy was performed to calculate functional microcirculatory parameters as follows: number (N) and length (L) of microvessels, vascular area fraction (AF), and red blood cell velocity. Microvessel density, microvessel fractal dimension, and pericyte coverage were assessed histologically., Results: Active angiogenesis was observed in control animals, resulting in a significant increase in N, L, and AF. In nadroparin- and enoxaparin-treated animals, however, AF did not change significantly over time and N and L remained significantly lower than untreated animals on day 7. Compared with control animals, nadroparin- and enoxaparin-treated animals showed a significantly lower microvessel density, but a higher pericyte coverage index, indicating a more mature microvessel network., Conclusions: The LMWHs nadroparin and enoxaparin inhibit tumor angiogenesis and result in microvessel normalization in this in vivo observed colorectal xenograft model., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Venous ulcers are common, especially in the elderly, accounting for more than 50% of all lower extremity ulcers with important socioeconomic problems. Improving extracellular matrix functioning, by heparin administration, seems to be a way to support wound healing. A total of 284 patients with venous ulcers were recruited in a 4-year period. All patients were subjected to the most appropriate treatment after considering their preference (compression therapy followed or not by vein surgery). Patients were randomised into two groups of 142 persons in each (group A and group B as cases and controls, respectively). Patients of group A, in addition to the basic treatment as described earlier, received administration of nadroparin 2850 IU/0.3 ml through subcutaneous injection once a day for 12 months, whereas group B patients received basic treatment alone. Healing was assessed by means of direct ulcer tracing with computerised planimetry. Group A showed a healing rate of 83·80% at 12 months, whereas that of group B was 60·56%. Results by age group surprisingly showed that the group of older patients took the most advantage from long-term treatment with low molecular weight heparin; this group also had lowest recurrence rate., (© 2013 The Authors. International Wound Journal © 2013 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Analysis of thrombohemorrhagic complications was conducted in 98 patients, operated on for various forms of chemoresistant pulmonary tuberculosis. To prevent such complications it is necessary to prescribe heparin in minimal doses or fraxiparine preoperatively and intraoperatively. It permits to lower the prethrombotic background significantly, to prevent thrombohemorrhagic complications, and in their incidence--to eliminate thrombotic and hemorrhagic clinical features with minimal losses.

Background: Since hypercoagulability might result in recurrent miscarriage, anticoagulant agents could potentially increase the chance of live birth in subsequent pregnancies in women with unexplained recurrent miscarriage, with or without inherited thrombophilia., Objectives: To evaluate the efficacy and safety of anticoagulant agents, such as aspirin and heparin, in women with a history of at least two unexplained miscarriages with or without inherited thrombophilia., Search Methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 October 2013) and scanned bibliographies of all located articles for any unidentified articles., Selection Criteria: Randomised and quasi-randomised controlled trials that assessed the effect of anticoagulant treatment on live birth in women with a history of at least two unexplained miscarriages with or without inherited thrombophilia were eligible. Interventions included aspirin, unfractionated heparin (UFH), and low molecular weight heparin (LMWH) for the prevention of miscarriage. One treatment could be compared with another or with no-treatment (or placebo)., Data Collection and Analysis: Two review authors (PJ and SK) assessed the studies for inclusion in the review and extracted the data. If necessary they contacted study authors for more information. We double checked the data., Main Results: Nine studies, including data of 1228 women, were included in the review evaluating the effect of either LMWH (enoxaparin or nadroparin in varying doses) or aspirin or a combination of both, on the chance of live birth in women with recurrent miscarriage, with or without inherited thrombophilia. Studies were heterogeneous with regard to study design and treatment regimen and three studies were considered to be at high risk of bias. Two of these three studies at high risk of bias showed a benefit of one treatment over the other, but in sensitivity analyses (in which studies at high risk of bias were excluded) anticoagulants did not have a beneficial effect on live birth, regardless of which anticoagulant was evaluated (risk ratio (RR) for live birth in women who received aspirin compared to placebo 0.94, (95% confidence interval (CI) 0.80 to 1.11, n = 256), in women who received LMWH compared to aspirin RR 1.08 (95% CI 0.93 to 1.26, n = 239), and in women who received LMWH and aspirin compared to no-treatment RR 1.01 (95% CI 0.87 to 1.16) n = 322).Obstetric complications such as preterm delivery, pre-eclampsia, intrauterine growth restriction and congenital malformations were not significantly affected by any treatment regimen. In included studies, aspirin did not increase the risk of bleeding, but treatment with LWMH and aspirin increased the risk of bleeding significantly in one study. Local skin reactions (pain, itching, swelling) to injection of LMWH were reported in almost 40% of patients in the same study., Authors' Conclusions: There is a limited number of studies on the efficacy and safety of aspirin and heparin in women with a history of at least two unexplained miscarriages with or without inherited thrombophilia. Of the nine reviewed studies quality varied, different treatments were studied and of the studies at low risk of bias only one was placebo-controlled. No beneficial effect of anticoagulants in studies at low risk of bias was found. Therefore, this review does not support the use of anticoagulants in women with unexplained recurrent miscarriage. The effect of anticoagulants in women with unexplained recurrent miscarriage and inherited thrombophilia needs to be assessed in further randomised controlled trials; at present there is no evidence of a beneficial effect.

Introduction: Severe and acute exacerbation of chronic obstructive pulmonary disease (COPD) is associated with a high mortality. Since COPD is an airway inflammatory disease, and heparin has shown anti-inflammatory effects in previous studies, we evaluated the clinical effect of low molecular weight heparin (LMWH; nadroparin) in COPD patients admitted into the hospital due to acute exacerbations., Methods: Sixty-six patients admitted to the intensive care unit (ICU) were randomly divided into control group (n = 33) and LMWH group (n = 33). The control group received conventional treatment, including oxygen therapy (non-invasive or conventional mechanical ventilation), anti-infection, atomization expectorant, spasmolysis, anti-asthmatics, and nutritional support. The LMWH group received the same treatment plus LMWH for 1 week. The levels of plasma C-reactive protein, interleukin-6, and fibrinogen were measured. The main outcomes were duration of mechanical ventilation, length of ICU stay, and hospital stay., Results: There were no significant differences between the groups with respect to demographics, severity of illness, and gas exchange variables. The levels of plasma C-reactive protein, interleukin-6, and fibrinogen were significantly decreased in the LMWH group. LMWH significantly reduced the mean duration of mechanical ventilation (6.6 days vs. 3.8 days; p < 0.01), the length of ICU stay (8.5 days vs. 5.6 days; p < 0.01) and hospital stay (14.3 days vs. 11.3 days; p < 0.01)., Conclusions: The addition of LMWH to standard therapy benefits COPD patients with acute exacerbation.

Background: Chronic kidney disease patients show changes in the endothelial surface layer (ESL). Whether hemodialysis (HD) itself or low molecular weight heparins (LMWH) induce ESL alterations is unknown., Methods: We studied the ESL in 20 HD patients with Sidestream Dark Field Imaging [measuring perfused boundary region (PBR)] and measurement of ESL constituents in plasma during HD in 2 studies. LMWH was administered at the start of HD in study A, and 120 min after the start of HD in study B. Mean platelet volume (MPV) and platelet large cell ratio (P-LCR) were also measured., Results: Syndecan-1 increased significantly 30 min after LMWH administration. sP-Selectin increased 120 min after HD start, and MPV and P-LCR decreased significantly during HD. No significant changes of PBR, sE-Selectin, sICAM-1, or sVCAM-1 were perceived., Conclusions: HD caused a significant increase in Syndecan-1 without a change in PBR. The administration of LMWH appeared to precede the rise in Syndecan-1., (© 2014 S. Karger AG, Basel.)

The aim of the study was to assess the value of D-dimer as an event predicitor for deep vein thrombosis (DVT) in patients given low molecular weight heparin (LMWH) after total hip arthroplasty (THA). Plasma D-dimer levels were obtained preoperatively and at days 1, 3, and 7 postoperatively in 83 consecutive patients undergoing THA treated with nadroparin prophylaxis plus intermittent pneumatic compression. Unilateral ascending venography was performed at postoperative day 7 or 8. There was a significant difference between the D-dimer levels in the DVT group (28 patients) and non-DVT group (55 patients) on each day (P<0.01). ROC analysis showed the AUC on postoperative days 1, 3 and 7 was 0.706, 0.712 and 0.772 respectively. The D-dimer concentration on postoperative day 1, day 3 or day 7 is of moderate predicting value of DVT in patients undergoing THA, treated with nadroparin prophylaxis plus intermittent pneumatic compression.

Background: Symptomatic pulmonary embolism constitutes a significant risk following abdominal flap breast reconstruction. Reported rates vary from 0 to 6 percent. The authors assessed risk factors associated with symptomatic pulmonary embolism and constructed a prediction model to identify high-risk patients., Methods: Patients undergoing deep inferior epigastric perforator or transverse rectus abdominis musculocutaneous flap breast reconstructions at two academic centers from January of 2005 through January of 2011 were included. Thromboprophylaxis measures included early ambulation, low-molecular-weight heparin, elastic stockings, A-V Impulse System foot pumps, and pneumatic stockings. Risk factors for symptomatic pulmonary embolism were analyzed and weights were assigned to these risk factors. Sensitivity and specificity were maximized using receiver operating characteristic curves., Results: Of 430 consecutive patients, symptomatic pulmonary embolism occurred in 17 cases (4.0 percent). Two independent predictors for symptomatic pulmonary embolism were found, body mass index higher than 25, additionally higher than 28, and the BRCA gene mutation. Operation duration and bilaterality of reconstructions were dependent on the BRCA mutation and both indirect predictors for symptomatic pulmonary embolism. Optimization of sensitivity and specificity resulted in a prediction model. No significant differences in efficacy were found between the different thromboprophylaxis measures., Conclusions: The rate of symptomatic pulmonary embolism was 4.0 percent, despite standard thromboprophylaxis. Body mass index and BRCA were significant predictors for symptomatic pulmonary embolism. The authors integrated these factors into a prediction model, which provides a useful tool for identification of high-risk patients. This latter category may benefit from a more aggressive thromboprophylaxis approach., Clinical Question/level of Evidence: Risk, III.

Introduction: Thromboembolic complications are the most common preventable cause of mortality and morbidity in trauma and arthroplasty patients. Therefore, this group of patients receive a prophylaxis for thromboemboli by mechanical or pharmacological methods. This study was designed to evaluate the effect of enoxaparin, nadroparin, dalteparin and fondaparinux on fracture healing in an experimental rat femur fracture model., Materials and Methods: Thirty male, Wistar-Albino rats were divided randomly into five groups. A retrograde intramedullary kirschner wire was inserted under general anesthesia and then standard closed femoral shaft fractures were produced. After the production of fractures, treatment groups received enoxaparin, nadroparin, dalteparin and fondaparinux via subcutaneous injections and the control group received placebo injections for four weeks. The formation and healing of the bones were determined by clinical manual evaluation, radiographic and histopathological analyses., Results: Histological callus formation scores were found to be significantly increased in the fondaparinux group when compared to the control group at the end of the fourth week. Other treatment groups' histological scores did not show any significant difference with the control group. The histological scores of all groups were compared and the fondaparinux group histological score was found to be significantly increased. The clinical and radiological scores between the groups did not show any significant difference., Conclusions: A positive histological effect of fondaparinux on fracture healing was observed in this study. This enhancing effect of fondaparinux may be related to its synthetic and selective composition and non-inhibitory effects on osteoblasts and growth factors., (Copyright © 2013 Elsevier Ltd. All rights reserved.)