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Effect of a direct thrombin inhibitor compared with dalteparin and unfractionated heparin on human osteoblasts.

ABSTRACT: PURPOSE:Osteoporosis is a relevant problem after long term administration of unfractionated heparin (UFH) and low molecular weight heparin. Melagatran is a representative of a new group of direct thrombin inhibitors with comparable data in the prevention of thromboembolic events after orthopaedic surgery. The aim of our in vitro study was to investigate the effect of a direct thrombin inhibitor compared with dalteparin and UFH on human osteoblasts. MATERIALS AND METHODS:Melagatran, dalteparin and UFH were added to primary osteoblast cultures in their therapeutic range and two decimal powers below and above. Cell number, protein synthesis, mitochondrial and alkaline phosphatase activity and collagen type I synthesis were evaluated. RESULTS:Melagatran showed the least influence on protein synthesis and cell proliferation with a reduction of cell number to 83.5 ± 9% (p = 0.027) of the control group only in the highest investigated concentration after 15 days of incubation. Mitochondrial and alkaline phosphatase activity and collagen type I synthesis in osteoblasts incubated with melagatran and dalteparin showed similar patterns. UFH showed the most pronounced influence on cellular metabolism. CONCLUSIONS:Melagatran showed less inhibitory in vitro effects on human osteoblasts than dalteparin or UFH. The presented study gives first hints that direct thrombin inhibitors may help prevent heparin-induced negative effects on bone metabolism.

SUBMITTER: Winkler T

PROVIDER: S-EPMC3087215 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Effect of a direct thrombin inhibitor compared with dalteparin and unfractionated heparin on human osteoblasts.

Winkler Tobias T Perka Carsten C Matziolis Dörte D Matziolis Georg G

The open orthopaedics journal 20110316

<h4>Purpose</h4>Osteoporosis is a relevant problem after long term administration of unfractionated heparin (UFH) and low molecular weight heparin. Melagatran is a representative of a new group of direct thrombin inhibitors with comparable data in the prevention of thromboembolic events after orthopaedic surgery. The aim of our in vitro study was to investigate the effect of a direct thrombin inhibitor compared with dalteparin and UFH on human osteoblasts.<h4>Materials and methods</h4>Melagatran ...[more]

PMID: 21552458

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

Project description:BackgroundLow molecular weight heparins (LMWH) have been extensively studied and became the treatment of choice for several indications including pulmonary embolism. While their efficacy in hemodialysis is considered similar to unfractionated heparin (UFH), their safety remains controversial mainly due to a risk of bioaccumulation in patients with renal impairment. The aim of this systematic review was to evaluate the safety of LMWH when compared to UFH for extracorporeal circuit (ECC) anticoagulation.MethodsWe used Pubmed, Embase, Cochrane central register of controlled trials, Trip database and NICE to retrieve relevant studies with no language restriction. We looked for controlled experimental trials comparing LMWH to UFH for ECC anticoagulation among end-stage renal disease patients undergoing chronic hemodialysis. Studies were kept if they reported at least one of the following outcomes: bleeding, lipid profile, cardiovascular events, osteoporosis or heparin-induced thrombocytopenia. Two independent reviewers conducted studies selection, quality assessment and data extraction with discrepancies solved by a third reviewer. Relative risk and 95% CI was calculated for dichotomous outcomes and mean weighted difference (MWD) with 95% CI was used to pool continuous variables.ResultsSeventeen studies were selected as part of the systematic. The relative risk for total bleeding was 0.76 (95% CI 0.26-2.22). The WMD calculated for total cholesterol was -28.70 mg/dl (95% CI -51.43 to -5.98), a WMD for triglycerides of -55.57 mg/dl (95% CI -94.49 to -16.66) was estimated, and finally LDL-cholesterol had a WMD of -14.88 mg/dl (95% CI -36.27 to 6.51).ConclusionsLMWH showed to be at least as safe as UFH for ECC anticoagulation in chronic hemodialysis. The limited number of studies reporting on osteoporosis and HIT does not allow any conclusion for these outcomes. Larger studies are needed to evaluate properly the safety of LMWH in chronic hemodialysis.

Project description:INTRODUCTION:The interaction between anticoagulants and platelet function is complex. Previous publications showed mixed results regarding the role of heparins in platelet aggregation. On the other hand, the direct thrombin inhibitor (DTI) dabigatran might enhance the risk of myocardial infarction in patients with atrial fibrillation, which could be related to increased platelet aggregability. METHODS:This was a prospective, interventional study of patients with chronic coronary artery disease (CAD) taking low-dose aspirin. The objective of the current study was to compare the effects of dabigatran versus enoxaparin on platelet aggregability. Subjects initially were on orally administered dabigatran for 5 days followed by subcutaneously administered enoxaparin after a 30-day washout period. Platelet function was assessed at baseline and after each intervention by multiple electrode aggregometry (MEA-ASPI) (primary endpoint), serum thromboxane B2 (TXB2), VerifyNow Aspirin™, and coagulation tests (secondary endpoints). RESULTS:Compared to baseline MEA-ASPI values, dabigatran increased platelet aggregation while enoxaparin decreased platelet aggregation (+?5 U?±?24.1 vs - 6 U?±?22.2, respectively, p?=?0.012). The TXB2 assay showed the same pattern (+ 2 pg/ml for dabigatran vs - 13 pg/ml for enoxaparin, p?=?0.011). None of the additional tests showed significant differences between the groups. Individually, compared to baseline TXB2 results, enoxaparin significantly decreased platelet activation [33 (16.5-95) pg/mL vs 20 (10-52) pg/mL, respectively, p?=?0.026], but no significant differences were observed with dabigatran. CONCLUSIONS:DTI and anti-Xa drugs exert opposite effects on platelet function. A significant decrease in platelet activation through COX1 (also known as prostaglandin G/H synthase 1) was observed with enoxaparin, but no significant differences in platelet function were observed with dabigatran. TRIAL REGISTRATION:ClinicalTrials.gov identifier, NCT02389582.

Dataset Information

Effect of a direct thrombin inhibitor compared with dalteparin and unfractionated heparin on human osteoblasts.

Publications

Effect of a direct thrombin inhibitor compared with dalteparin and unfractionated heparin on human osteoblasts.

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