Sylvie Labrouche

Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: Two observational studies in patients undergoing total hip or total knee replacement

INTRODUCTION Dabigatran and rivaroxaban have recently been added to the armamentarium for thromboprophylaxis in orthopedic surgery. Although this is their first licensed indication, others will soon follow. Owing to their claimed predictable anticoagulant response that dispenses with the need for monitoring coagulation, their effects are poorly described in routine cases. However, interpreting blood coagulation results and evaluating whether a treatment is properly targeted in the case of untoward incidents will become a common concern for clinicians. METHODS Eighty patients undergoing total hip or knee replacement were included in two studies. Forty of them received dabigatran (study 1) and 40 rivaroxaban (study 2). Blood samples (n = 176 and 166) were taken preoperatively and twice a week from the first postoperative day. RESULTS Dabigatran increased aPTTr about two-fold and PT about 1.2-fold, and it was mostly an initiation-phase modulator of thrombin generation. Mean circulating concentrations as measured by a diluted thrombin time were 105 ± 85 ng/mL at T(max) in samples from patients receiving the full dosing. They depended significantly on renal function, body weight and gender. Rivaroxaban increased aPTTr and PTr around 1.5 fold and modified the initiation and amplification phases of thrombin generation, with a lowered and prolonged thrombin burst. Mean circulating concentrations as measured by an antiXa test were 117 ± 78 ng/mL at T(max). With both drugs, routine coagulation tests, thrombin generation curves and functionally determined concentrations exhibited high interindividual variability. CONCLUSION Routine coagulation tests are altered in patients receiving dabigatran or rivaroxaban, but their alterations poorly reflect the circulating concentrations as determined by functional approaches.

Influence of Hyperbaric Oxygen on Leukocyte Functions and Haemostasis in Normal Volunteer Divers

dant regulating pathways. Most have been demonstrated in isolated in vitro systems, but their relative

Neuropeptide FF in the Rat Adrenal Gland: Presence, Distribution and Pharmacological Effects

Neuropeptide FF (NPFF, FLFQPQRFamide) is an FMRFamide‐like octapeptide exhibiting antiopiate activity. The presence of both NPFF‐immunoreactivity (NPFF‐IR) and NPFF‐specific receptors has been described in the mammalian central nervous system (CNS). The peripheral effects of NPFF indicate that NPFF‐IR material is present outside the CNS. Biochemical and immunohistochemical methods enabled us to determine the presence and distribution of NPFF‐IR in the rat adrenal gland. The amount of NPFF‐IR material in whole gland was estimated by radioimmunoassay to be 19.00±4.00 fmol/gland. High performance liquid chromatography analysis of adrenal extracts revealed a single molecular form which coeluted with authentic NPFF. Demedullation decreased adrenal NPFF‐IR content, indicating that NPFF‐IR was present in both cortex and medulla. Light microscopy revealed NPFF‐IR in beaded fibers confined in the outer part of the cortex and in medullary cells. Double‐labeling with antityrosine‐hydroxylase and anti‐NPFF antibodies showed NPFF‐IR in cortical catecholaminergic postganglionic fibers restricted to the subcapsular and glomerulosa zonae. NPFF‐IR was also located in medullary chromaffin cells and in rays and islets of chromaffin cells dispersed throughout the cortex. Insulin‐induced hypoglycemia did not alter NPFF‐IR content. Denervation lowered adrenal NPFF‐IR content. These data indicate that this peptide is present in nerve fibers of extrinsic origin. In vitro approaches using adrenal slices have shown that NPFF inhibited aldosterone release in a dose‐dependent manner. Taken together, these data suggest that NPFF may participate in the control of aldosterone production and adrenal blood supply.

Rapid ELISA D-Dimer Testing in the Exclusion of Venous Thromboembolism in Hospitalized Patients

The clinical diagnosis of deep-vein thrombosis (DVT) and pulmonary embolism (PE) is known to be unreli able. Until now, no biological marker has been found to con firm thrombosis, but help can be gained from a biological marker ruling out the diagnosis of DVT or PE, i.e., the sensitive measurement of D-dimer (DD) species. This article summa rizes our experience in introducing a rapid D-dimer test (ELISA VIDAS D-dimères test, bioMérieux) in a collaborative strategy for thrombosis diagnosis during 9 consecutive months involving 1,131 measurements. The efficacy of the DD test was very different according the type of patient, and departments where the DD test provides a real diagnostic benefit were iden tified. High clinical probability for thrombosis was encountered in 32 patients and radiology was carried out, although D-dimer was negative: none of these patients was found to have a throm bosis after radiologic examination. However, extensive prog ress must be made in test prescription to reduce the excessive rate of positive D-dimer tests (78%) and positive measurements that are not followed up by radiology (42%).

Rivaroxaban and apixaban in orthopaedics: is there a difference in their plasma concentrations and anticoagulant effects?

The aim of this study was to improve knowledge of what happens in the coagulation of orthopaedic patients under rivaroxaban and apixaban, in order to finalize and cross-validate effective measurement methods and to provide arguments for helping to reference one or the other drug in our central pharmacy. One hundred and two patients undergoing total hip or knee replacement were included. Half of them received rivaroxaban and the other half received apixaban. Blood samples (n = 244 with each drug) were taken at Cmax preoperatively and twice a week, apart from the day of the patients discharge, when Ctrough concentration was targeted. Routine coagulation parameters, and functional and liquid chromatography tandem mass spectrometry assays for measurement of circulating concentrations were studied. The LC-MS/MS assay and the functional assays carried out in patients under routine conditions were highly correlated, apart from low concentrations (<30 ng/ml), which were affected by the variable individual potential to inhibit the exogenous bovine Xa used in the functional assays. After 1 week of treatment, the drugs differed: Cmax and Ctrough were closer when apixaban was taken twice daily (83 ± 39 and 58 ± 17 ng/ml) than with rivaroxaban taken once a day (113 ± 67 and 13 ± 20 ng/ml). Rivaroxaban had a greater influence on routine coagulation tests and reduced the maximum thrombin concentration more efficiently, as assessed by the thrombin generation test. Although rivaroxaban and apixaban present apparently similar constant rates, they exhibit significant differences in their concentrations and anticoagulant effects when studied ex vivo in orthopedic patients.

Lysis Timer: a new sensitive tool to diagnose hyperfibrinolysis in liver transplantation

Aims Diagnosis of hyperfibrinolysis in orthotopic liver transplantation (OLT) remains challenging. Euglobulin clot lysis time (ECLT) is not adapted to clinical situations. ROTEM is specific but seldom sensitive to hyperfibrinolysis. The Lysis Timer assesses ‘Global Fibrinolytic Capacity’ in citrated plasma (GFC/LT). GFC/LT associates reagents for in vitro triggering of the clot (thrombin and calcium) and its lysis (tissue-plasminogenactivator (t-PA)), turbidity signal acquisition by the Lysis Timer, and dedicated software converting the digital signal into an optical curve. A visual check of the curves was systematic to ascertain the lysis time values calculated by the software. The primary aim of this prospective observational study was to evaluate the ability of GFC/LT to recognise hyperfibrinolysis during OLT. The secondary aim was to compare its results with ROTEM maximum lysis (EXTEM ML) and with standard laboratory tests. Methods Thirty consecutive adult patients undergoing OLT were included (NCT03012633). Standard laboratory tests, ROTEM, GFC/LT, ECLT and fibrinolysis parameters were assayed at five sample times. Results GFC/LT was correlated with ECLT, plasmin activator inhibitor 1 antigen and activity and t-PA activity (r=0.490, 0.681, 0.643 and –0.359, respectively). Hyperfibrinolysis was defined as ECLT ≤60 min. Receiver operating characteristic curve analysis showed that GFC/LT with a threshold of 31 min detected hyperfibrinolysis with a sensitivity of 0.88 (95% CI 0.73 to 0.96), a specificity of 0.68 (95% CI 0.56 to 0.78) and an area under the curve (AUC) of 0.85 (95% CI 0.74 to 0.94). EXTEM ML >12% did not detect hyperfibrinolysis (sensitivity 0.38 (95% CI 0.24 to 0.55), specificity 0.95 (95% CI 0.86 to 0.99) and AUC 0.60 (95% CI 0.46 to 0.75)). Conclusions GFC/LT recognised hyperfibrinolysis during OLT with a significant agreement with the other tests of fibrinolysis. Trial registration number NCT03012633.