Search

Background:  rVIII-SingleChain is a recombinant factor VIII (FVIII) with increased binding affinity to von Willebrand factor compared with other FVIII products. rVIII-SingleChain is indicated for the treatment and prevention of bleeding episodes in patients with hemophilia A., Objectives:  To collect real-world evidence data from patients treated with rVIII-SingleChain to confirm the efficacy and safety established in the clinical trial program and carry out a population pharmacokinetic (PK) analysis., Methods:  This interim analysis includes data, collected between January 2018 - September 2021, from patients treated with rVIII-SingleChain prophylaxis at French Hemophilia Treatment centers. Data on annualized bleeding rates, dosing frequency, and consumption before and after switching to rVIII-SingleChain were recorded. A population PK analysis was also conducted to estimate PK parameters., Results:  Overall, 43 patients switched to prophylaxis with rVIII-SingleChain either from a previous prophylaxis regimen or from on-demand treatment. Following the switch to rVIII-SingleChain, patients maintained excellent bleed control. After switching to rVIII-SingleChain, most patients maintained or reduced their regimen. Interestingly, a majority of patients treated >2 ×/weekly with a standard half-life FVIII reduced both injection frequency and FVIII consumption with rVIII-SingleChain. A PK analysis revealed a lower clearance of rVIII-SingleChain (1.9 vs. 2.1 dL/h) and a longer half-life both in adolescents/adults ( n  = 28) and pediatric ( n  = 6) patients (15.5 and 11.9 hours, respectively vs. 14.5 and 10.3 hours) than previously reported., Conclusions:  Patients who switched to rVIII-SingleChain prophylaxis demonstrated excellent bleed control and a reduction in infusion frequency. A population PK analysis revealed improved PK parameters compared with those reported in the clinical trial., Competing Interests: B.G. has been a consultant for Baxter/Baxalta/Shire/Takeda, CSL Behring, LFB, Novo Nordisk, Octapharma, Roche-Chugaï, and Sobi. Abel H. has been a consultant for Bayer, CSL Behring, and Sobi. B.W. has received consulting fees from SOBI, Roche (fees go to Lille University Hospital or association pour le Développement de la Recherche et de l'Innovation dans le NORD PAS DE CALAIS). Annie H. has been a consultant for CSL Behring, Takeda, Novo Nordisk, LFB, Sobi, and Roche. C.B.-A. has received funding from CSL-Behring, Takeda, Sobi, LFB, and Roche. Y.R. has been a consultant for Baxter/Baxalta/Shire/Takeda, CSL Behring, LFB, Octapharma, Roche-Chugaï, and Sobi. R.d.O. has been a consultant for Bayer, Baxter/Baxalta/Shire/Takeda, Biomarin, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, and Spark Therapeutics. B.T. has received research funding from CSL Behring, Takeda, Novo Nordisk, LFB, Sobi, Roche, and Octapharma. B.P.P. has been a consultant for Sobi, CSL Behring, Takeda, Biomarin, NovoNordisk, and Roche/Chugai. P.C. has been a consultant for Sobi. V.G. has received honoraria for participation in symposia by NovoNordisk and Sobi. M.F. has been a consultant for CSL Behring, Roche, and SOBI, and has received research funding from SOBI and Novo Nordisk. C.P. has been a consultant for Baxter/Baxalta/Shire/Takeda, CSL Behring, Roche, and Sobi. C.M. and H.C. are employees of CSL Behring. X.D. has received honoraria for participation in symposia by CSL Behring, Shire, Octapharma, and Sobi., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Laboratory confirmation of heparin-induced thrombocytopenia (HIT) is of crucial importance and remains challenging and relies on platelet functional assays highlighting the presence of heparin-dependent platelet-activating antibodies in patient serum or plasma. Platelet functional assays using washed platelets include the 14 C-serotonin release assay (SRA), usually described as the gold standard, and the heparin-induced platelet activation assay (HIPA). Since its first comparison with SRA there has been no additional published study regarding HIPA diagnostic performances compared with SRA. Aim of our retrospective study was to compare the concordance between HIPA and SRA in HIT suspected-patients with positive anti-PF4/heparin antibodies between October 2010 and October 2015. Fifty-five HIT-suspected patients who beneficiated from both HIPA and SRA were included. Positive and negative percent agreements were 83.8% (95% CI 68.0-93.8%) and 66.7% (95% CI 41.0-86.7%), respectively. Overall percent agreement was 78.2% (95% CI 65.0-92.2%). Agreement was higher in patients who underwent cardiopulmonary bypass with extracorporeal circulation circuit for cardiac surgery. We also confirm that the use of a minimum of 2 platelet donors to establish positive HIT diagnosis and 4 platelet donors to exclude HIT diagnosis allows obtaining a good agreement with SRA. Although HIPA and SRA were performed with different platelet donors and in different laboratories, HIPA had a good positive agreement with SRA for HIT diagnosis, showing that HIPA is a useful functional assay that does not require radioactivity and could be developed worldwide to improve HIT diagnosis., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Background:  Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin treatments, and only a few large patient cohorts have been reported. In this study, biological and clinical data from 144 French patients with HIT were analyzed in comparison with the literature., Methods:  The diagnosis of HIT was confirmed in all patients by an immunoassay combined with serotonin release assay. In the literature, only cohorts of at least 20 HIT patients published from 1992 were selected for a comparative analysis., Results:  Two-thirds of patients were hospitalized in surgery and most were treated with unfractionated heparin (83.2% vs. 16.8% with low molecular weight heparin only). Thrombotic events in 54 patients (39.7%) were mainly venous (41/54). However, arterial thrombosis was more frequent after cardiac surgery (13.2% vs. 2.4% in other surgeries, p  = 0.042) with a shorter recovery time (median = 3 vs. 5 days, p  < 0.001). The mortality rate was lower in our series than in the 22 selected published studies (median = 6.3% vs. 15.9%). Three genetic polymorphisms were also studied and homozygous subjects FcγRIIA RR were more frequent in patients with thrombosis (37.8 vs. 18.2% in those without thrombosis, p  = 0.03)., Conclusion:  This study shows that the mortality rate due to HIT has recently decreased in France, possibly due to earlier diagnosis and improved medical care. It also confirms the strong association between polymorphism FcγRIIA H131R and thrombosis in HIT., Competing Interests: Y.G.: Consulting and/or travel fees from Octapharma, Shire, CSL Behring, Novo Nordisk, Bayer, LFB, and Léo Pharma. J.R.: Travel fees from Octapharma, Shire, and CSL Behring. C.V.: Travel fees from Sobi, Roche, Shire, and CSL Behring. D.F.: Consulting and/or travel fees from Aspen, Boehringer, Werfen, Stago, and Léo Pharma. A.B.: Travel fees from Aspen, Boehringer, Werfen, Pfizer, and LFB. A.L.: Consulting and/or travel fees from Bayer, LFB, Pfizer, Sobi, and Octapharma. E.D.M.: Travel fees from Sobi, Bayer, Novo Nordisk, and Pfizer. B.T.P.: Consulting and/or travel fees from Sobi, Bayer, Shire, CSL Behring, and Pfizer. I.E.: Consulting and/or travel fees from BMS, Aspen, Léo Pharma, Daiichi Sankyo, Pfizer, Sanofi-Aventis, and Shire. C.L.B.: Travel fees from Sobi, Octapharma, CSL Berhing, and Novo Nordisk. C.M.: Consulting and/or travel fees from BMS, Aspen, Pfizer, and Bayer. C.B.: Consulting and/or travel fees from CSL, Sobi, Bayer, and Novo Nordisk. C.T.: Consulting and travel fees from Sobi, Roche, Octapharma. F.N.G.: Travel fees from Sobi, Bayer, BMS, and Boehringer. J.D.: Travel fees from CSL and Novo Nordisk. T.B.A.: Travel fees from Servier and MSD. E.D.R.: Consulting and/or travel fees from Shire, Alexion, Sobi, Bayer, and Novo Nordisk. I.G.T.: Consulting and/or travel fees from Bayer, MSD, Pfizer, Sanofi-Aventis, and BMS. L.R.: Consulting and/or travel fees from CSL, LFB, Novo Nordisk, Sobi, and Bayer. B.T.: Consulting and/or travel fees from Sobi, Bayer, Novo Nordisk Aspen, CSL Behring, and Pfizer. C.P.: Consulting and/or travel fees from Sobi, Roche, Novo Nordisk, and CSL Behring. P.W., M.A.G., S.V., V.G.G., J.P., and B.G. have no conflict to disclose. All the authors did not receive any personal honorarium or funds related to the study reported in this manuscript. Y.G. reports grants from Ministère de la Santé (Government), during the conduct of the study; personal fees and nonfinancial support from CSL Behring, personal fees and nonfinancial support from Octapharma, nonfinancial support from Shire, personal fees from Léo Pharma, personal fees and nonfinancial support from LFB, nonfinancial support from Bayer, nonfinancial support from Novo Nordisk, outside the submitted work., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Nonlinear frequency compression (NLFC) and digital noise reduction (DNR) are hearing aid features often used simultaneously in the adult population with hearing loss. Although each feature has been studied extensively in isolation, the effects of using them in combination are unclear., Purpose: The effects of NLFC and DNR in noise on word recognition and satisfaction ratings in noise in adult hearing aid users were evaluated., Research Design: A repeated measures design was used., Study Sample: Two females and 13 males between the ages of 55 and 83 yr who were experienced hearing aid users participated. Thirteen were experienced with NLFC and all were experienced with DNR. Each participant was fit with Phonak Bolero Q90-P hearing instruments using their specific audiometric data and the Desired Sensation Level v5.0 (adult) fitting strategy. Fittings were verified with probe microphone measurements using speech at 65-dB sound pressure level (SPL). NLFC verification was performed using the Protocol for the Provision of Amplification, Version 2014.01., Data Collection and Analysis: All testing was conducted in a double-walled sound booth. Four hearing aid conditions were used for all testing: Baseline (NLFC off, DNR off), NLFC only, DNR only, and Combination (NLFC on, DNR on). A modified version of the Pascoe's High-Frequency Word List was presented at 65-dB SPL with speech spectrum noise at 6-dB signal-to-noise ratio (SNR) and 1-dB SNR for each hearing aid condition. Listener satisfaction ratings were obtained after each listening condition in terms of word comfort, word clarity, and average satisfaction. Two-way repeated measures analyses of variance were conducted to assess listener performance. Pairwise comparisons were then completed for significant main effects., Results: Word recognition results indicated a significant SNR effect only (6 dB SNR > 1 dB SNR). Satisfaction ratings results indicated a significant SNR and hearing aid condition effect for clarity, comfort, and average satisfaction. Clarity ratings were significantly higher for DNR and Combination than NLFC. Comfort ratings were significantly higher for DNR than NLFC. Average satisfaction was significantly higher for DNR and Combination than for NLFC. Also, average ratings were significantly higher for Combination than Baseline., Conclusions: Activating NLFC or DNR in isolation or in combination did not significantly impact word recognition in noise. Activating NLFC in isolation reduced satisfaction ratings relative to the DNR or Combination conditions. The isolated use of DNR significantly improved all satisfaction ratings when compared with the isolated use of NLFC. These findings suggest NLFC should not be used in isolation and should be coupled with DNR for best results. Future research should include a field trial as this was a limitation of the study., (American Academy of Audiology.)

The ristocetin cofactor activity assay (VWF:RCo) is the reference method for assessing von Willebrand factor (VWF) activity but remains difficult to perform, and the coefficient of variation of the method is high (about 20-30%). This study evaluated and compared the performance for measuring the VWF activity of two newly commercialised assays [VWF:Ac Innovance (VWF:Ac) and VWF:RCo Acustar (VWF:RCo Acu)] with the reference VWF:RCo aggregation in 123 pathological plasma samples. The correlation and concordance between both new tests (VWF:RCo-Acu and VWF:Ac) and the reference VWF:RCo were good. The results of the VWF activity to VWF antigen ratio were also comparable whatever the method for the classification of VWF deficiency in all patients. Our results showed that both new tests could replace the "gold standard" VWF:RCo in aggregometry with several benefits: they are fully automated, easier and faster to perform, better adapted to emergency situations if necessary.

There is no in vitro data on the comparison of the effects of danaparoid, argatroban and fondaparinux on thrombin generation in patients with heparin-induced thrombocytopenia. It was the study objective to compare the in vitro anticoagulant potential of argatroban, danaparoid and fondaparinux using a thrombin generation assay TGA on a mixture of control platelet-rich plasma (PRP) and HIT patient platelet-poor plasma (PPP). The plasma of seven patients with a clear HIT diagnosed at our institution was selected. Mixtures of donor PRP and patient PPP were incubated with unfractionated heparin 0.2 U.mL⁻¹, argatroban at 600 ng.mL⁻¹, argatroban at 400 ng.mL⁻¹, danaparoid at 0.65 IU.mL⁻¹ and fondaparinux at 1 μg.mL⁻¹. Thrombin generation was assessed by calibrated thrombinography. The percentage of inhibition of the endogenous thrombin potential observed with argatroban at 600 ng.mL⁻¹ was statistically significantly higher compared with those observed with fondaparinux (median: 53.6% vs. 3.9%; p=0.031) but not compared with argatroban at 400 ng.mL⁻¹ and danaparoid. The percentage of inhibition of the thrombin peak observed with argatroban at 600 ng.mL⁻¹ was statistically significantly higher compared with those observed with danaparoid (median: 71.2 vs. 56.8; p=0.031) and fondaparinux (mean: 71.2 vs. 30; p=0.031) but not with argatroban at 400 ng.mL⁻¹. In conclusion, the in vitro effect of argatroban and danaparoid on thrombin generation seems to corroborate the results of clinical studies of these drugs in the treatment of HIT in term of efficiency. Fondaparinux showed a very small effect on thrombin generation evaluated by calibrated thrombinography.

The prognosis of patients with myocardial infarction (MI) and normal coronary arteries (NCA) in the presence of an inherited coagulation disorder is unknown. The purpose of this study was to compare the clinical thrombosis outcome of patients with (GpI) or without (GpII), inherited coagulation disorders, who suffered from an acute MI with NCA. Eighty two consecutive patients (mean age 49 +/- 15 years; 29 females) with MI, but NCA, were recruited. Twelve patients (15%) had an inherited coagulation disorder. GpI and GpII were statistically similar regarding age (45 +/- 11 vs 50 +/- 16 years-old), gender (33 vs. 36% female), tobacco consumption (50 vs. 53%), diabetes mellitus (8 vs. 10%), hypertension (25 vs. 17%), obesity (8.3 vs. 14%), family history of coronary heart disease (33 vs. 19%), hypercholesterolemia (50 vs. 21%; p =.08), left ventricular ejection fraction (58 +/- 13 vs. 61 +/- 13%) and spasm (8.3% vs. 17%). All patients were initially treated with antiplatelet agents with the exception of one (8%) in GpI, and 6 (9%) in GpII who were taking oral anticoagulant therapy (ns). The mean follow-up was 57 +/- 26 (range from 2-91 months). During the outcome, 12/78 (15.4%) thrombosis events occurred, including venous thrombosis or pulmonary embolism (1/12 vs. 1/66), reinfarction (2/12 vs. 4/66), and stroke (2/12 vs. 2/66), with two events in one patient (GpI). Kaplan-Meier event-free survival, with combined end-point, defined as venous thrombo-embolic event, reinfarction, or stroke differed between the two groups: 4/12 (33.3%) in GpI and 7/66 (10.6%) in Gp II (p <.02). Patients with MI, NCA and congenital coagulation disorder present a high risk of thrombosis recurrence under antiplatelet agent.

Factor V Leiden is associated with an increased risk of venous thrombosis and myocardial infarction in young women, but not in men in this latter case. The aim of this study was to evaluate the prevalence of this mutation in patients with myocardial infarction but normal coronary angiography. We compared 3 groups of patients: one group consisted of 107 patients with premature myocardial infarction but no significant coronary artery stenosis; another group of 244 patients with myocardial infarction and significant coronary artery stenosis; a third group of 400 healthy controls. Factor V Leiden was found in 13 patients (12.1%) who had a myocardial infarction without significant coronary artery stenosis, 11 patients (4.5%) who had a myocardial infarction with significant coronary artery stenosis (p = 0.01) and in 20 controls (5%) (p = 0.01). Odds ratio associated with factor V Leiden were respectively 2.93 (CI95: 1.18-7.31 ) and 2.63 (CI95: 1.19-5.78) when we compared myocardial infarction patients without significant coronary artery stenosis to controls or to patients with significant coronary artery stenosis. In myocardial infarction patients without significant coronary artery stenosis, prevalence of factor V Leiden is significantly higher than in controls. This new finding supports the hypothesis that thrombosis plays a key role in this selected situation.

Background: The prevention of venous thromboembolic disease is less studied in medical patients than in surgery., Methods: We performed a meta-analysis of randomised trials studying prophylactic unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) in internal medicine, excluding acute myocardial infarction or ischaemic stroke. Deep-vein thrombosis (DVT) systematically detected at the end of the treatment period, clinical pulmonary embolism (PE), death and major bleeding were recorded., Results: Seven trials comparing a prophylactic heparin treatment to a control (15,095 patients) were selected. A significant decrease in DVT and in clinical PE were observed with heparins as compared to control (risk reductions = 56% and 58% respectively, p <0.001 in both cases), without significant difference in the incidence of major bleedings or deaths. Nine trials comparing LMWH to UFH (4,669 patients) were also included. No significant effect was observed on either DVT, clinical PE or mortality. However LMWH reduced by 52% the risk of major haemorrhage (p = 0.049)., Conclusions: This meta-analysis, based on the pooling of data available for several heparins, shows that heparins are beneficial in the prevention of venous thromboembolism in internal medicine.

Study Objective: To determine the clinical usefulness of D-dimer ELISA test in elderly patients with clinically suspected pulmonary embolism (PE)., Design: Prospective cohort study., Patients: Ninety-six consecutive outpatients older than 70 years with a duration of symptoms shorter than one week and without metastatic cancer or recent surgery, trauma, infection, stroke, myocardial infarction, deep vein thrombosis (DVT) or PE, or treatment with curative doses of heparin or oral anticoagulant., Intervention: All patients underwent at least ventilation/perfusion scan and bilateral ultrasonic duplex scan and a blood sample collection within 24 hours of admission. When necessary a pulmonary angiography and/or a bilateral venography were also performed. Patients were classified as follows: (1) PE-positive: positive angiography or high probability V/Q scan and deep vein thrombosis (proven either by venography or by ultrasonic duplex scan) or non high probability V/Q scan and either DVT (proven at presentation by venography or by ultrasonic duplex scan) or symptomatic thromboembolic event within 3 months of follow-up; or (2) PE-negative; normal V/Q scan or normal angiography or non high probability V/Q scan and either negative ultrasonic duplex scan or normal venography and low clinical probability and absence of symptomatic thromboembolism within 3 months of follow-up. D-dimer measurements were performed using both a conventional and a single semi-quantitative ELISA test (Asserachrom D-di, Instant I.A.D-dimer)., Results: Using a cutoff value of 500 ng/ml, the conventional ELISA D-dimer test showed a sensitivity and a negative predictive value of 100% with poor specificity and positive predictive value of 14.3% and 45.5% respectively. The new rapid semi-quantitative D-dimer test displays worse results with sensitivity, negative predictive value, specificity and positive predictive value of 92.3%, 82.4%, 25% and 46% respectively., Conclusion: In a geriatric population, conventional ELISA D-dimer is a good marker to exclude PE but, due to the comorbid conditions, only a few patients presented with D-dimer values less than 500 ng/ml.