Low thrombin generation in users of a contraceptive containing estetrol and drospirenone

OBJECTIVE: To compare the impact on thrombin generation of the new combined oral contraceptive containing 15 mg estetrol and 3 mg drospirenone with ethinylestradiol (30 or 20 mcg) associated either with 150 mcg levonorgestrel or with 3 mg drospirenone. METHODS: Data were collected from the “E4/DRSP Endocrine Function, Metabolic Control and Hemostasis Study” (NCT02957630). Overall, the per-protocol set population included 24 subjects in the ethinylestradiol/levonorgestrel arm, 28 subjects in the ethinylestradiol/drospirenone arm, and 34 subjects in the estetrol/drospirenone arm. Thrombograms and thrombin generation parameters (lag time, peak, time to peak, endogenous thrombin potential, and mean velocity rate index) were extracted for each subject at baseline and after 6 cycles of treatment. RESULTS: After 6 cycles of treatment, ethinylestradiol-containing products arms show a mean thrombogram outside the upper limit of the reference range, that is the 97.5th percentile of all baseline thrombograms. On the other hand, the mean thrombogram of estetrol/drospirenone is within this reference interval. After 6 cycles of treatment, all thrombin generation parameters are statistically less affected by estetrol/drospirenone than ethinylestradiol-containing products. CONCLUSIONS: In conclusion, an association of 15 mg estetrol with 3 mg drospirenone does not have an impact on thrombin generation compared with ethinylestradiol-containing products that, either associated with levonorgestrel or drospirenone, are able to increase the production of procoagulant factors and decrease the production of anticoagulant ones, shifting the patient to a prothrombotic state. Ethinylestradiol-containing products thus generate prothrombotic environments contrary to estetrol which demonstrates a neutral profile on hemostasis

Dynamics of Neutralizing Antibody Responses Following Natural SARS-CoV-2 Infection and Correlation with Commercial Serologic Tests:A Reappraisal and Indirect Comparison with Vaccinated Subjects

Neutralising antibodies (NAbs) represent the real source of protection against SARS-CoV-2 infections by preventing the virus from entering target cells. The gold standard in the detection of these antibodies is the plaque reduction neutralization test (PRNT). As these experiments must be done in a very secure environment, other techniques based on pseudoviruses: pseudovirus neutralization test (pVNT) or surrogate virus neutralization test (sVNT) have been developed. Binding assays, on the other hand, measure total antibodies or IgG, IgM, and IgA directed against one epitope of the SARS-CoV-2, independently of their neutralizing capacity. The aim of this study is to compare the performance of six commercial binding assays to the pVNT and sVNT. In this study, we used blood samples from a cohort of 62 RT-PCR confirmed COVID-19 patients. Based on the results of the neutralizing assays, adapted cut-offs for the binding assays were calculated. The use of these adapted cut-offs does not permit to improve the accuracy of the serological assays and we did not find an adapted cut-off able to improve the capacity of these tests to detect NAbs. For a part of the population, a longitudinal follow-up with at least two samples for the same patient was performed. From day 14 to day 291, more than 75% of the samples were positive for NAbs (n = 87/110, 79.1%). Interestingly, 6 months post symptoms onset, the majority of the samples (N = 44/52, 84.6%) were still positive for NAbs. This is in sharp contrast with the results we obtained 6 months post-vaccination in our cohort of healthcare workers who have received the two-dose regimens of BNT162b2. In this cohort of vaccinated subjects, 43% (n = 25/58) of the participants no longer exhibit NAbs activity 180 days after the administration of the first dose of BNT162b2

Identification of SARS-CoV-2 Neutralizing Antibody with Pseudotyped Virus-based Test on HEK-293T hACE2 Cells

Neutralizing antibodies (NAbs) are of particular importance because they can prevent binding of the receptor binding domain (RBD) of the spike protein (S protein) to the angiotensin-converting enzyme 2 (ACE2) receptor present at the surface of human cells, preventing virus entry into the host cells. The gold standard method for detection of NAbs is the plaque reduction neutralization test (PRNT). Based on the measurement of cell lysis due to viral infection, this test is able to detect antibodies that prevent cell infection (Muruato et al., 2020; Lau et al., 2021). This technique requires the use of live pathogens, i.e., SARS-CoV-2 in this case, and must be done in a biosafety level 3 (BL3) laboratory. In addition, it requires expensive installations, skillful and meticulous staff, and a high workload, which prevents its wide implementation even in research laboratories. A SARS-CoV-2 pseudovirus will express the S protein responsible for cell entrance, but will not express the pathogenic genetic material of the virus, making them less dangerous for laboratory staff and the environment. Graphic abstract: [Image: see text

Mychael Danna: l'atípic

Abstract not availabl

Long-Term Survival, Vascular Occlusive Events and Efficacy Biomarkers of First-Line Treatment of CML:A Meta-Analysis

Large randomized clinical trials and prior meta-analyses indicate that second-generation BCR-ABL tyrosine kinase inhibitors (TKIs) improve surrogate biomarkers in patients with chronic myeloid leukemia (CML) without providing survival benefits. The objective is to evaluate the long-term efficacy and the occurrence of vascular occlusion with second-generation BCR-ABL TKIs compared with imatinib in patients with CML. Three scientific databases, a clinical registry and abstracts from congress were searched to identify all randomized controlled trials that compared a second-generation BCR-ABL TKI to imatinib in patients with CML. Outcomes extracted were overall survival, major molecular response and complete cytogenetic response, arterial occlusive events and venous thromboembolism. These data were synthesized by odds ratios using a fixed-effect model. This meta-analysis included 4659 participants from 14 trials. Second-generation BCR-ABL TKIs did not improve overall survival compared with imatinib, even at longer follow-up (OR, 1.17 (95% CI, 0.91-1.52)). They improved surrogate biomarkers at 12 and 24 months but increased the risk of arterial occlusion (OR, 2.81 (95% CI, 2.11-3.73)). The long-term benefits of second-generation TKIs are restricted to surrogate outcomes and do not translate into prolonged survival compared to imatinib. Given the long-term use, frontline therapy should be chosen carefully, with special attention to the patients' quality of life and cardiovascular risks

Early antibody response in healthcare professionals after two doses of SARS-CoV-2 mRNA vaccine (BNT162b2)

Data on the immune response after two doses of BNT162b2 are so far limited. Previously infected individuals were excluded from pivotal clinical trials and the optimal dose regimen in this population has not been clearly studied. The CRO-VAX HCP study aims at investigate the early antibody response in a population of healthcare professionals having received two doses of the BNT162b2 mRNA COVID-19 vaccine. The CRO-VAX HCP study is a multicenter, prospective, interventional study conducted in several sites in Belgium. The study included 231 healthcare professional volunteers who received the two-dose regimen of the BNT162b2 mRNA COVID-19 vaccine. Of these, 73 were previously infected by SARS-CoV-2 and 158 were uninfected and seronegative. In the first group, blood samples were collected at baseline and after 2, 4, 7, 10, 14, 21, and 28 days. In the second group, samples were obtained at baseline and after 14 and 28 days. Antibodies against the SARS-CoV-2 nucleocapsid and the receptor binding domain of the S1 subunit of the spike protein were measured in all individuals at different time points. In uninfected individuals, 95.5% (95% CI 91.0-98.2%) developed anti-spike antibodies after 14 days and a 24.9-fold rise (95% CI 21.4-28.9%) in antibody titer was observed after the second dose. In previously infected individuals, peak antibody response was reached after 7 days (i.e. 6,347 U/mL) and the second dose did not lead to significantly higher antibody titers (i.e. 8,856 to 11,911 U/mL). Antibody titers were higher in previously infected individuals. This study supports the concept that a single dose of BNT162b2 would be sufficient in previously infected individuals

Dose tailoring of dabigatran etexilate:Obvious or excessive?

Introduction: Dabigatran etexilate is used for preventing blood clots and tends to replace older anticoagulants in many of their indications. However, the ‘one dose fits all’ policy is subject to criticism. Recent findings assert the anxiety of the scientific community concerning the pharmacokinetic properties of dabigatran etexilate, that is, an important interindividual variability including an important genetic variant with a significant dependence of the renal function as route of elimination. Areas covered: This meta-opinion provides an overview of the current knowledge and evidence on the dose tailoring of dabigatran etexilate. It also discusses the remaining challenges to benefit from this perspective strategy to enhance the benefit–risk balance of dabigatran etexilate. Data were searched in the published literature and on regulatory agencies’ websites. Additionally, unpublished data were searched and discussed. Expert opinion: Causality between dabigatran exposure and bleeding risk is now established and recommendations on how to best estimate the drug exposure are published. Additionally, simulating studies revealed that a dose adaptation based on dabigatran plasma concentration estimations could improve the benefit–risk profile of the drug. This accumulating evidence suggests that some patients under dabigatran etexilate may benefit from a tailoring of the dose beyond the ones already proposed by the manufacturer