Efficacy and Safety Analyses of Recombinant Factor VIIa in Severe Post-Partum Hemorrhage

Background: Despite a range of available treatments, it is still sometimes challenging to treat patients with severe post-partum hemorrhage (sPPH). Objective: This study evaluated the efficacy and safety of recombinant activated factor VIIa (rFVIIa) in sPPH management. Methods: An open-label, multi-center, randomized controlled trial (RCT; NCT00370877) and four observational studies (OS; OS-1 (NCT04723979), OS-2, OS-3, and OS-4) were analyzed regarding efficacy (need for subsequent invasive procedures, including uterine compression sutures, uterine or iliac artery ligations, arterial embolization, or hysterectomy) and safety (incidence of thromboembolic events (TE) and maternal mortality) of rFVIIa for sPPH. The RCT, and OS-1 and OS-2, included a control group of women who did not receive rFVIIa (with propensity score-matching used in OS-1 and OS-2), whereas OS-3 and OS-4 provided descriptive data for rFVIIa-exposed women only. Results: A total of 446 women exposed to rFVIIa and 1717 non-exposed controls were included. In the RCT, fewer rFVIIa-exposed women (50% [21/42]) had an invasive procedure versus non-exposed women (91% [38/42]; odds ratio: 0.11; 95% confidence interval: 0.03–0.35). In OS-1, more rFVIIa-exposed women (58% [22/38]) had an invasive procedure versus non-exposed women (35% [13.3/38]; odds ratio: 2.46; 95% confidence interval: 1.06–5.99). In OS-2, 17% (3/18) of rFVIIa-exposed women and 32% (5.6/17.8) of non-exposed women had an invasive procedure (odds ratio: 0.33; 95% confidence interval: 0.03–1.75). Across all included women, TEs occurred in 1.5% (0.2% arterial and 1.2% venous) of rFVIIa-exposed women and 1.6% (0.2% arterial and 1.4% venous) of non-exposed women with available data. Conclusions: The positive treatment effect of rFVIIa on the RCT was not confirmed in the OS. However, the safety analysis did not show any increased incidence of TEs with rFVIIa treatment

A common polymorphism in NR1H2 (LXRbeta) is associated with preeclampsia

<p>Abstract</p> <p>Background</p> <p>Preeclampsia is a frequent complication of pregnancy and a leading cause of perinatal mortality. Both genetic and environmental risk factors have been identified. Lipid metabolism, particularly cholesterol metabolism, is associated with this disease. Liver X receptors alpha (NR1H3, also known as LXRalpha) and beta (NR1H2, also known as LXRbeta) play a key role in lipid metabolism. They belong to the nuclear receptor superfamily and are activated by cholesterol derivatives. They have been implicated in preeclampsia because they modulate trophoblast invasion and regulate the expression of the endoglin (CD105) gene, a marker of preeclampsia. The aim of this study was to investigate associations between the <it>NR1H3 </it>and <it>NR1H2 </it>genes and preeclampsia.</p> <p>Methods</p> <p>We assessed associations between single nucleotide polymorphisms of <it>NR1H3 </it>(rs2279238 and rs7120118) and <it>NR1H2 </it>(rs35463555 and rs2695121) and the disease in 155 individuals with preeclampsia and 305 controls. Genotypes were determined by high-resolution melting analysis. We then used a logistic regression model to analyze the different alleles and genotypes for those polymorphisms as a function of case/control status.</p> <p>Results</p> <p>We found no association between <it>NR1H3 </it>SNPs and the disease, but the <it>NR1H2 </it>polymorphism rs2695121 was found to be strongly associated with preeclampsia (genotype C/C: adjusted odds ratio, 2.05; 95% CI, 1.04-4.05; <it>p </it>= 0.039 and genotype T/C: adjusted odds ratio, 1.85; 95% CI, 1.01-3.42; <it>p </it>= 0.049).</p> <p>Conclusions</p> <p>This study provides the first evidence of an association between the <it>NR1H2 </it>gene and preeclampsia, adding to our understanding of the links between cholesterol metabolism and this disease.</p

Are low-density lipoprotein receptor-related protein 1 or non-neutralizing antibodies predictors of FVIII in vivo recovery in haemophilia A patients?

International audienc

Recommendations for assessment, monitoring and follow-up of patients with haemophilia.

Summary. Over the last few decades, clinical follow-up of patients with haemophilia has become more complex as a result of the introduction of new treatment strategies, the presence of comorbidities related to haemophilia or ageing, as well as the emergence of new tools to evaluate the medical and social consequences of haemophilia. This publication describes the parameters and information that should be documented and the tests, examinations and interventions required for optimal follow-up of a patient with haemophilia. In the absence of formal studies, the present recommendations have been established as result of a series of consensus meetings in the frame of the European Haemophilia Therapy Standardization Board (EHTSB). The following 11 domains were identified: Baseline information, Current status, Treatment, Inhibitor status, Bleeding, Joint status and pain, Comorbidities, Dental care, Physical activities, Social participation and Quality of life. For each domain, details are proposed for the relevant parameters to be captured and monitored as well as the relevant tools that facilitate data collection. Adopting these recommendations should help the individual care of patients and, even though this is not the primary objective of this article, it should also help at national and international level to shape a new approach to haemophilia by working towards a more standardized outcome assessment. Greater standardization should have implications for data collection, improvements in treatment evaluation and optimizing resources

Circulating FVIII-specific IgG, IgA and IgM memory B cells from haemophilia A patients

International audienceINTRODUCTION:Approximately, 25% of haemophilia A (HA) patients treated by factor VIII (FVIII), develop antibodies, known as inhibitors, neutralizing the activity of infused FVIII. This immune response involves B cells (BC), including FVIII-specific memory B cells (MBC). Production of anti-FVIII antibodies after stimulation of FVIII-specific MBC suggests a role of these cells in the immune response to FVIII. Animal models allowed the study of circulating FVIII-specific cells, however few data are available on HA patients.AIM AND METHODS:In the present study, we simultaneously detected, via ELISpot assay, different isotypes of MBC in the blood of HA patients, after polyclonal activation. Patients included: three with active inhibitors; three with a history of inhibitors; six without any past or active inhibitor.RESULTS:FVIII-specific MBC were detected in peripheral blood of HA patients: (i) patients with active inhibitors (IgG: 4-5.2/10(6) BC; IgA: 2.9-4/10(6) BC) (ii) patients with a past of inhibitors (no IgG BC; IgA: 5-7.5/10(6) BC) (iii) patients without inhibitors (no IgG BC or IgA BC except one patient had two FVIII-specific IgA BC/10(6) BC).CONCLUSION:FVIII-specific IgA MBC were detected in HA patients with past and current immune responses against FVIII and FVIII-specific IgG MBC were found only in those with positive inhibitors. This study shows the possibility to detect and characterize easily and simultaneously the MBC from patient blood and that MBC seem different according to anti-FVIII immune history. It could be a useful tool to study anti-FVIII response and Immune Tolerance Induction cellular mechanisms

Anti-A2 and anti-A1 domain antibodies are potential predictors of immune tolerance induction outcome in children with hemophilia A

International audienceBACKGROUND:Hemophilia A (HA) is a congenital bleeding disorder resulting from factor VIII deficiency. The most serious complication of HA management is the appearance of inhibitory antibodies (Abs) against injected FVIII concentrates. To eradicate inhibitors, immune tolerance induction (ITI) is usually attempted, but it fails in up to 30% of cases. Currently, no undisputed predictive marker of ITI outcome is available to facilitate the clinical decision.OBJECTIVES:To identify predictive markers of ITI efficacy.METHODS:The isotypic and epitopic repertoires of inhibitory Abs were analyzed in plasma samples collected before ITI initiation from 15 children with severe HA and high-titer inhibitors, and their levels were compared in the two outcome groups (ITI success [n = 7] and ITI failure [n = 8]). The predictive value of these candidate biomarkers and of the currently used indicators (inhibitor titer and age at ITI initiation, highest inhibitor titer before ITI, and interval between inhibitor diagnosis and ITI initiation) was then compared by statistical analysis (Wilcoxon test and receiver receiver operating characteristic [ROC] curve analysis).RESULTS:Whereas current indicators seemed to fail in discriminating patients in the two outcome groups (ITI success or failure), anti-A1 and anti-A2 Ab levels before ITI initiation appeared to be good potential predictive markers of ITI outcome (P 0.875).CONCLUSION:Anti-A1 and anti-A2 Abs could represent new promising tools for the development of ITI outcome prediction tests for children with severe HA