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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.

Data are limited on prostate cancer (PC) management in patients with haemophilia (PWH).To describe PC screening and diagnosis, treatment modalities and bleeding complications in a group of unselected PWH followed at French Haemophilia Treatment Centres (HTCs) PATIENTS AND METHODS: PC screening, management and bleeding complications were retrospectively investigated at 14 French HTCs between 2003 and 2018.Among1549 50-year-old PWHs, 73 (4.7%) underwent PC screening (median age 71.1 years; 67/6 HA/HB, 17/56 severe-moderate/mild). At diagnosis, haematuria was infrequent. Prophylaxis was administered during 76/86 (88%) prostate biopsies (PB) (n = 67 clotting factor concentrates, CFC; n = 9 desmopressin; n = 17 associated with tranexamic acid, TA). Bleeding (11/86, 12.8%) occurred mainly post-prophylaxis (median delay: 7 days): haematuria (9/11, 81.8%), and rectal bleeding (2/11, 18.2%) including one major (1.2%). PC was confirmed in 50/86 PB and in two prostatectomy specimens (total n = 50 patients, n = 6 with only active surveillance). Surgery (n = 28/44 patients) was managed with CFC. Fifteen patients had radiotherapy/brachytherapy, 10 had hormone therapy; CFC-based prophylaxis was only prescribed for brachytherapy (n = 2). Major bleedings occurred in 3/28 (10.7%) and 2/15 (13.3%) patients who underwent surgery and radio/brachytherapy, respectively. No bleeding risk factor was found.Our data indicate that PB requires prophylaxis for atleast 7 days, using CFC, desmopressin or TA in function of haemophilia severity. PC surgery should be considered at high bleeding risk. Long-term post-procedural CFC or oral TA could be discussed. Radiotherapy/brachytherapy also should be managed with prophylaxis (CFC or TA).

International audience; Introduction Emicizumab (Hemlibra (R)) recently became available and requires an adaptation for managing bleeding, suspected bleeding and emergency or scheduled invasive procedures in haemophilia A patients with inhibitor. This implicates a multidisciplinary approach and redaction of recommendations for care that must be regularly adapted to the available data. Aim The following text aims to provide a guide for the management of people with haemophilia A with inhibitor treated with emicizumab in case of bleeding or invasives procedures. Methods The French network on inherited bleeding disorders (MHEMO), the French Reference Centre on Haemophilia (CRH), in collaboration with the French Working Group on Perioperative Haemostasis (GIHP) have been working together to make proposals for the management of these situations. Results Haemostatic treatment and other medications should be given stepwise, according to the severity and location of the bleeding or the risk of bleeding of the procedure as well as the haemostatic response obtained at each step in order to ensure an optimal benefit/risk ratio. Conclusion The lack of data means that it is only possible to issue proposals rather than recommendations.

International audience; Introduction - Antihaemophilic factor (recombinant) (rAHF; ADVATE ) is approved for prophylaxis and treatment of bleeding in children and adults with haemophilia A. Reconstitution in 2 mL sterile water for injection instead of 5 mL allows for a 60% reduction in infusion volume and administration time, but could increase the likelihood of hypersensitivity and infusion-related reactions, especially in children. Aim - To assess local tolerability, safety and effectiveness of rAHF 2 mL during routine clinical practice factor VIII (FVIII) replacement (on-demand and prophylaxis) in children with severe (FVIII

International audience; This FranceCoag network study assessed 33 patients with congenital factor XIII (FXIII) deficiency presenting FXIII levels

International audience; Objectives: To evaluate the applicability and compliance with guidelines for early initiation of long-term prophylaxis in infants with severe hemophilia A and to identify factors associated with guideline compliance.Study design: This real-world, prospective, multicenter, population-based FranceCoag study included almost all French boys with severe hemophilia A, born between 2000 and 2009 (ie, after guideline implementation).Results: We included 333 boys in the study cohort. The cumulative incidence of long-term prophylaxis use was 61.2% at 3 years of age vs 9.5% in a historical cohort of 39 boys born in 1996 (ie, before guideline implementation). The guidelines were not applicable in 23.1% of patients due to an early intracranial bleeding or inhibitor development. Long-term prophylaxis was delayed in 10.8% of patients. In the multivariate analysis, 2 variables were significantly associated with "timely long-term prophylaxis" as compared with "delayed long-term prophylaxis": hemophilia treating center location in the southern regions of France (OR 23.6, 95% CI 1.9-286.7, P = .013 vs Paris area) and older age at long-term prophylaxis indication (OR 7.2 for each additional year, 95% CI 1.2-43.2, P = .031). Long-term prophylaxis anticipation was observed in 39.0% of patients. Earlier birth year (OR 0.5, 95% CI 0.3-0.8, P = .010 for birth years 2005-2009 vs 2000-2004) and age at first factor replacement (OR 1.9 for each additional year, 95% CI 1.2-3.0, P = .005) were significantly associated with "long-term prophylaxis guideline compliance" vs "long-term prophylaxis anticipation."Conclusions: This study suggests that long-term prophylaxis guidelines are associated with increased long-term prophylaxis use. However, early initiation of long-term prophylaxis remains a challenge.

IntroductionSevere haemophilia is a rare disease characterised by spontaneous bleeding from early childhood, which may lead to various complications, especially in joints. It is nowadays possible to avoid these complications thanks to substitutive therapies for which the issue of adherence is major. The transition from adolescence to adulthood in young people with severe haemophilia is a critical period as it is associated with a high risk of lack of adherence to healthcare, which might have serious consequences on daily activities and on quality of life.Methods and analysisWe present the protocol for a cross-sectional, observational, multicentric study to assess the differences between adolescents and young adults with severe haemophilia in France through the transition process, especially on adherence to healthcare. This study is based on a mixed methods design, with two complementary and consecutive phases, comparing data from a group of adolescents (aged 14–17 years) with those from a group of young adults (aged 20–29 years). The quantitative phase focuses on the determinants (medical, organisational, sociodemographic and social and psychosocial and behavioural factors) of adherence to healthcare (considered as a marker of the success of transition). The qualitative phase explores participants’ views in more depth to explain and refine the results from the quantitative phase. Eligible patients are contacted by the various Haemophilia Treatment Centres participating in the French national registry FranceCoag.Ethics and disseminationThe study was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2016-A01034-47). Study findings will be disseminated to the scientific and medical community in peer-reviewed journals and presented at scientific meetings. Results will be popularised to be communicated via the French association for people with haemophilia to participants and to the general public.Trial registration numberNCT02866526; Pre-results.

Introduction: Over the last decades, life expectancy of patients with hemophilia (PWH) has significantly improved and therefore, age-related comorbidities like cardiovascular disease (CVD) are now common features. Using antithrombotic and antiplatelet agents, as needed for managing CVD, proves complex in PWH given that these drugs, along with the often required invasive procedures, interfere with hemostasis; general recommendations are not applicable as such. Method: To collect data on current real-life practices in this patient population, the COCHE registry (COmorbidités Cardiovasculaires chez les patients HEmophiles) has been implemented back in July 2011. This French observational study sought to describe prospectively the management of CVD in PWH who require treatment with antiplatelet agents, antithrombotics, or both. Results: By January 2018, this registry had prospectively included 67 PWH: 59 hemophilia A and 8 hemophilia B patients (47 mild, 10 moderate, and 10 severe), with a median age of 65±12.5 years. Overall, 52 patients were included for coronary artery disease (CAD) and 16 for atrial fibrillation (AF), with one patient presenting both CAD and AF. Among the 67 patients enrolled, 49 were receiving on-demand replacement therapy. Identified cardiovascular risk factors were arterial hypertension (n=44), overweight or obesity (n= 35), dyslipidemia (n=30; four tested positive for human immune deficiency virus [HIV]), smoking (n=17), family coronary disease history (n=11), non-insulin dependent diabetes mellitus (NIDDM) (n=11), and insulin dependent diabetes mellitus (IDDM) (n=3). Conclusion: The proposals discussed herein are largely based on the experience we gained whilst managing PWH with CVD from the COCHE registry. To us, a multidisciplinary approach appears paramount. Disclosures Lebreton: Sobi: Consultancy, Research Funding.

Resume La drepanocytose est une anemie hemolytique corpusculaire constitutionnelle liee a une anomalie de structure de la chaine β de l’hemoglobine. La polymerisation de l’hemoglobine S anormale en milieu desoxygene et la deformation des globules rouges sont responsables de l’hemolyse chronique et des crises vaso-occlusives observees chez les sujets homozygotes ou heterozygotes composites. Les complications aigues les plus frequentes sont l’anemie et les crises douloureuses (en particulier articulaires) dont l’expression clinique la plus grave est le syndrome thoracique aigu. Leur incidence augmente avec la grossesse, l’accouchement et le postpartum. Les complications fœtales sont le retard de croissance intra-uterin et la mort fœtale inopinee. La prise en charge transfusionnelle au cours de la grossesse vise a abaisser les concentrations d’HbS en deca de 40 a 50 % afin de diminuer l’incidence des complications maternelles et fœtales. Ses modalites sont determinees par l’hematologue en charge du suivi de la patiente : exsanguinotransfusion, transfusion simple ou erythrocytapherese. En peripartum, les mesures preventives ont pour objectif d’eviter l’hypoxie, la douleur, l’hypovolemie, l’hypothermie et l’acidose qui sont des facteurs declenchants de crise vaso-occlusive. L’analgesie et l’anesthesie perimedullaire pour l’accouchement ou la cesarienne sont indiquees parce qu’elles previennent la douleur et favorisent la vasodilatation. Le traitement des crises vaso-occlusives repose sur l’oxygenation, l’hydratation, la transfusion, voire l’exsanguinotransfusion. L’analgesie peridurale a ete proposee avec succes pour le traitement du syndrome thoracique rebelle aux antalgiques habituels.

Background The absence of expression of C/c and E/e antigens has been associated with rare variant RHCE alleles, referred to as silent RHCE alleles, classically identified among individuals with a rare D– – or Rhnull phenotype. This work reports on different molecular mechanisms identified in three novel silent RHCE alleles. Study Design and Methods Samples from D– – or Rhnull individuals and their family members, from families for whom Rh phenotype and/or serologic data were unexplained by inheritance of conventional RH alleles, were analyzed. Genomic DNA and transcripts were tested by sequencing analysis. Results The first silent allele was a RHCE*cE allele carrying an intronic IVS3+5G>A mutation. The second was a RHCE*ce allele carrying an intronic IVS7-2A>G mutation, whereas the third was a silent RHCE*ce allele carrying a 5-bp deletion (Nucleotides 679-683) in Exon 5. Conclusion In addition to hybrid alleles and nucleotide deletion, intronic mutations may be associated with the nonexpression of RhCE antigens. Regarding the RH system, silent alleles may not be investigated among D– – or Rhnull individuals only. Rh phenotype and/or serologic data unexplained by inheritance of conventional RH alleles should lead to molecular investigations.

The absence of expression of C/c and E/e antigens has been associated with rare variant RHCE alleles, referred to as silent RHCE alleles, classically identified among individuals with a rare D- - or Rhnull phenotype. This work reports on different molecular mechanisms identified in three novel silent RHCE alleles.Samples from D- - or Rhnull individuals and their family members, from families for whom Rh phenotype and/or serologic data were unexplained by inheritance of conventional RH alleles, were analyzed. Genomic DNA and transcripts were tested by sequencing analysis.The first silent allele was a RHCE*cE allele carrying an intronic IVS3+5GA mutation. The second was a RHCE*ce allele carrying an intronic IVS7-2AG mutation, whereas the third was a silent RHCE*ce allele carrying a 5-bp deletion (Nucleotides 679-683) in Exon 5.In addition to hybrid alleles and nucleotide deletion, intronic mutations may be associated with the nonexpression of RhCE antigens. Regarding the RH system, silent alleles may not be investigated among D- - or Rhnull individuals only. Rh phenotype and/or serologic data unexplained by inheritance of conventional RH alleles should lead to molecular investigations.

Introduction The identification of molecular defects in haemophilia is essential for the optimization of patient treatment and the formal characterization of female carriers. The Sanger method is the gold standard for sequencing F8 and F9 genes but is time-consuming and expensive. We aimed to develop a high-throughput method to genotype haemophilia A (HA) and B (HB) patients using the Next-Generation Sequencing (NGS) technology for an exhaustive and less expensive analysis of F8 and F9 genes. Material & Methods We developed a small panel containing F8 and F9 for exons and introns/exons junctions sequencing. We used two different methods for library preparation (AmpliSeq™, Life Technologies™ and HaloPlex™, Agilent™), performed in the same PCR emulsion system (Ion One Touch 2™, Life Technologies™) and sequenced with a Ion 316™ chip in a PGM™ Ion Torrent sequencer, or a Ion PI™ chip in a Proton™ sequencer (Life Technologies™) respectively. The promoter and 3' regions of F8 and F9 were always studied by Sanger. NGS analysis was first performed in 62 samples (HA: n= 42; HB: n=13; carriers: n=7) previously characterized for F8 or F9 mutations by Sanger method or Multiplex Ligation-Probe Amplification (MLPA). All types of mutations were studied (nonsense, missense, splice, small insertion/deletion and exons deletion/duplication) and were distributed in all exons of F8 and F9. NGS analysis was further performed in 42 haemophilia patients (HA: n=31, HB: n=11; of which 36 presented a mild phenotype), with unknown mutation status. All patients were included by the local Comprehensive Care Haemophilia Center of Lille University Hospital after written informed consent. Data were analyzed with SeqNext™ software (JCI Medical System™). A Normalized Reads Depth (NRD) ratio was used to detect exons deletion/duplication. Results All exons were well covered by AmpliSeq™ (average number of reads, ANR = 300) and overall by HaloPlex™ (ANR = 15000, except small parts of exons 14 and 19 in F8). The average quality value for mutation detection was 60 (risk of false result In previously-genotyped patients, 92% (57/62) of F8 and F9 mutations were detected by AmpliSeq™ and 85% (53/62) by HaloPlex™. The detection rate of small insertion/deletion in homopolymers of exon 14 in F8 was only 20% (1/5) with both methods and 71% (5/7) in other exons of F8. Four deletions and one duplication of exons accounting for a severe haemophilia phenotype were identified (3 HA, 1 HB and 1 HA-carrier). In 5 uncharacterized patients by Sanger method, neither AmpliSeq™ nor HaloPlex™ were able to find a mutation suggesting that the molecular defect is located in introns of F8 or F9. In never-genotyped patients, a mutation was detected in 90% (38/42) of cases (including 34 missense, 2 nonsense and 2 splice mutations in both F8 and F9). A duplication of exons 10 to 14 was also detected in a severe HA patient and was confirmed by MLPA. In NGS negative patients, no mutation was found in promoter or 3' regions. Of the ten candidate mutations identified in our cohort, seven were predicted to be deleterious by in silico analysis and/or co-segregation studies. No mutation was found in 10% (4/42) of never-genotyped patients with mild haemophilia A, in consistence with the available data for the mild phenotype. The technical development and laboratory protocol was easier and less expensive ($530 vs $602 including reagents and technical/medical staff) with AmpliSeq™ than HaloPlex™. Conclusion We confirmed that NGS is able to detect the main types of mutations in F8 and F9 genes, albeit with a lower mutation detection rate with HaloPlex™ compared to AmpliSeq™. These detections were associated with an important depth of reads and high Quality Values, except for exons 14 and 19 in F8 with HaloPlex™. AmpliSeq™ seems also an interesting screening method for the detection of exons deletion/duplication using the NRD ratio. However, both strategies fail to detect small insertion/deletion located in homopolymers of exon 14 in F8, whom identification will still rely on Sanger sequencing. AmpliSeq™ protocol performed in the PGM™ sequencer appears as a new interesting tool in genotyping of HA and HB patients of the Lille University Hospital. Disclosures Zawadzki: Pfizer Pharmaceutical Company: Research Funding.

Pregnancy and puerperium are well-known risk factors for venous thromboembolism, but the actual incidence of the disease is low (about 1/1,500 pregnancies). Pregnancy-associated venous thromboembolism is rare, though it is still the second cause of maternal death in France. Several types of prophylaxis are available, mainly clinical vigilance and aggressive investigation of women with symptoms of venous thromboembolism, or antithrombotic prophylaxis. Given the low incidence of the pathology, it seems desirable to select high-risk groups of women for such strategies. The most studied and identified risk factors are prior episodes of venous thromboembolism and biological thrombophilias. Prophylaxis through low molecular weight heparin during pregnancy and the puerperium should be considered mainly in these two groups. Noteworthy, no prospective and randomized study is available, and treatment recommendations are grade C.

Introduction Les dispositifs d’acces veineux central (voies veineuses centrales, VVC) peuvent faciliter l’administration d’urgence et/ou repetee de facteurs de la coagulation chez les jeunes patients hemophiles. Dix ans apres la mise en œuvre de recommandations nationales de prophylaxie precoce dans notre pays, nous avons realise une etude nationale extensive sur les VVC chez les jeunes garcons atteints d’hemophilie grâce au suivi dans la sous-cohorte PUPs du Reseau FranceCoag (RFC). Materiel et methodes Le groupe d’etude etait constitue des enfants atteints d’hemophilie A ou B (HA/HB), severe ou moderee (FVIII or FIX Resultats Cent soixante douze VVC ont ete mises en place pour une longue duree d’utilisation chez 100 des 343 patients inclus (29,2 %). Les indications de premiere pose etaient les suivantes : induction de tolerance immune (ITI) ( n = 47), prophylaxie a long terme (LTP) ( n = 35), prophylaxie secondaire a une hemorragie intracrânienne ( n = 12) et acces veineux peripherique difficile ( n = 6). La duree mediane de l’utilisation des VVC etait de 2,5 ans (IQR : 7,8 mois–4,5 ans). La premiere indication de retrait etait un dysfonctionnement mecanique 52/117 (44 %). Trente-cinq infections ont ete enregistrees pour les 172 VVC (20,3 %). Le taux d’infection etait de 0,22 pour 1000 jours de VVC pour l’ensemble du groupe avec un impact significatif de l’indication initiale : ITI (0,31 infection/1000 jours ; IC 95 % : 0,05-1,96) vs groupe LTP (0,08 infection/1000 jours ; IC 95 % : 0,03–0,18) ( p = 0,01). Conclusion Si l’acces peripherique reste la voie veineuse de choix, notre etude suggere qu’en cas d’impossibilite, le recours a une VVC peut permettre un acces veineux sur vis-a-vis des risques d’infection ou autre complication.