Background: Information on inhibitor development in nonsevere hemophilia and its association with clotting factor concentrate type is limited. Objectives: To assess inhibitor development in patients with nonsevere hemophilia A (HA) and hemophilia B (HB) in the European Haemophilia Safety Surveillance system. Methods: Inhibitors and total treated patients are reported annually. Any exposure to concentrate per year was considered a treatment year. Incidence rates per 1000 treatment years and 95% CIs were calculated according to type of concentrate and compared using incidence rate ratios (IRRs). Results: During 2008 to 2023, 90 centers reported on 36,074 (HA) and 9238 (HB) treatment years. The inhibitor rate for nonsevere HA receiving factor (F)VIII was 4.2 per 1000 treatment years (95% CI, 3.5-4.9). Inhibitors developed at median 47.5 years (P25-P75 [IQR], 17.0-69.0), after median 40 exposure days (EDs; IQR, 17-80), with 58% occurring <50 EDs and 88% <100 EDs. Overall, 4 of 149 (2.7%) patients in the inhibitor group were female. Only one inhibitor was reported in nonsevere HB, in a female patient (FIX 7%, after 6 EDs), resulting in an inhibitor rate of 0.1 per 1000 treatment years (95% CI, 0.0-0.6). Compared with standard half-life recombinant FVIII, inhibitor rates on both plasma-derived FVIII (IRR, 0.27; 95% CI, 0.11-0.58; P < .001) and extended half-life FVIII (IRR, 0.18; 95% CI, 0.02-0.68; P = .002) were significantly reduced. Conclusion: Inhibitors in nonsevere hemophilia occurred at a rate of 4.2 per 1000 treatment years in HA and 0.1 per 1000 treatment years in HB. Compared with standard half-life FVIII, inhibitor development on plasma-derived and extended half-life FVIII were reduced. These data show that inhibitor monitoring is relevant with nonsevere HA in both sexes and should be continued lifelong.

Le réseau bilatéral des conventions fiscales internationales est dense. Deux modèles de convention sont à la disposition des États : celui de l’ONU et celui de l’OCDE, plus largement répandu. Une utilisation habile des conventions par les contribuables peut toutefois conduire à des cas de double non-imposition et à des stratégies de planification fiscale agressive. La convention multilatérale adoptée dans le cadre de l’OCDE et du G20, proposée à la signature des États depuis 2017, vise à mettre fin à cette situation et à contrarier notamment le chalandage fiscal. Elle participe à la refondation des principes fondamentaux du droit fiscal international .

BACKGROUND:The last 15 years have seen new extended half-life (EHL) recombinant FVIII/IX concentrates and nonreplacement therapy for haemophilia A (emicizumab) introduced in Europe. These changes affect FVIII/IX exposure in previously untreated patients (PUPs) and previously treated patients (PTPs) with severe haemophilia A and B (SHA and SHB) and may modify inhibitor development and/or detection. AIM:To report trends in treatment for severe haemophilia and concomitant changes in inhibitor incidence. METHODS:Between 2008 and 2022, 97 centres reported inhibitor development against FVIII/IX concentrates to the European Haemophilia Safety Surveillance System (EUHASS). Inhibitors were reported quarterly, and PUPs without inhibitor development annually. Cumulative inhibitor incidences (95% confidence intervals [CI]) were calculated for PUPs and incidence rates/1000 years (CI) for PTPs. RESULTS:By 2022, SHA-PUPs (n = 1574) received emicizumab (44%), SHL-rFVIII (21.5%), pdFVIII (17.5%) and EHL-rFVIII (17%). SHB-PUPs (n = 236) received EHL-rFIX (79%) and SHL-rFIX (21%). SHA-PTPs (68,772 years) received EHL-rFVIII (31%), SHL-rFVIII (28%), emicizumab (25%), and pdFVIII (15%). SHB PTPs (11,185 years) received EHL-rFIX (69%), pdFIX (15%) and SHL-rFIX (15%). Observed Inhibitor incidence in SHA-PUPs decreased from 24% before 2016 to 6% in 2022 (p < 0.001), and potentially in SHB-PUPs too (from 9% to 3%; p = 0.066), but remained stable in SHA/SHB PTPs. CONCLUSION:In 2022, 44% of SHA-PUPs and 25% of SHA-PTPs received emicizumab prophylaxis. Concomitantly, observed inhibitor incidence reduced to 6% in SHA-PUPs. In SHB, EHL-rFIX treatment increased to 79% in SHB-PUPs and 69% in SHB-PTPs. Assessing inhibitor incidence for new concentrates is likely to be hampered by novel treatments causing delayed exposure to FVIII/FIX.

Background:Patients with hemophilia have a life-long risk of developing neutralizing antibodies (inhibitors) against clotting factor concentrates. After the first 50 exposure days (EDs), ie, in previously treated patients (PTPs), data on inhibitor development are limited. Objectives:To report inhibitor development according to factor (F)VIII or FIX concentrate use in PTPs with severe hemophilia A and B. Methods:Inhibitor development in PTPs was collected since 2008 from 97 centers participating in European HAemophilia Safety Surveillance. Per concentrate, inhibitors were reported quarterly and the number of PTPs treated annually. Incidence rates (IRs)/1000 treatment years with 95% CIs were compared between concentrate types (plasma derived FVIII/FIX, standard half-life recombinant FVIII/FIX, and extended half-life recombinant (EHL-rFVIII/IX) concentrates using IR ratios with CI. Medians and IQRs were calculated for inhibitor characteristics. Results:For severe haemophilia A, inhibitor rate was 66/65,200 treatment years, IR 1.00/1000 years (CI 0.80-1.30), occurring at median 13.5 years (2.7-31.5) and 150 EDs (80-773). IR on plasma-derived pdFVIII (IR, 1.13) and standard half-life recombinant FVIII (IR, 1.12) were similar, whereas IR on EHL-rFVIII was lower at 0.13 (incidence rate ratio, 0.12; 95% CI, <0.01-0.70; P < .01).For severe hemophilia B, inhibitor rate was 5/11,160 treatment years and IR was 0.45/1000 years (95% CI, 0.15-1.04), at median 3.7 years (95% CI, 2.1-42.4) and 260 EDs (95% CI, 130 to >1000). Data were insufficient to compare by type of FIX concentrates. Conclusion:Low inhibitor rates were observed for PTPs with severe hemophilia A and B. Data suggested reduced inhibitor development on EHL-rFVIII, but no significant difference between plasma-derived FVIII and standard half-life recombinant FVIII. FIX inhibitor rates were too low for robust statistical analysis.

Background: Clotting factor concentrates have been the mainstay of severe hemophilia treatment over the last 50 years. Differences in risk of neutralizing antibody (inhibitor) formation according to concentrate used remain clinically relevant.Objectives: To assess inhibitor development according to type of clotting factor concentrate in previously untreated patients (PUPs) with severe hemophilia A and B.Methods: The European Haemophilia Safety Surveillance (EUHASS) and Canadian Bleeding Disorders Registry (CBDR) have been monitoring adverse events overall and according to concentrate for 11 and 8 years, respectively. Inhibitors were reported quarterly, and PUPs completed 50 exposure days without inhibitor development annually. Cumulative inhibitor incidences and 95% confidence intervals (CIs) were compared without adjustment for other risk factors.Results: Fifty-six European and 23 Canadian centers reported inhibitor development in 312 of 1219 (26%; CI, 23%-28%) PUPs with severe hemophilia A and 14 of 173 (8%; CI, 5%-13%) PUPs with severe hemophilia B. Inhibitor development was lower on plasma -derived factor (F)VIII (pdFVIII, 20%; CI, 14%-26%) than on standard half-life recom-binant FVIII (SHL-rFVIII, 27%; CI, 24%-30% and odds ratio, 0.67; CI, 0.45%-0.98%; P = .04). Extended half-life recombinant FVIII (EHL-rFVIII, 22%; CI, 12%-36%) showed an intermediate inhibitor rate, while inhibitor rates for Advate (26%; CI, 22%-31%) and Kogenate/Helixate (30%; CI, 24%-36%) overlapped. For other SHL-rFVIII concentrates, inhibitor rates varied from 3% to 43%. Inhibitor development was similar for pdFIX (11%; CI, 3%-25%), SHL-rFIX (8%; CI, 3%-15%), and EHL-rFIX (7%; CI, 1%-22%).Conclusion: While confirming expected rates of inhibitors in PUPs, inhibitor develop-ment was lower in pdFVIII than in SHL-rFVIII. Preliminary data suggest variation in inhibitor development among different SHL-rFVIII and EHL-rFVIII concentrates.

BACKGROUND:The NuProtect study reported data on the immunogenicity, efficacy and tolerability of simoctocog alfa (Nuwiq® ) in 108 previously untreated patients with severe haemophilia A planned to be treated for ≥100 exposure days or up to 5 years. The NuProtect-Extension study collected long-term prophylaxis data in children with severe haemophilia A.METHODS:Patients who completed the NuProtect study according to the protocol were eligible for the NuProtect-Extension study, a prospective, multinational, non-controlled, Phase 3b study.RESULTS:Of 48 patients who entered the extension study, 47 (median age 2.8 years) received prophylaxis with simoctocog alfa for a median of 24 months, with 82%-88% on a twice-weekly or less regimen. No patient developed FVIII inhibitors during the extension study. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 0 (0-0.5) for spontaneous bleeding episodes (BEs) and 1.00 (0-1.95) for all BEs. ABRs estimated using a negative binomial model were .28 (95% CI: .15, .53) for spontaneous and 1.62 (95% CI: 1.09, 2.42) for all BEs. During the median follow-up of 24 months, 34 (72%) patients had zero spontaneous BEs and 46 (98%) had zero spontaneous joint BEs. Efficacy in treating BEs was excellent or good for 78.2% of rated BEs, and efficacy of surgical prophylaxis was excellent for two rated surgeries. No treatment-related adverse events were reported.CONCLUSION:No FVIII inhibitors developed during long-term prophylaxis in the NuProtect-Extension study. Prophylaxis with simoctocog alfa was efficacious and well-tolerated, and is therefore an attractive long-term option for children with severe haemophilia A.

H. Brouk1,*; A. Amireche1; A. Kessira1 1Hemobiology and blood transfusion center, faculty of medicine, University Badji Mokhtar of Annaba, Annaba, Algeria Introduction: Combined deficiency of coagulation factors V and VIII (F5F8D) is a constitutional bleeding disorder, described since 1954 by Oeri. It is rare, autosomal recessive, with an estimated prevalence of 1/100,000 to 1/1,000,000, representing the most frequent form of constitutional abnormality, associating more than one coagulation factor, and not related to the accidental coincidence of several genetically distinct inherited deficiencies, but related to a single genetic abnormality. Methods: A 56-year-old woman consulted an outpatient clinic with a complaint of continuous bleeding after tooth extraction. The patient's medical history revealed that she had been experiencing long-term bleeding episodes following a minor trauma, as well as easy bruising, ecchymoses, and menorrhagia following menstruation. Melena, hematochezia, hemoptysis, and hemarthrosis were not present in her case. Her parents were unrelated, and her vital signs and physical examination results were normal. Results: The coagulation profile revealed prolonged activated partial thromboplastin time and prothrombin time (17–20 sec and 45–66 sec, respectively). aPTT and PT values were normal after mixing the patient's plasma with a healthy plasma in a 1:1 ratio. Fibrinogen, factor VII, factor IX, factor X, and factor XI and von Willebrand factor levels were all normal. Factor V and VIII levels were measured twice, and both measured levels were low (respectively 10% and 15%). According to these findings, the patient was diagnosed as having a combined factor V and VIII deficiency. Discussion/Conclusion: Regular prophylaxisis not required during bleeding episodes in patients with combined factor V and VIII insufficiency, and the patient is often treated only as necessary. The treatment of the bleeding is replacement of factor V and VIII. Disclosure of Interest: None declared S. Christidi1,*; A. Kourampa2; G. Thivaios1; D. Katrisiotis2; P. Christoforou2; A. Chanos2; T. Tryfou3; M.-C. Kyrtsoni3; O. Katsarou2 1Trauma & Orthopaedics; 2Blood unit and National Reference Center for Congenital Bleeding Disorders, “Laiko” General Hospital; 3First Department of Propaedeutic Internal Medicine, “Laiko” General Hospital, National and Kapodistrian University of Athens, Athens, Greece Introduction: In PWH, intrarticular bleedings cause severe hemophilic arthropathy(ΗΑ). Replacement of the missing clotting factor is effective to prevent bleeding events and the ΗΑ progression. There are studies suggesting that FVIII can regulate the OPG/RANKL system, which seems to play a role in ΗΑ. The purpose of this study is to measure the OPG levels in PWH A/B and their correlation with the FVIII/FIX levels. Methods: From 11/2021 to 7/2022. 124 samples were collected for OPG and FVIII/FIX measurement in 65 PWH, mean age 38 years (IQR18–83): 55 (84.6%) with Hemophilia A and 10 with Hemophilia B(15.4%).Severe Hemophilia had 87.7%, moderate 10.8%, and mild 1.5%, of patients 8 out of them (12.3%) had anti-FVIII/FIX inhibitor and 8 (12.3%) were HIV(+). 36 samples from healthy supplies, mean age 43 years (IQR22–73) were used as controls. OPG and FVIII/FIX activity were measured by ELISA method and one stage clotting assay (Stago) respectively. Comparisons of OPG levels were made between PWH and controls, and were correlated with hemophilia type, disease severity, FVIII/FIX levels, presence of inhibitor & HIV infection. Results: The data reveals a statistically significant difference mean in OPG levels between controls and PWH (p<0.001): 1712.13 pg/ml(IQR 248.54–8828.58)vs.1015.92 pg /ml(IQR66.21–8302.30) respectively. OPG levels were not statistically associated to haemophilia type, the presence of FVIII/FIX inhibitor and HIV infection. Statistically significant differences were noted in OPG levels in relation to hemophilia severity with mean values 935.49 pg/ml(113.02-8302.30) for severe vs 1771.19 pg/ml (66.21-5728,48) for moderate and mild hemophilia (p<0.001). A statistically significant positive correlation of OPG levels with FVIII activity was found (p<0.05): Specifically, for FVIII:C<1% mean OPG value were: 938.78pg/ml(IQR 538.57–1202.15),for FVIII:C1-5% 982.93pg/ml(IQR163.04–7980.60), for FVIII:C 5-15% 1056.36pg/ml (IQR66.20–5570.78) and for FVIII:C>15% 1163.81pg/ml (IQR113.02–8302.30). Discussion/Conclusion: Based in our preliminary results, it seems that PWH have lower OPG levels than the general population. Higher levels of FVIII activity increase OPG expression which confirms the hypothesis that OPG plays a role in the progression of ΗΑ. Our study cintinues by searching for a correlation of OPG levels with the severity of arthropathy, the degree of osteoporosis and RANKL levels in the serum of PWH. Disclosure of Interest: None declared N. Vilalta1,*; N. Butta2; F. J. Rodríguez-Martorell3; A. Bernardo4; S. Mojal1; V. Cortina5 1Hemostasis Unit, Hospital de la Santa Creu i Sant Pau, Barcelona; 2Hematology, La Paz University Hospital-IdiPaz, Madrid; 3Unidad de Gestión Clínica Intercentros de Hematología, Hospital Universitario Virgen Macarena y Hospital Universitario Virgen del Rocío, Sevilla; 4 Laboratorio de Diagnóstico Clínico Hematología, Hospital Universitario Central de Asturias, Oviedo; 5Hemostasis Laboratory, Vall d'Hebron University Hospital, Barcelona, Spain Introduction: Emicizumab has emerged as a novel non-factor therapy to treat hemophilia A patients (HA). It does not exist a standardized monitoring protocol. Our aim was to test the utility of thromboplastin time (aPTT), and global tests: Rotational Thromboelastography (ROTEM -NATEM) and Thrombin generation time (TGT) to evaluate emicizumab concentration and hemostatic effect Methods: Ninety one samples from emicizumab patients obtained from 4 Spanish Hemophilia Centers have been analyzed to obtain the following parameters: aPTT, emicizumab concentration, ROTEM-NATEM parameters [Clotting time (CT), clotting formation time (CFT), Maximum clot Firmness (MCF)and alfa-angle] and TGT parameters [Lag time (LT), Thrombin peak (ThP), Time to Peak (TTP), endogenous thrombin potential (ETP) and velocity Index (VI)]. Correlation has been measured using Spearman correlation coefficient. Results: We found a positive correlation between aPTT and CT (R=0.51, p<0.001), CFT (R=0.49, p<0.001) and velocity index (R=0.53, p<0.005 ) and a negative correlation with alfa-angle (R=-0.47, p<0.001). A negative correlation was also found between Emicizumab concentration and MCF (R=-0.563, p<0.001). Discussion/Conclusion: aPTT and global tests are a good alternative to monitor HA patients under emicizumab treatment. According our results, CT, CFT and alfa angle are the ROTEM -NATEM parameters which better correlate with aPTT and emicizumab concentration. We need to report a limitation, TGT was not tested in all samples and it could be a reason because we don't find correlation with all parameters. More studies are needed. Disclosure of Interest: None declared A. Dos Santos Ortas1,*; J. M. Martín de Bustamante González-Iglesias1; M. I. Pérez Vaquero1; M. T. Álvarez-Román1,2,3; M. I. Rivas Pollmar1,2; E. G Arias-Salgado1,2; P. Acuña1,2; E. Monzón Manzano1,2; E. García Pérez1; M. D. M. Gutiérrez Alvariño1; M. Martín Salcés1,2; N. Butta1,2; V. Jiménez-Yuste1,2,3 1Hematology department, Hospital Universitario La Paz; 2IdiPAZ; 3Medical School, Universidad autónoma de Madrid, Madrid, Spain Introduction: Administration of FVIII concentrates to manage breakthrough bleeding or invasive procedures in patients with severe Hemophilia A (sHA) without inhibitor under Emicizumab (EMI) prophylaxis remains necessary nowadays. Current guidelines recommend using chromogenic FVIII (FVIII:C) levels to monitor the hemostatic response to the combination of both drugs. Here we describe the hemostatic management and monitoring with global coagulation assays (GCA) of two patients with sHA on EMI treatment undergoing orthopedic surgery. Methods: Perioperative FVIII:C levels were performed for both patients during surgery and postoperative period. Samples for GCA were collected in tubes with CTI to prevent contact pathway activation. Clotting time (CT) was evaluated by ROTEM®, using whole blood activated by tissue factor solution plus recalcification, and Thrombin peak (TP) was assessed by TGT in plasma, using tissue factor and phospholipids. Both techniques were performed in samples collected before and after FVIII administration. Samples obtained before FVIII dosing were also spiked in vitro with therapeutic amounts of FVIII products. Results: Patient 1 is a 55-year-old male who underwent an ankle arthrodesis with osteosynthesis due to hemophilic arthropathy. He received 50 U/kg of plasma-derived (pd) FVIII/FVW every day until day +7 after surgery. Patient 2 is a 52-year-old male with a cubital tunnel syndrome that required surgery. In this case, we used a single dose of 50 U/Kg of extended half-life rFVIII concentrate (rFVIII EHL) before procedure. In both cases, the postoperative course was uneventful. GCA showed that treatment with EMI was insufficient for complete normalization of hemostatic parameters. We observed an improvement in CT and TP values after every administration of both FVIII products. We noted that this improvement was similar to that obtained with in vitro spiking of equivalent doses of FVIII, and a correlation between FVIII:C levels and CT or TP values was also observed. Discussion/Conclusion: The hemostatic profile obtained with both GCA could be an important complement to FVIII:C levels for the follow-up of complex cases of bleeding or surgery in patients with severe HA without inhibitor undergoing EMI prophylaxis. Funding: ISCIII-FEDER PI19/00631; Catedra UAM-Roche. Disclosure of Interest: None declared H. Elmahmoudi1,*; R. Ghorbel1; A. Zaier1; C. Jbali1; S. Besbes1; O. Ghali1; K. Zahra1; E. gouider1 1Aziza Othmana Hospital, tunis, Tunisia Introduction: Genetic factors have been shown to be a risk factor for the development of inhibitors. Several types of mutations including small and large deletions, insertions or point mutations associated with deleterious changes such as missense mutation, nonsense mutations and splicing alterations were reported in PWH. The most common mutations in 45% of severe hemophilia A cases are the inversion of introns 22 and 1. Our goal is to identify the genetic profile in severe hemophilia A with inhibitor in our center. Methods: PWHA carrying inhibitors were included in our study. The search for the inversion of intron 22 and intron 1 is done by IS-PCR. The search for point mutations is done with PCR/sequencing. Results: Sixteen PWHA and inhibitors were identified. The most frequent mutation was the intron 22 inversion (30%, n = 5), followed by two large deletions of exon 14 and exons 1-13 respectively (12.5%, n=2). A missense mutation at exon 1 (6.25%, n=1) was also identified. For the remaining 8 patients, the inversion of intron 22 is absent and the search for the molecular defect is in progress. Discussion/Conclusion: The most common mutations reported in 45% of severe hemophilia A cases are the inversion of introns 22 and 1. Mutations inducing an absent or truncated FVIII protein are associated with a 20 to 80% risk of developing inhibitors. Reversal of introns 1 and 22, large deletions, nonsense mutations and splice site mutations are considered high risk mutations for developing an inhibitor. Missense mutations are considered low risk mutations.In our study, the inversion of intron 22 is present with a frequency of 30% (5/16). This frequency seems to be lower compared to data in the literature, where it varies between 40% and 50%. The p-value of PWHA with inhibitors carrying inversion 22 and PWHA without inhibitors carrying the same mutation is not significant (p between 0.9 and 0.1), as reported in some cohort. An increase in the number of patients is advised to better define the association between the presence of the inversion of intron 22 and the appearance of inhibitors in our Tunisian population. Knowing the type of mutation and its association as a risk factor for generating an inhibitor would make it possible to propose individualized therapeutic strategies. Disclosure of Interest: None declared F. J. López-Jaime1; A. Montaño1,2; A. Marco3; P. Marco3,4; I. Fernadez-Bello1,*; Á. Palomo-Bravo1 1Haematology and Haemotherapy, Regional University Hospital of Málaga, Málaga; 2University of Salamanca, Salamanca; 3Haematology and Haemotherapy, General University Hospital of Alicante; 4Department of Clinical Medicine, Universidad Miguel Hernández, Alicante, Spain Introduction: Emicizumab is a bispecific antibody mimicking the activity of coagulation factor VIII (FVIII). Plasma level of emicizumab might be variable, therefore, it has been proposed to measure its plasma concentration in order to adjust the dose if it were necessary. Thrombin generation test (TGT) and thromboelastometry (ROTEM) might be useful to individualize therapy with emicizumab, thus, evaluation of correlation between emicizumab plasma levels and global assays could useful in the individualization of emicizumab dosing. We aimed to determine the plasma levels of emicizumab in a group of patients on prophylaxis with this agent and to evaluate the correlation between their levels and the TGT and ROTEM tests. Methods: TGT was determined in platelet poor plasma using Genesia®. ROTEM was evaluated by naTEM test (only recalcification). Levels of emicizumab was evaluated by an aPTT modified test (Stago). Statistical analysis was performed using SPSS software taking into account the distribution of data. Results: Six patients were included. Median age (25th-75th percentiles) and plasma levels of emicizumab was 11.4 (6.5-15.5) years old and 47.5 (40.8-58.7) μg/mL respectively. No correlation between TGT, ROTEM and emicizumab plasma levels were found. No modification of emicizumab doses were needed. Discussion/Conclusion: Emicizumab is a bispecific antibody which switch-on mechanism depends on presence of activated factor IX (FIXa). Both TGT and ROTEM are affected by contact pathway activation which may produce important amount of FIXa. This could affect the TGT and ROTEM assay, thus, the use of contact activation pathway inhibitors such as corn trypsin inhibitor (CTI) could be needed. A comparative wider study using samples with and without CTI should be performed in order to evaluate this hypothesis. Disclosure of Interest: None declared J. Obregón1; J. M. Calvo Villas1; A. Marco Rico2; S. Herrero Martin3; L. E. Ureña4; F. J. Lopez Jaime5; B. Díaz Jordán6; C. García Díaz7; S. Jurado Herrera8; N. F. Perez Gonzalez9; F. Garcia Candel10; P. Marco Vera2; I. Fernández Bello5,*; A. Montaño Brioso11; on behalf of Mediterranean Hemophilia Group 1Hospital Universitario Miguel Servet, Zaragoza; 2Hospital General Universitario de Alicante Doctor Balmis, Alicante; 3Hospital Universitario de Guadalajara, Guadalajara; 4Hospital Universitario Virgen de las Nieves, Granada; 5Hospital Universitario Regional de Malaga, Malaga; 6Hospital General de Valdepeñas, Ciudad Real; 7Hospital Universitario de Burgos, Burgos; 8Hospital Universitario Torrcardenas; 9Hospital Universitario Torrecardenas, Almeria; 10Hospital Clínico Universitario Virgen de la Arrixaca, Murcia; 11Hospital Universitario Regional de Malaga. Universidad de Salamanca, Malaga, Spain Introduction: Thirty percent of patients with mild haemophilia A showed discrepancy in FVIII levels between one-stage clotting assay (FVIII:C1) and two-stage chromogenic assay (FVIII:CR). This phenomenon has been associated with genetic alterations in the FVIII gene. Methods: In an observational, ambispective and multicenter study, 52 non-severe haemophilia A (nSHA) patients from 9 Spanish hospitals were studied. FVIII:C1 and FVIII:CR were determined. TGT was evaluated in platelet poor plasma by Genesia®. Mutation analysis was performed by direct sequencing on individuals with discrepancy between FVIII:C1 and FVIII:CR assays. We defined discrepancy as FVIII:C1/FVIII:CR ≥ 2 (standard discrepancy) or FVIII:C1/FVIII:CR ≤ 0.5 (reverse discrepancy). Results: Median (IQR) of FVIII:CR= 20.3% (15.4-25.2) was higher than FVIII:C1= 17.5% (14.2-20.8) (p<0.001), with a significant correlation between FVIII:C1 and FVIII:CR (r= 0.68, p<0.001). 7 cases (63.6%) showed a reverse discrepancy and 4 (36.4%) showed a standard discrepancy. A significant correlation was observed between FVIII:CR and all TGT parameters (lag time: r= 0.57 [p 0.001], thrombin generation peak: r= 0.30 [p= 0.03] and endogenous thrombin potential (ETP): r= 0.27 [p=0.05]. Taking into account that TGT uses the own patient levels of FIX, FX and thrombin generation capacity, it might be possible to think that activation of FVIII in TGT is produced in a more physiologic condition compared with those used in the clotting or chromogenic assays. Nonetheless, the absence of correlation between FVIII:C1 and TGT might indicate that FVIII:CR might have a closer correspondence with the bleeding phenotype of the patients. Eight out 47 patients (17%) changed the diagnosis severity taking in consideration the FVIII:CR. Nine missense mutations were found in the 11 cases with discrepant FVIII results, of which 7 were within the A2 and A3 domains. It was previously reported that the p.Ser1810Pro variant, presented in 4 of our patients, were associated with FVIII assay discrepancies. Discussion/Conclusion: Discrepancy was found in 23.4% of nSHA patients. A significant correlation between FVIII:CR and TGT parameters might indicate that FVIII:CR might have more correspondence with the bleeding phenotype of the patients though this hypothesis should be evaluated in a wider study. Disclosure of Interest: None declared S. Guy1,*; E. Oliver-Newman1; A. Bowyer1; S. Kitchen1 1Sheffield Haemophilia and Thrombosis Centre, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom Introduction: Rurioctocog alfa pegol (Adynovi, Takeda) is a PEGylated recombinant extended half-life FVIII:C replacement product, it has a half-life of 1.4 to 1.5-fold longer than Advate. According to the summary of product characteristics, the potency is assigned by chromogenic assay (CSA); it also references a field study which previously suggested that both OSA (one stage assay) and CSA methods are suitable for monitoring treatment. In this study we will look at the suitability of different APTT reagents and CSA methods using FVIII deficient plasma spiked with Adynovi to a range of concentrations. Methods: Adynovi was spiked into congenital FVIII deficient plasma (HRF Inc) producing final concentrations of 2.5,5,10,25,50,75,100 and 125 IU/dL based on labelled potency. OSA and CSA were performed on the spiked samples on three separate days. The OSA used Actin, Actin FS, Actin FSL, Pathromtin SL (all Siemens) APTT reagents performed on CS5100 (Sysmex); SynthASil, SynthAFax, and APTT-SP APTT reagents were performed on ACL TOP (all Werfen). CSA methods performed on the CS5100 were Biophen FVIII:C (Hyphen Biomed) and Siemens FVIII Chromogenic Assay (Siemens), whilst Coamatic Factor VIII (Chromogenix) and CRYOcheck Factor VIII (Precision BioLogic) were performed on ACL TOP. Results: The mean for each reagent was calculated for all spiked concentrations. Mean OSA ranged from 40.7 IU/dL (SynthASil) to 49.2 IU/dL (Pathromtin SL). Mean CSA ranged from 53.5 IU/dL (Siemens) to 69.1 IU/dL (Coamatic). For samples with >25 IU/dL Adynovi, all the OSA and Siemens and CRYOcheck CSA recovered levels within 25% of expected FVIII:C level based on potency, however the Biophen FVIII:C recovered 25% only at 125 IU/d L. At lower levels Actin demonstrated most overestimation at 2.5, 5.0 and 10 IU/dL with results of 5, 8.2 and 14 IU/dL respectively; Pathromtin SL and APTT-SP produced little variation at the lower concentrations. The CSA methods produced similar results for 2.5 and 5.0 IU/dL; however, at 10 IU/dL Adynovi: Siemens and CRYOCheck 8.9 and 8.8 IU/dL respectively but this was within expected variability. Discussion/Conclusion: Some variation was seen between the methods. Overall, APTT-SP, Pathromtin SL, Siemens and CRYOCheck gave consistent results for all the range of spiked samples, more data is required in patient samples to confirm these results. Disclosure of Interest: None declared Y. Jourdy1,*; A. Dericquebourg1; M. Frétigny1; C. Vinciguerra1 1Hospices Civils de Lyon, LYON, France Introduction: The disease-causative variant remains unidentified in about 2-4% of non-severe hemophilia A (HA) patients using conventional genetic investigations, and F8 deep intronic variations could be responsible in these cases. In this study, we performed Whole F8 gene sequencing in genetically unsolved non-severe HA patients in order to identify the causal variation. Methods: We performed whole F8 sequencing using Next Generation Sequencing (NGS) in 49 genetically unsolved non-severe HA patients. The putative splicing impact of the candidate deep intronic variations was studied using both in silico (SpliceAI and MaxEntScan) and splicing functional analysis (either F8 mRNA analysis or minigene analysis). Results: The mean (range) number of variations per patient revealed by NGS was 30 (10-63). Among them, only those with a Minor allele frequency < 0.01% were further analyzed. After filtering, 33 deep intronic variants remained (31 single nucleotide variations (SNPs), one 173-bp deletion and an 869-bp tandem triplication) from 43 propositi. No F8 candidate variant was found in 6 propositi.Four variations have been previously described in the literature as HA-causing: c.1537+325A>G (n=2), c.2113+601G>A (n=2), c.2113+1152delA (n=2), c.5587-93C>T (n=3) and no further analysis were performed for them. The most frequent variants found were c.2114-6529C>G and the association of 2113+1154G>C and c.5374-304C>T identified in 9 and 5 unrelated individuals, respectively. In silico analysis predicted splicing impact for 2/27 SNPs only (c.788-312A>G and c.6901-2992A>G). RNA sample was available for 5 cases. F8 mRNA analyzing showed a deleterious splicing impact for 3 deep intronic variations (c.6900+4104A>C, c.2114-6529C>G and c.2113+1154G>C). The minigene assay showed a splicing impact for 8/18 of the studied variants (c.671-94G>A, c.788-312A>G, c.6901-2992A>G, c.5999-820A>T, c.5999-786C>A, c.5999-669G>T, c.5999-669G>C and c.5999-669G>A). Finally, the HA causing variant was identify in 33/49 (67%) cases. Discussion/Conclusion: In this study, we described 11 new deep intronic variations as HA-causing. About the two thirds of the non-severe HA patients included in this study were elucidated. This study highlights the usefulness of the association of whole F8 gene sequencing and functional assays for the progressive reduction of unexplained HA. Disclosure of Interest: None declared M. Kjalke1,*; C. Augustsson2; K. Strandberg2 1Department of Rare Blood Disorders, Novo Nordisk A/S, Måløv, Denmark; 2Department of Clinical Chemistry and Pharmacology, Coagulation Laboratory Malmö, Division of Laboratory Medicine, Region Skåne, Sweden Introduction: Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody in phase 3 clinical development as a once-daily subcutaneous prophylactic treatment for haemophilia A or B (HA/B) with or without inhibitors. To inform potential future clinical analysis of plasma samples from patients on concizumab prophylaxis, this study assessed the impact of concizumab on coagulation assays validated for use in clinical monitoring, i.e., prothrombin time (PT) using Quick and Owren assays, activated partial thromboplastin time (aPTT), factor (F) VIII and IX one-stage clot assays (OSA) and chromogenic substrate assays (CSA). Methods: Concizumab at concentrations of 0, 250, 1000, 4000 and 16000 ng/mL (covering clinically relevant exposures) were added to normal human plasma (NHP); or pooled plasma samples from patients with HA or HB separately or with recombinant FVIII or FIX (0.1 and 1 IU/mL). Plasma samples ± concizumab were analysed on an Atellica COAG 360 analyser (Siemens) using commercially available diagnostic kits and calibrators. Differences between measurements were considered relevant for clinical practice if the measurement with concizumab was outside ±25% of the corresponding measurement without concizumab. Results: Concizumab had no influence on PT clot time. The aPTT clot time of NHP was shortened up to 0.4 s (250–16000 ng/mL concizumab), however, measurements remained within the NHP reference range (21–30 s). For haemophilia plasma, aPTT clot times were shortened by 2.6–3.4 s (HA; 250–16000 ng/mL concizumab), or 3.3–5.2 s (HB; 250–16000 ng/mL concizumab) but were within 25% of measurements without concizumab. Concizumab (4000 and 16000 ng/mL) resulted in <20% increased recovery of FVIII and FIX activity when measured in the respective OSAs. No influence of concizumab on FIX activity was detected in CSAs, however, a small decrease in recovery of FVIII activity (<5%) was observed. Discussion/Conclusion: Concizumab had no, or only a minor, effect on standard PT and aPTT assays, and FVIII or FIX activity measurements. Therefore, these assays can be used in clinical practice for monitoring patients on concizumab prophylaxis. Disclosure of Interest: M. Kjalke Shareholder of: Novo Nordisk, Employee of: Novo Nordisk, C. Augustsson Grant/Research support from: Access to insight (Novo Nordisk Health Care A.G.), K. Strandberg Consultant for: Sobi, Novo Nordisk, BioMarin, Speaker Bureau of: Octapharma, Sobi, Shire, Novo Nordisk R. Korir1,*; C. Njuguna1; C. Kilach1; A. Greist2; F. Njuguna3 1Hematology and Oncology, AMPATH/Moi Teaching and Referral Hospital, Eldoret, Kenya; 2Hematology, Indiana Hemophilia and Thrombosis Center Thrombosis, Indianapolis, United States; 3Pediatrics, Moi University, Eldoret, Kenya Introduction: The development of inhibitors is one of the most serious complications in the management of persons with hemophilia (PWH). It renders factor replacement therapy ineffective, requiring the use of by-passing products. Inhibitor testing is critical in order to offer effective treatment; this has not been fully implemented in resource-limited settings. Barriers including, limited knowledge, lack of laboratory expertise, and inadequate supply of reagents have led to a lack of adequate testing. We did inhibitor testing on our patient cohort and evaluated how the availability of inhibitor results impacted the management of PWH. Methods: PWH who presented at the Moi Teaching and Referral Hospital (MTRH) between September 2021 and October 2022 were tested for inhibitors. We used the classical Bethesda method for testing. We then assessed how the availability of inhibitor results affected patient care. Results: In total, 94 PWH were tested for inhibitors. Of these, 81 have hemophilia A (HA) and 13 hemophilia B (HB). Those who have inhibitors are 14(14.9%) of whom 12 have severe HA, 1 mild HA, and 1 severe HB. The inhibitor titer values ranged from 0.98 to 61 Bethesda Unit (B.U), (5(36%) low responders and 9(64%) high responders). The availability of these results informed clinical decisions in the management of patients who had inhibitors. Of those tested, 11 underwent circumcision 10 of whom did not have inhibitors. They underwent the procedure using factor replacement. One of them with severe HB has an inhibitor level of 6BU and underwent the procedure using by-passing products (Activated Factor 7, Activated Prothrombin Complex Concentrates). The testing has also enabled us to start those with HA and inhibitors (10) on Emicizumab prophylaxis. Following these, there was an increased awareness among the clinical team on the importance of inhibitor testing for PWH. Discussion/Conclusion: The adoption of inhibitor testing at MTRH has greatly improved clinical decisions and management of PWH, demonstrating the need to increase routine inhibitor monitoring in hemophilia treatment centers throughout the country. Disclosure of Interest: None declared R. Maxhuni1,*; V. G. Uka1; B. Abrashi1 1Hemathology, University Clinical Centre of Kosovo, Pristina, Kosovo Introduction: Hemophilia is a rare disease characterized by an inherited bleeding disorder in which the blood does not clot properly.This can lead to spontaneous bleeding, and bleeding after injuries or surgery.Expected prevalence of hemophilia an inherited recessive disease that is linked to X chromosome which there is a gene that codes the synthesis of F VIII. Population of Kosovo: 1.831 million. Number of hemophilia patients diagnosed in my country from 0-18 years old is 39. The disease is diagnosed by bleeding history, family history, Laboratory analysis: blood count, peripheral smear, PT, PTT, Biochemistry analysis and clotting factor tests (except Factor XIII) and genetics. Methods: The purpose of the work: to present the cases of hemophilia A and B in our country with a population of 1.831 milion residents and their hemophilia treatment. Material and methods: children aged 0-18 were included in a total of 39 cases. With hemophilia A, we have 24 and with hemophilia B, there are 15 cases. Results: The result: all cases with severe hemophilia were treated prophylactically, but the cases that could not be treated in time and prophylactically developed various complications such as hamartrosis. The treatment was done with human plasma factors and recombinant factors. Discussion/Conclusion: To create the Hemophylia centre of treatment.Patient registration Prophylactic treatment for all patients, laboratory testing for factor VIII and IX inhibitors, genetic testing. As a rare disease, it needs continuous and multidiciplined treatment. More work in education. The treatment of this category needs t

Key Points • This is the largest summary to date of the management of people with hemophilia A on emicizumab prophylaxis undergoing surgery.• Major and minor surgeries were performed safely in people receiving emicizumab, regardless of factor VIII inhibitor status.

Background Nonacog alfa, a standard half-life recombinant factor IX (FIX), is used as a prophylactic treatment in severe haemophilia B (SHB) patients. Its half-life determined in clinical studies involving a limited sampling (72 h) was shown to be rather short. In our clinical practice, we suspected that its half-life could have been underestimated. Objectives We aimed to evaluate nonacog alfa pharmacokinetics in real world clinical practice based on FIX levels in patients receiving prophylaxis. Methods We retrospectively collected data on patients with SHB receiving prophylaxis from eight centres across France. The terminal half-life (THL), time to reach 5-2 IU/dl and FIX activity at 48, 72 and 96 h were derived by Bayesian estimations using NONMEM analysis. Results and conclusions Infusion data (n = 455) were collected from 64 patients with SHB. The median THL measured in 92 pharmacokinetic (PK) studies was 43.4 h. In 26 patients <= 12 years of age, 51 PK studies showed a median time to reach 5 IU/dl of FIX of 70.5 h and a median time to reach 2 IU/dl of 121.5 h. In 38 patients 13-75 years of age, 41 PK studies showed a median time to reach 5 IU/dl of FIX of 92.0 h and a median time to reach 2 IU/dl of 167.5 h. Extending the sampling beyond 72 h makes it possible to observe a plateau, with FIX remaining between 2 and 5 IU/dl for several days and shows that the THL of nonacog alfa might be longer than previously described. Essentials Nonacog alfa terminal half-life (THL) in patients receiving regular prophylaxis was evaluated in clinical practice. The median THL was estimated to be 36.9 h for patients aged .8-12 years. The median THL was estimated to be 49.9 h for patients aged 13-75 years. For patients aged <= 12 and >12 years, the median times to reach 5 IU/dl were 70.5 and 92 h, respectively; to reach 3 IU/dl, 95.5 and 131.5 h, respectively; to reach 2 IU/dl, 121.5 and 167.5 h, respectively. We suggest that the half-life of nonacog alfa might be longer than previously described in both younger and older patients.

BACKGROUND AND AIMS:Pluripotent stem cell-derived hepatocytes differentiated in monolayer culture are known to have more fetal than adult hepatocyte characteristics. If numerous studies tend to show that this immature phenotype might not necessarily be an obstacle to their use in transplantation, other applications such as drug screening, toxicological studies, or bioartificial livers are reliant on hepatocyte functionality and require full differentiation of hepatocytes. New technologies have been used to improve the differentiation process in recent years, usually evaluated by measuring the albumin production and CYP450 activity. Here we used the complex production and most importantly the activity of the coagulation factor IX (FIX) produced by mature hepatocytes to assess the differentiation of hemophilia B (HB) patient's induced pluripotent stem cells (iPSCs) in both monolayer culture and organoids.APPROACH AND RESULTS:Indeed, HB is an X-linked monogenic disease due to an impaired activity of FIX synthesized by hepatocytes in the liver. We have developed an in vitro model of HB hepatocytes using iPSCs generated from fibroblasts of a severe HB patient. We used CRISPR/Cas9 technology to target the genomic insertion of a coagulation factor 9 minigene bearing the Padua mutation to enhance FIX activity. Noncorrected and corrected iPSCs were differentiated into hepatocytes under both two-dimensional and three-dimensional differentiation protocols and deciphered the production of active FIX in vitro. Finally, we assessed the therapeutic efficacy of this approach in vivo using a mouse model of HB.CONCLUSIONS:Functional FIX, whose post-translational modifications only occur in fully mature hepatocytes, was only produced in corrected iPSCs differentiated in organoids. Immunohistochemistry analyses of mouse livers indicated a good cell engraftment, and the FIX activity detected in the plasma of transplanted animals confirmed rescue of the bleeding phenotype.

New therapeutic agents for haemophilia with inhibitors that are in development or already licensed are expected to provide transformative treatment options. Many of these new therapies are not based on simply replacing the missing factor; new strategies include bispecific antibody technology that mimics factor VIII coagulation function (emicizumab), and inhibition of anticoagulant proteins such as tissue factor pathway inhibitor (eg PF-06741086) and antithrombin (eg fitusiran). These agents are administered subcutaneously and should significantly reduce treatment burden and increase the ability to deliver prophylaxis for patients. Limited real-world data and validated practical guidance on these recently licensed/upcoming treatments resulted in the authors convening to discuss recommendations on their use. Emicizumab is currently the only licenced nonfactor therapy; thus, our recommendations focus on this product. Target candidates for emicizumab prophylaxis are difficult-to-treat patients with haemophilia A and inhibitors and/or venous access issues, frequent bleeds and target joints. In case of breakthrough bleeding while receiving emicizumab, patients still require treatment with bypassing agents; the adjunct treatment of choice is recombinant activated factor VII. This treatment is also recommended to prevent bleeds in patients with inhibitors undergoing surgery. Our recommendations on suitable laboratory assays and monitoring new products, as well as the benefit of patient-reported outcomes (such as pain and physical activity levels), are included. We also briefly discuss future treatment options for patients with haemophilia B and inhibitors. Although these nonfactor treatments offer great promise, further data and real-world evidence are needed.

INTRODUCTION:A phase 3b extension study evaluated the long-term safety and efficacy of a recombinant fusion protein-linking coagulation factor IX (FIX) with albumin (rIX-FP) for the routine prophylaxis and on-demand treatment of bleeding in pediatric hemophilia B patients. METHODS:Previously treated patients aged <12 years with moderate to severe hemophilia B enrolled in a 3-year extension study following a phase 3 pivotal study in which they received weekly rIX-FP prophylaxis. In the extension study, they could maintain or extend their prophylaxis interval to every 10 or 14 days if they were well controlled on the 7-day regimen. RESULTS:Compared with their initial regimen, by the end of the study, dosing intervals were the same, extended, and shortened in 16, 4, and 4 patients, respectively. Very low annualized spontaneous bleeding rates (AsBRs) were observed; median AsBR was 0.0 for the 7- and 10-day regimens, and 1.1 for the 14-day regimen. The 7- and 14-day regimens were comparable in preventing spontaneous bleeds; mean (95% confidence interval) difference in AsBR of -1.2 (-2.6 to 0.3) bleeding episodes/year/subject. Overall, 96% of bleeding episodes were successfully treated with one or two injections of rIX-FP. Patients on a 14-day regimen maintained a mean steady-state trough FIX level of >7.2 IU/dL. No patient developed an inhibitor. CONCLUSION:This extension study demonstrated the long-term safety and efficacy of weekly rIX-FP in pediatric patients. Additionally, it showed that adequate bleed protection can be achieved with 10- or 14-day rIX-FP regimens in selected pediatric patients while maintaining safety.

Background Single-factor replacement therapy is considered the most suitable treatment option for hereditary fibrinogen deficiency. A triple-secured plasma-derived human fibrinogen product was developed to increase the safety of the former fibrinogen concentrate. Objectives This non-randomized, open-label, prospective study investigated pharmacokinetics, efficacy, and safety of a novel fibrinogen concentrate (FibCLOT (R)/CLOTTAFACT (R) LFB, France) in inherited deficiency. Patients/Methods Fourteen patients >= 40 kg received fibrinogen concentrate for pharmacology and 16 >= 23 kg received treatment for bleeding or surgery. Each treatment was followed by a 3-week safety observation period. Key outcomes included number of infusions, dose, bleeding control, daily assessment, hemoglobin, blood loss, transfusions, and physicians' global assessment of response. Results Incremental recovery was 2.35 mg mL(-1) per mg kg(-1) and maximal concentration 1.41 g L-1 (geometric mean) after 0.060 g kg(-1) infusion in 14 afibrinogenemic patients. Terminal half-life was 69.3 h (non-compartmental analysis). The maximum clot firmness was increased by a mean of 10.3 mm from baseline to maximal effect. Sixteen patients participated to the efficacy phase: 32 bleeding episodes were treated in 9 patients, and 15 patients underwent 38 surgical/invasive procedures. All patients achieved appropriate hemostasis: response to treatment was successful in all bleeds (95% CI, 0.89-1.00) and procedures (95% CI, 0.91-1.00). Most (94%) bleeds were controlled with a single infusion (median 0.050 g kg(-1)). Two patients experienced asymptomatic distal venous thromboses identified by systematic ultrasound. Conclusion FibCLOT (R)/CLOTTAFACT (R) showed a pharmacokinetic profile comparable to that of other fibrinogen concentrates and provides safe and clinically effective substitution therapy for fibrinogen-deficient patients.

FranceCoag is an ongoing open prospective multicentre cohort project aimed at improving epidemiological knowledge about inherited bleeding disorders in France. The main objective of this article was to evaluate the project’s progress as of the 30th December 2016. Between 1994 and this date, of the 10,047 patients included in the study, 384 (3.8%) were reported by clinicians to have died and 159 (1.6%) to be lost to follow-up. Among the remaining 9504 patients still being followed up, 5748 (60.5%) had haemophilia A, 1300 (13.7%) haemophilia B, 1980 (20.8%) von Willebrand Disease while 476 (5.0%) had another clotting factor deficiency (Factor I, II, V, combined V and VIII, VII, X, XI and XIII). The median age of the population was 32 years (Inter-quartile range (IQR) 18–50 years) at data extraction on December 30th, 2016. The subgroup of children (i.e., < 18 years old) with severe haemophilia and comprehensive information available since the first exposure to treatment was identified as the PUPs (Previously Untreated Patients) cohort. Data for the 643 children included in the PUPs’ cohort had been collected since their birth. Follow-up data were collected by the clinicians in haemophilia treatment centres (HTC) every 12.9 months on median (IQR 11.4–21.3). In the PUPS cohort, data were updated every 6.2 months on median (IQR 3.7–11.7). A unique patient number assigned at study inclusion was kept at individual HTC by participating clinicians. The data collected included demographic, clinical, therapeutic and biological items on standard electronic forms. As of December 30th 2016, a plasma and serum samples was available for 2581 patients (27.1%).

HaemophiliaVolume 25, Issue 6 p. e361-e363 LETTER TO THE EDITOR FVIII dosages in persons with haemophilia A treated with extended half-life products: From local biology to optimized patient management Andréas Perrier-Cornet, Andréas Perrier-Cornet orcid.org/0000-0002-7884-2916 Service d’Hématologie Biologique, Centre Hospitalier Universitaire Bicêtre, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, FranceSearch for more papers by this authorAurélien Philippe, Aurélien Philippe Service d’Hématologie Biologique, Centre Hospitalier Universitaire Bicêtre, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, FranceSearch for more papers by this authorThierry Lambert, Thierry Lambert Centre de Référence de l’Hémophilie et des Maladies Hémorragiques Constitutionnelles (CRH-MHC), Centre Hospitalier Universitaire Bicêtre, Assistance Publique - Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, FranceSearch for more papers by this authorRoseline d’Oiron, Roseline d’Oiron Centre de Référence de l’Hémophilie et des Maladies Hémorragiques Constitutionnelles (CRH-MHC), Centre Hospitalier Universitaire Bicêtre, Assistance Publique - Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France INSERM, Unité Mixte de Recherche Scientifique 1176, Le Kremlin-Bicêtre FranceSearch for more papers by this authorAnne Rafowicz, Anne Rafowicz Centre de Référence de l’Hémophilie et des Maladies Hémorragiques Constitutionnelles (CRH-MHC), Centre Hospitalier Universitaire Bicêtre, Assistance Publique - Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, FranceSearch for more papers by this authorCécile Lavenu-Bombled, Cécile Lavenu-Bombled Service d’Hématologie Biologique, Centre Hospitalier Universitaire Bicêtre, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France INSERM, Unité Mixte de Recherche Scientifique 1176, Le Kremlin-Bicêtre FranceSearch for more papers by this authorSophie Combe, Sophie Combe Service d’Hématologie Biologique, Centre Hospitalier Universitaire Bicêtre, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, FranceSearch for more papers by this authorAndré Gillibert, André Gillibert Biostatistics Department, Rouen University Hospital, Rouen, FranceSearch for more papers by this authorValérie Proulle, Corresponding Author Valérie Proulle valerie.proulle@aphp.fr orcid.org/0000-0003-3620-9570 Service d’Hématologie Biologique, Centre Hospitalier Universitaire Bicêtre, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France INSERM, Unité Mixte de Recherche Scientifique 1176, Le Kremlin-Bicêtre France Correspondence Valerie Proulle, Service d’Hématologie Biologique, CHU Bicêtre, AP-HP, Université Paris Sud, Paris Saclay, 78 Rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France. Email: valerie.proulle@aphp.frSearch for more papers by this author Andréas Perrier-Cornet, Andréas Perrier-Cornet orcid.org/0000-0002-7884-2916 Service d’Hématologie Biologique, Centre Hospitalier Universitaire Bicêtre, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, FranceSearch for more papers by this authorAurélien Philippe, Aurélien Philippe Service d’Hématologie Biologique, Centre Hospitalier Universitaire Bicêtre, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, FranceSearch for more papers by this authorThierry Lambert, Thierry Lambert Centre de Référence de l’Hémophilie et des Maladies Hémorragiques Constitutionnelles (CRH-MHC), Centre Hospitalier Universitaire Bicêtre, Assistance Publique - Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, FranceSearch for more papers by this authorRoseline d’Oiron, Roseline d’Oiron Centre de Référence de l’Hémophilie et des Maladies Hémorragiques Constitutionnelles (CRH-MHC), Centre Hospitalier Universitaire Bicêtre, Assistance Publique - Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France INSERM, Unité Mixte de Recherche Scientifique 1176, Le Kremlin-Bicêtre FranceSearch for more papers by this authorAnne Rafowicz, Anne Rafowicz Centre de Référence de l’Hémophilie et des Maladies Hémorragiques Constitutionnelles (CRH-MHC), Centre Hospitalier Universitaire Bicêtre, Assistance Publique - Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, FranceSearch for more papers by this authorCécile Lavenu-Bombled, Cécile Lavenu-Bombled Service d’Hématologie Biologique, Centre Hospitalier Universitaire Bicêtre, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France INSERM, Unité Mixte de Recherche Scientifique 1176, Le Kremlin-Bicêtre FranceSearch for more papers by this authorSophie Combe, Sophie Combe Service d’Hématologie Biologique, Centre Hospitalier Universitaire Bicêtre, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, FranceSearch for more papers by this authorAndré Gillibert, André Gillibert Biostatistics Department, Rouen University Hospital, Rouen, FranceSearch for more papers by this authorValérie Proulle, Corresponding Author Valérie Proulle valerie.proulle@aphp.fr orcid.org/0000-0003-3620-9570 Service d’Hématologie Biologique, Centre Hospitalier Universitaire Bicêtre, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France INSERM, Unité Mixte de Recherche Scientifique 1176, Le Kremlin-Bicêtre France Correspondence Valerie Proulle, Service d’Hématologie Biologique, CHU Bicêtre, AP-HP, Université Paris Sud, Paris Saclay, 78 Rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France. Email: valerie.proulle@aphp.frSearch for more papers by this author First published: 17 June 2019 https://doi.org/10.1111/hae.13801 This study was performed in the Haemostasis laboratory, Centre Hospitalier Universitaire Bicêtre, Assistance Publique Hôpitaux de Paris, Université Paris Sud, Paris Saclay.78 Rue du Général Leclerc, 94270 Le Kremlin-Bicêtre. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume25, Issue6November 2019Pages e361-e363 RelatedInformation

Haemophilia A and haemophilia B are congenital X-linked bleeding disorders caused by deficiency of coagulation factor VIII (FVIII) and IX (FIX), respectively. The preferred treatment option for patients with haemophilia is replacement therapy. For patients with severe disease, prophylactic replacement of coagulation factor is the treatment of choice; this has been shown to reduce arthropathy significantly, reduce the frequency of bleeds and improve patients’ quality of life. Prophylaxis with standard recombinant factor requires regular intravenous infusion at least two (FIX) to three (FVIII) times a week. Recombinant FVIII and FIX products with an extended half-life are in development, or have been recently licensed. With reported mean half-life extensions of 1.5–1.8 times that of standard products for FVIII and 3–5 times that of standard products for FIX, these products have the potential to address many of the unmet needs of patients currently treated with standard factor concentrates. For example, they may encourage patients to switch from on-demand treatment to prophylaxis and improve the quality of life of patients receiving prophylaxis. Indeed, extended half-life products have the potential to reduce the burden of frequent intravenous injections, reducing the need for central venous lines in children, promote adherence, improve outcomes, potentially allow for more active lifestyles and, depending on the dosing regimen, increase factor trough levels. Members of the Zürich Haemophilia Forum convened for their 19th meeting to discuss the practicalities of incorporating new treatments into the management of people with haemophilia. This review of extended half-life products considers their introduction in haemophilia treatment, including the appropriate dose and schedule of infusions, laboratory monitoring, patient selection, safety considerations, and the economic aspects of care.