Patient Experience With Efanesoctocog Alfa for Severe Hemophilia A: Results From the XTEND-1 Phase 3 Clinical Study Exit Interviews.

PURPOSE: Hemophilia A is a rare bleeding disorder that leads to recurrent hemarthrosis, which can ultimately result in reduced mobility and poor quality of life. Qualitative exit interviews provide insights into patient perspectives and support the interpretation of quantitative trial data, such as patient-reported outcome measures. In the Phase 3 XTEND-1 study (NCT04161495) of efanesoctocog alfa in participants with severe hemophilia A, exit interviews were conducted to understand pre- and post-study experiences with pain and physical functioning and to evaluate participants' treatment experiences. METHODS: In XTEND-1, participants (≥12 years old) received once-weekly efanesoctocog alfa prophylaxis 50 IU/kg for 52 weeks (Arm A) or on-demand efanesoctocog alfa 50 IU/kg for 26 weeks followed by 26 weeks once-weekly prophylaxis (50 IU/kg; Arm B). Optional qualitative exit interviews were conducted using a semi-structured guide in a subset of participants following study completion. Interviews included open-ended questions about participants' pre- and post-study experiences with hemophilia A and targeted questions relating to improvements in patient-reported outcomes assessed during XTEND-1, including the Haemophilia Quality of Life Questionnaire for Adults Physical Health subscale (Haem-A-QoL PH). Content validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Intensity 3a measure was also assessed, particularly the worst pain item. FINDINGS: Exit interviews were conducted with 29 of 159 patients enrolled in XTEND-1 (mean [range] age 40 [16-73] years). Of 17 participants enrolled in Arm A, 13 (76.5%) reported a "wearing off" feeling with pre-study treatment, including more aches/pain, breakthrough bleeds, and limited physical activities. Joint pain was the most reported pre-study symptom (96.6%; n = 28/29), followed by a reduced ability to move without pain (89.7%, n = 26/29). Improvements following efanesoctocog alfa prophylaxis in ≥1 Haem-A-QoL PH domain were reported by 89.7% (n = 26/29) of participants, with improvements in joint pain, the ability to move without pain, and painful swellings reported by at least 21 (84%) participants. Participants reported that the PROMIS Pain Intensity 3a items were relevant, clear, and easy to answer. Most participants (96.6%) were "quite satisfied" or "very satisfied" with efanesoctocog alfa prophylaxis. All participants preferred efanesoctocog alfa over pre-study treatment. IMPLICATIONS: The exit interviews demonstrated that once-weekly efanesoctocog alfa prophylaxis resulted in patient-relevant and meaningful improvements in pain and physical functioning, consistent with the quantitative findings from XTEND-1. These results support the validity of the Haem-A-QoL PH and PROMIS Pain Intensity 3a assessed during XTEND-1, demonstrating the potential for change with efficacious treatment. TRIAL REGISTRY: ClinicalTrials.gov TRIAL REGISTRATION NUMBER: NCT04161495 REGISTRY URL: https://clinicaltrials.gov/study/NCT04161495.

A rare case of acquired von Willebrand syndrome type 2B: diagnosis, treatment, and underlying pathophysiology.

Background: Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that usually mimics type 1 or 2A von Willebrand disease (VWD). Key Clinical Question: Can AVWS mimic the phenotype of type 2B VWD? Clinical Approach: A 64-year-old male patient presented with thrombocytopenia, normal routine hemostasis results, and normal VWF antigen and factor VIII levels but reduced von Willebrand factor (VWF) activity (31 IU/dL). The ristocetin-induced platelet aggregation test showed paradoxical aggregation at low doses of ristocetin, suggesting type 2B VWD, but no deleterious sequence variation was found in either the VWF or GP1BA genes, compatible with AVWS. Serum protein electrophoresis revealed a monoclonal immunoglobulin G antibody. Conclusion: This AVWS with a 2B phenotype VWD was probably related to a monoclonal immunoglobulin G antibody causing a VWF conformational change, resulting in increased affinity to platelet glycoprotein-Ib. In the event of surgery or bleeding, treatment with vonicog alfa seems to be the best option for this patient.

Type 2N von Willebrand disease: genotype drives different bleeding phenotypes and treatment needs.

BACKGROUND: Type 2 Normandy von Willebrand disease (VWD2N) is usually perceived as a mild bleeding disorder that can be treated with desmopressin (DDAVP). However, VWD2N patients can be compound heterozygous or homozygous for different variants, with p.Arg854Gln (R854Q) being the most frequent causative one. There are limited data about the impact of 2N variants on VWD2N phenotype and DDAVP response. OBJECTIVES: This study aims to describe the phenotype of VWD2N, including DDAVP response, according to genotype. METHODS: VWD2N patients with a complete genotype/phenotype characterization by the French reference center for VWD, including MCMDM-1VWD bleeding score, were eligible to be included in the study. Results of the DDAVP trial were also collected. RESULTS: A total of 123 VWD2N patients from the French registry were included in this study. Results were stratified according to the presence (R854QPos, n = 114) or absence (R854QNeg, n = 9) of at least 1 R854Q allele. Three R854QPos subgroups were further individualized: patients homozygous (R854QHmz, n = 55), compound heterozygous for R854Q and a null allele (R854Q/3, n = 48), or compound heterozygous for R854Q and another 2N variant (R854Q/2N, n = 11). FVIII: C levels were significantly lower in R854QNeg and R854Q/3 patients compared with R854QHmz ones (P < .001 and P < .0001, respectively). R854QNeg patients were diagnosed earlier due to bleeding symptoms and had a higher bleeding score than R854QPos patients (P < .001). In DDAVP trial, FVIII:C survival was lower in VWD type 2N than in type 1 patients. R854QPos patients had a heterogeneous DDAVP response, which was best predicted by baseline FVIII:C level. CONCLUSION: The heterogeneous genetic background of VWD2N drives different bleeding phenotypes and response patterns to DDAVP, underlining the clinical relevance of DDAVP trial to identify patients potentially eligible to alternative therapeutic options.

Predelivery Haemostatic Biomarkers in Women with Non-Severe Postpartum Haemorrhage.

Background: Postpartum haemorrhage (PPH) is a frequent complication of childbirth that is difficult to predict. Predelivery coagulation biomarkers may help to guide preventive strategies. Our objective was to evaluate the association of predelivery haemostatic biomarkers with non-severe PPH. Methods: A nested case-control study was conducted within the « Study of Biological Determinants of Bleeding Postpartum ¼ in order to compare different haemostatic biomarkers in plasma from pregnant women with non-severe PPH (cases) and controls without PPH matched for age, body mass index, term, and mode of delivery. Blood was collected at entry in the delivery room. Global haemostatic assays (thrombin generation assay (TGA) and plasmin generation assay (PGA)) were then performed on freshly thawed aliquots of platelet-poor plasma. Results: A total of 370 pregnant women (185 cases and 185 controls) were included. Median [interquartile range] predelivery platelet count was lower in PPH cases than in controls (217 [181-259] versus 242 [196-280] G/L). TGA and PGA parameters were similar between cases and controls. In a subset analysis of vaginal deliveries (n = 144), median predelivery TGA thrombin peak was lower, and median predelivery PGA lag phase was longer in cases compared to controls. In multivariable analysis, only predelivery platelet count was independently associated with non-severe PPH. Conclusions: Predelivery platelet count is associated with non-severe PPH. Differences in other haemostatic parameters are tenuous, questioning their usefulness in predicting non-severe PPH.

Key Drivers of Coagulation Factor Use in Von Willebrand Disease During Hospitalization: An Overview of the French BERHLINGO Cohort.

BACKGROUND: Von Willebrand disease (VWD) is the most common inherited bleeding disorder. However, studies of hospitalisation patterns with replacement treatment are scarce. OBJECTIVES: The aim of this study was to investigate the current therapeutic management of VWD and determine the key drivers of coagulation factor uses in patients during hospitalisation. METHODS: Hopscotch-WILL was a multi-centric retrospective study conducted over a 48-month period in any patients with VWD. The data were collected from the BERHLINGO Research Database and the French Hospital database. RESULTS: A total of 988 patients were included; 153 patients (15%) were hospitalised during 293 stays requiring treatment with von Willebrand factor (VWF) concentrates-pure or in association with Factor VIII (FVIII). Their median basal concentrations of VWF and FVIII were significantly lower than in untreated patients: VWF antigen < 30 IU/dL, VWF activity < 20 IU/dL and FVIII:C < 40 IU/dL. The median (interquartile range) concentrate consumption was similar between highly purified VWF or VWF combined with FVIII (72 [110] vs 57 [89] IU/kg/stay, p = 0.154). The use of VWF was highly heterogeneous by VWD type; type 3 had a particularly high impact on VWF consumption in non-surgical situations. The main admissions were for ear/nose/throat, hepato-gastroenterology, and trauma/orthopaedic conditions, besides gynaecological-obstetric causes in women. CONCLUSIONS: The use of VWF concentrates is mostly influenced by low basal levels of VWF and FVIII, but also by VWD type or the cause for hospitalisation. These results could inform future studies of newly released recombinant VWF.

Women with severe postpartum hemorrhage have a decreased endogenous thrombin potential before delivery.

BACKGROUND: Severe postpartum hemorrhage (PPH), defined as a blood loss ≥1000 mL, is associated with maternal morbidity and mortality. OBJECTIVES: We aimed at characterizing coagulation properties of predelivery plasmas from pregnant women with thrombin generation assay and hemostatic biomarkers (plasminogen activator inhibitor-1, tissue factor [TF], and thrombomodulin). METHODS: A nested case-control study was conducted within the "Study of Biological Determinants of Bleeding Postpartum," a French prospective cohort study, in order to compare women with severe PPH (cases) and controls matched for age, body mass index, term, and mode of delivery. Plasma was collected at entry in the delivery room, and blood loss was measured objectively. The predelivery endogenous thrombin generation potential (ETP) was measured in plasma using calibrated automated thrombinography and low TF concentration. Hemostatic biomarkers were measured using ELISA kits. RESULTS: A total of 142 women (71 cases and 71 controls) were investigated. There was no difference in the median lag phase, thrombin peak, and time to peak between cases and controls. However, median predelivery ETP was lower in cases than in controls (2170 vs 2408 nM.min, P < .0001), independently of mode of delivery and PPH etiology. Median plasminogen activator inhibitor-1 and TF levels were higher in cases compared with controls (107.4 vs 68.1 ng/mL, P = .0003; 34.4 vs 27.4 pg/mL, P = .007), whereas thrombomodulin levels did not differ between the 2 groups. CONCLUSION: Among thrombin generation assay parameters, predelivery ETP levels may have a predictive value for severe PPH.

Family history of postpartum hemorrhage is a risk factor for postpartum hemorrhage after vaginal delivery: results from the French prospective multicenter Haemorrhages and Thromboembolic Venous Disease of the Postpartum cohort study.

BACKGROUND: Postpartum hemorrhage is a major component of perinatal morbidity and mortality that affects young women worldwide and is still often unpredictable. Reducing the incidence of postpartum hemorrhage is a major health issue and identifying women at risk for postpartum hemorrhage is a key element in preventing this complication. OBJECTIVE: This study aimed to estimate postpartum hemorrhage prevalence after vaginal delivery and to identify postpartum hemorrhage risk factors. STUDY DESIGN: Unselected pregnant women ≥16 years of age admitted to 1 of 6 maternity wards in Brittany (France) for vaginal birth after 15 weeks of gestation were recruited in this prospective, multicenter cohort study between June 1, 2015, and January 31, 2019. Postpartum hemorrhage was defined as blood loss ≥500 mL in the 24 hours following delivery. Independent risk factors for postpartum hemorrhage were determined using logistic regression. Missing data were imputed using the Multivariate Imputation by Chained Equations method. RESULTS: Among 16,382 included women, the postpartum hemorrhage prevalence was 5.37%. A first-degree family history of postpartum hemorrhage (adjusted odds ratio, 1.63; 95% confidence interval, 1.24-2.14) and a personal transfusion history (adjusted odds ratio, 1.90; 95% confidence interval, 1.23-2.92) were significantly associated with postpartum hemorrhage. The use of oxytocin during labor was also a risk factor for postpartum hemorrhage (adjusted odds ratio, 1.24; 95% confidence interval, 1.06-1.44). Inversely, smoking during pregnancy and intrauterine growth restriction were associated with a reduced risk for postpartum hemorrhage (adjusted odds ratio, 0.76; 95% confidence interval, 0.63-0.91, and 0.34; 95% confidence interval, 0.13-0.87, respectively). CONCLUSION: In addition to classical risk factors, this study identified a family history of postpartum hemorrhage and personal transfusion history as new characteristics associated with postpartum hemorrhage after vaginal delivery. The association of postpartum hemorrhage with a family history of postpartum hemorrhage suggests a hereditary hemorrhagic phenotype and calls for genetic studies. Identifying women at risk for postpartum hemorrhage is a key element of being prepared for this complication.

Atrial fibrillation and peripheral arterial disease define MPN patients with very high risk of thrombosis.

Myeloproliferative neoplasms (MPNs) are associated with a high risk of thrombotic and hemorrhagic complications, especially in elderly patients. Atrial fibrillation (AF) and peripheral arterial disease (PAD), also frequently discovered in aging patients, are associated with similar complications. We analysed the incidence and complication rates of AF and PAD in a large cohort of MPN patients. In total, 289/1113 patients (26 %) suffered at least one of these diseases as follows: 179 (16.1 %) with AF alone, 81 with PAD alone (7.3 %) and 29 (2.6 %) with both conditions. Postdiagnosis thrombotic events were observed in 31.3 % of AF patients (p = 0.002, OR = 1.80 [1.23;2.61]), 35.8 % of PAD patients (p = 0.002, OR = 2.21[1.31;3.67]) and 62.1 % of AF/PAD patients (p < 0.0001, OR = 6.47 [2.83;15.46]) compared to 20.1 % of no-AF/no-PAD patients. Postdiagnosis hemorrhagic events were also identified in 17.9 %, 16 %, 24.1 % and 10.1 % of AF, PAD, AF/PAD, and no-AF/no-PAD patients, respectively (p = 0.003). This significantly higher risk of thrombosis/bleeding was also observed in patients <60 years old. AF and PAD were significant risk factors for both thrombotic and hemorrhagic risks in multivariate analysis. We identified AF and PAD as criteria for high risk of thrombosis, hemorrhage, and death, emphasizing the interest in early detection and efficient treatment of these conditions.

A French Real-World Evidence Study Evaluating the Efficacy, Safety, and Pharmacokinetic Parameters of rVIII-SingleChain in Patients with Hemophilia A Receiving Prophylaxis.

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.

Differences between aquagenic and non-aquagenic pruritus in myeloproliferative neoplasms: An observational study of 500 patients.

BACKGROUND: Pruritus is a frequent symptom experienced by patients with myeloproliferative neoplasms (MPN). Aquagenic pruritus (AP) is the most common type. The Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) self-report questionnaires were distributed to MPN patients before consultations. OBJECTIVES: The aim of this study was to assess clinical incidence (phenotypical evolution and response to treatment) of pruritus, especially AP, in MPN patients during their follow-ups. PATIENTS AND METHODS: We collected 1444 questionnaires from 504 patients [54.4% essential thrombocythaemia (ET) patients, 37.7% polycythaemia vera (PV) patients, and 7.9% primary myelofibrosis (PMF) patients]. RESULTS: Pruritus was reported by 49.8% of the patients, including 44.6% of AP patients, regardless of type of MPN or driver mutations. Patients suffering from pruritus were more symptomatic and had a higher rate of evolution into myelofibrosis/acute myeloid leukaemia (19.5% vs. 9.1%, OR = 2.42 [1.39; 4.32], p = 0.0009) than MPN patients without pruritus. Patients with AP had the highest pruritus intensity values (p = 0.008) and a higher rate of evolution (25.9% vs. 14.4%, p = 0.025, OR = 2.07) than patients with non-AP. Disappearance of pruritus was observed in only 16.7% of AP cases, compared to 31.7% of cases with other types of pruritus (p < 0.0001). Ruxolitinib and hydroxyurea were the most effective drugs to reduce AP intensity. CONCLUSIONS: In this study, we demonstrate the global incidence of pruritus across all MPN. Pruritus, especially AP, which is a major constitutional symptom observed in MPN, should be assessed in all MPN patients due to higher symptom burden and higher risk of evolution.

Clinical risk factors for vasculo-placental disorders: results from a prospective case-control study nested in HEMOTHEPP French cohort study.

OBJECTIVE: Determine clinical risk factors for vasculo-placental disorders in singleton pregnancies. DESIGN: Prospective case-control study nested in HEMOTHEPP French cohort. SETTING: Women delivered between June, 2015 and January, 2019 in any maternity ward of Finistère. POPULATION: Cases were women with vasculo-placental disorders (pre-eclampsia, intrauterine growth restriction (IUGR), placental abruption or stillbirth). Controls were women matched for age at delivery and parity. METHODS: Clinical data were collected by obstetricians or midwives during antenatal care visits and delivery, and recorded by trained research assistants. MAIN OUTCOME MEASURES: Occurrence of a vasculo-placental disorder. RESULTS: 505 women with vasculo-placental disorder (299 pre-eclampsia, 253 IUGR, 44 placental abruptions, 11 stillbirths) and 1515 matched controls were selected out of 20,075 participants. In multivariable analysis, four clinical parameters were associated with pre-eclampsia: obesity (Odd ratio (OR) = 3.11, 95%CI 2.11-4.58), French overseas origin (OR = 4.41, 95%CI 1.87-10.42), previous vasculo-placental disorder (OR = 5.14, 95%CI 2.72-9.70), aspirin during pregnancy (OR = 10.10, 95%CI 1.99-51.08). Three clinical parameters were associated with IUGR: auto-immune/inflammatory disorder (OR = 3.75, 95%CI 1.83-7.68), previous vasculo-placental disorder (OR = 3.63, 95%CI 2.06-6.41), smoking during pregnancy (OR = 2.66, 95%CI 1.91- 3.71). A previous venous thromboembolism (VTE) was associated with IUGR in univariable but not in multivariable analysis (OR = 3.72, 95%CI 0.82-17.00, p = 0.09). CONCLUSIONS: Clinical risk factors differ between IUGR and pre-eclampsia, the later, but not the former, being associated with cardiovascular risk factors.

Immune thrombocytopenia and pregnancy: an exposed/nonexposed cohort study.

The risk of immune thrombocytopenia (ITP) worsening during pregnancy and neonatal ITP (NITP) have never been prospectively studied. We included 180 pregnant and 168 nonpregnant women with ITP in a prospective, multicenter, observational cohort study. A total of 131 pregnant women with ITP were matched to 131 nonpregnant women with ITP by history of splenectomy, ITP status (no response, response, complete response), and duration. Groups were followed for 15 months. The primary outcome was the first occurrence of ITP worsening defined by a composite end point including bleeding events and/or severe thrombocytopenia (<30 × 109/L) and/or ITP treatment modification. We also studied the recurrence of ITP worsening and the incidence of NITP and risk factors. The first occurrence of ITP worsening did not differ between pregnant and nonpregnant women with ITP (53.4 per 100 person-years [95% confidence interval {CI}, 40.8-69.9] vs 37.1 [95% CI, 27.5-50.0]; hazard ratio {HR}, 1.35 [95% CI, 0.89-2.03], P = .16). Pregnant women with ITP were more likely to have recurrence of severe thrombocytopenia and treatment modification (HR, 2.71 [95% CI, 1.41-5.23], P = .003; HR, 2.01 [95% CI, 1.14-3.57], P = .017, respectively). However, recurrence of severe bleeding events was not different between groups (P = .4). Nineteen (14%) neonates showed NITP <50 × 109/L. By multivariable analysis, NITP was associated with a previous offspring with NITP and maternal platelet count <50 × 109/L within 3 months before delivery (adjusted odds ratio, 5.55 [95% CI, 1.72-17.89], P = .004 and 4.07 [95% CI, 1.41-11.73], P = .009). To conclude, women with ITP do not increase their risk of severe bleeding during pregnancy. NITP is associated with NITP history and the severity of maternal ITP during pregnancy. These results will be useful for counseling women with ITP.

Acquired von Willebrand syndrome and lymphoid neoplasms: A review of malignancy management, and propositions of practical recommendations.

INTRODUCTION: Acquired von Willebrand syndrome (AWS) is a rare and potentially life-threatening bleeding disorder. AWS is primarily associated with lymphocyte-related disorders (AWS-LRD), such as lymphoma and IgM monoclonal gammopathy of undetermined significance (MGUS), and plasmocyte-related disorders (AWS-PRD), such as non-IgM MGUS and myeloma. Symptomatic treatments are important to control and prevent bleeding, but AWS-LRD and AWS-PRD can only be cured by targeting the responsible clonal cell. No reviews exist on this specific subgroup of AWS. AIM: We performed a literature review to help manage these rare cases. METHOD: Thirty-two AWS-PRD and 43 AWS-LRD cases with data on malignancy treatment were reported in 56 articles from the Medline database. RESULTS: LRDs were exclusively indolent and primarily associated with IgM monoclonal compounds. LRDs and PRDs may be treated because of severe bleeding symptoms, but severe VWF deficiency did not necessarily correlate with severe bleeding. Immunosuppressive drugs in AWS-PRD, including rituximab, provided an overall response rate of AWS (AWS-ORR) of 30% (3/10), including short responses. Anti-myeloma drugs provided an AWS-ORR of 71.4% (20/28), with long-lasting remissions. Bortezomib was the most commonly used drug and provided an AWS-ORR of 66.7% (6/9), including therapeutic associations with other anti-myeloma drugs. Autologous and allogeneic stem cell transplantation was performed in eight and two patients, respectively, and some details on the management of AWS during these procedures were provided. Rituximab in AWS-LRD provided an AWS-ORR of 60% (3/5), and a chemotherapy + rituximab regimen increased the AWS-ORR to above 50%. Bleeding syndrome in AWS-PRD and AWS-LRD generally improved prior to AWS biological improvement. CONCLUSION: Long term remission of AWS due to lymphoid neoplasms is attainable by treating the underlying clonal cell. Some data and recommendations are provided to help answer difficult questions, including treatment timing, choice of drug, and the timing of evaluations and treatment changes.

rFVIII-Fc in severe haemophilia A: The incentive switch in case of high risk of joint bleedings.

BACKGROUND: Efmoroctocog alfa, the first recombinant factor VIII fusion protein with extended half-life (rFVIII-Fc), has been hypothesized to lower FVIII consumption in patients with severe Haemophilia A (pwSHA), without reducing clinical efficacy. What about real life? METHOD: MOTHIF-II was a noninterventional, multicentre, before/after study, via the collection of retrospective data from July 2015 to June 2016 (called T1), and from July 2017 to June 2018 (called T2), in 7 French haemophilia treatment centres. We examined the prescriptions and dispensations of factor VIII and the Annual Bleeding Rate (ABR), in pwSHA without current inhibitors on prophylaxis, before and after the introduction of rFVIII-Fc. The data gathered from the BERHLINGO research database and from the French Healthcare claims database with a determinist pairing process based on the national unique identification number. RESULTS: A total of 156 pwSHA were included in the prescription cohort and 83 in the ABR cohort. For switched patients, the mean amounts of prescribed FVIII were significantly higher during T1 compared to T2 (4333 (2052) vs. 3921 (2029) IU/kg/year/patient, p: 0.028); a significant decrease in their ABR was also observed between T1 and T2 (6.3 (6.0) vs. 4.4 (5.4), p: 0.047). These patients had a more severe bleeding profile centred on haemarthrosis. CONCLUSION: The results are related to those of the pivotal clinical trials for the reduction in FVIII consumption following the switch to rFVIII-Fc, with a significant improvement in the haemorrhagic phenotype for pwSHA.

Benefice and pitfall of direct oral anticoagulants in very high-risk myeloproliferative neoplasms.

INTRODUCTION: Direct oral anticoagulants (DOACs) have recently proven their efficacy and safety, as primary and secondary prevention agents for thrombosis in cancer patients. We aimed to determine if DOACs might be a suitable choice to reduce the thrombotic risk in myeloproliferative neoplasm (MPN) patients. MATERIALS AND METHODS: We analysed a large multicentric cohort of MPN patients treated with rivaroxaban or apixaban after atrial fibrillation (AF) or thrombotic events. RESULTS: We included 135 MPN patients with a median follow-up of 23.8 months since DOAC initiation. Twenty patients (14.8 %) developed 30 thrombotic events (28 arterial thromboses in 19 patients) for a global incidence of 6.5 % patient-years. No difference was highlighted between apixaban and rivaroxaban in terms of thrombosis risk, but the incidence of arterial thrombosis was significantly higher on low-dose DOACs (11.9 vs. 4.5 % patient-years, p = 0.04). Bleeding events were more frequent in the full-dose group (41.2 vs. 15.2 %, p = 0.006). However, major and clinically relevant non major (CRNM) bleeding events occurred in 18 patients (13.3 %), with no difference between the groups. Age was the only identified thrombotic risk factor, whereas risk factors for major or CRNM bleeding were a full-dose treatment regimen and a combination of DOAC/low-dose aspirin. CONCLUSIONS: DOACs seem effective in preventing venous thrombosis in MPN patients with AF or VTE. For these high-risk patients, low-dose DOACs exposed patients to more arterial thrombosis but fewer bleeding events. Prospective studies are needed to evaluate and compare DOACs to the currently recommended antithrombotic drugs for high-risk MPN patients.

Excessive gestational weight gain is an independent risk factor for gestational diabetes mellitus in singleton pregnancies: Results from a French cohort study.

OBJECTIVE: Increase in prevalence of maternal obesity worldwide raises concern among health professionals. Our purpose was to evaluate the impact of maternal obesity and of excessive gestational weight gain (GWG) on the course of singleton pregnancies in a French maternity ward. STUDY DESIGN: 3599 consecutive women who delivered from April 2013 to May 2015 at Brest University Hospital were included in HPP-IPF cohort study, a study designed to evaluate clinical and biological determinants of postpartum hemorrhage (PPH). Maternal obesity was defined by a pre-pregnancy Body Mass Index (BMI) ≥ 30 kg/m2 and excessive GWG was defined according to the Institute of Medicine 2009 guidelines. Obstetric complications(including gestational diabetes mellitus (GDM), gestational hypertension, pre-eclampsia, venous thromboembolism, PPH, cesarean section (C-section) and macrosomia) were collected prospectively in a standardized case report form. For each complication, Odd Ratios (OR) according to pre-pregnancy BMI and GWG were calculated in univariable and multivariable analyses. RESULTS: Out of the 3162 women analyzed for this report, 583 (18.4%) were overweight, 400 (12.7%) were obese and 36.6% had excessive GWG. In multivariable analysis, after adjustment for confounding factors, obese women were at increased risk of GDM (OR 5.83, 95%CI 4.37-7.79), PPH (OR 1.69, 95%CI 1.19-2.41), C-section (OR 2.50, 95%CI 1.92-3.26) and macrosomia (OR 1.90, 95%CI 1.31-2.76). Similarly, women with excessive GWG were at increased risk of GDM (OR 1.55, 95%CI 1.17-2.06), C-section (OR 1.46, 95%CI 1.16-1.83) and macrosomia (OR 2.09, 95%CI 1.50-2.91). CONCLUSIONS: Maternal obesity and excessive GWG are independent risk factors for GDM, C-section and macrosomia in singleton pregnancies. Further studies are needed to evaluate if a lifestyle intervention aiming at avoiding excessive GWG could improve clinical outcomes in pregnant women.

Hemorrhages in Polycythemia Vera and Essential Thrombocythemia: Epidemiology, Description, and Risk Factors-Learnings from a Large Cohort.

BACKGROUND: The management of myeloproliferative neoplasms (MPNs) is based on the reduction of thrombotic risk. The incidence, impact, and risk factors of bleedings have been less studied. METHODS: All patients with polycythemia vera (n=339) or essential thrombocythemia (n=528) treated in our center are included in OBENE (Observatoire BrEstois des NEoplasies myéloprolifératives) cohort (NCT02897297). Major bleeding (MB) and clinically relevant nonmajor bleeding (CRNMB) occurring after diagnosis were included, except after leukemic transformation. RESULTS: With a median follow-up of 8.3 years, incidence of hemorrhages was 1.85% patient/year, with an incidence of MB of 0.95% patient/year. The 10-year bleeding-free survival was 89%. The most frequent locations were digestive tract, "mouth, nose and throat," and muscular hematoma. The case fatality rate of MB was 25%. The proportion of potentially avoidable postoperative bleeding was remarkable (17.6%). In multivariable analysis, eight risk factors of bleeding were identified: leukocytes >20 G/L at diagnosis (hazard ratio [HR]=5.13, 95% confidence interval [CI]: 1.77-14.86), secondary hemopathies (HR=2.99, 95% CI: 1.27-7.04), aspirin use at diagnosis (HR=2.11, 95% CI: 1.24-3.6), platelet count >1,000 G/L at diagnosis (HR=1.93, 95% CI: 1.11-3.36), history of hemorrhage (HR=1.82, 95% CI: 1.03-3.24), secondary cancers (HR=1.71, 95% CI: 1.01-2.89), atrial fibrillation (HR=1.66, 95% CI: 1.01-2.72), and male sex (HR=1.54, 95% CI: 1.02-2.33). The occurrence of a CRNMB increased the risk of a secondary MB (odds ratio=6.13, 95% CI: 2.86-12.6, p<0.00001). Most patients taking hydroxyurea displayed a nonmacrocytic median corpuscular value in the months preceding bleeding (51.4%). DISCUSSION: The morbidity and mortality of bleedings in MPN should not be underestimated, and patients with platelet count >1,000 G/L and/or leukocytes >20 G/L, and possibly patients who suffered from a CRNMB could benefit from cytoreduction to reducing bleeding risk. Postoperative bleedings represent a substantial proportion of bleeding and could be better prevented.

Global Seroprevalence of Pre-existing Immunity Against AAV5 and Other AAV Serotypes in People with Hemophilia A.

Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited. In this global, prospective, noninterventional study, we determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and AAVrh10 among people ≥12 years of age with HA and residual FVIII levels ≤2 IU/dL. Antibodies against each serotype were detected using validated, electrochemiluminescent-based enzyme-linked immunosorbent assays. To evaluate changes in antibody titers over time, 20% of participants were retested at 3 and 6 months. In total, 546 participants with HA were enrolled at 19 sites in 9 countries. Mean (standard deviation) age at enrollment was 36.0 (14.87) years, including 12.5% younger than 18 years, and 20.0% 50 years of age and older. On day 1, global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10. Considerable geographic variability was observed in the prevalence of pre-existing antibodies against each serotype, but AAV5 consistently had the lowest seroprevalence across the countries studied. AAV5 seropositivity rates were 51.8% in South Africa (n = 56), 46.2% in Russia (n = 91), 40% in Italy (n = 20), 37.2% in France (n = 86), 26.8% in the United States (n = 71), 26.9% in Brazil (n = 26), 28.1% in Germany (n = 89), 29.8% in Japan (n = 84), and 5.9% in the United Kingdom (n = 17). For all serotypes, seropositivity tended to increase with age. Serostatus and antibody titer were generally stable over the 6-month sampling period. As clinical trials of AAV-mediated gene therapies progress, data on the natural prevalence of antibodies against various AAV serotypes may become increasingly important.