The thrombin generation (TG) assay evaluates haemostatic balance, which is influenced by the levels of many coagulation factors and inhibitors. Our objective was to identify the determinant factors ...of TG in haemophilia A (HA) and haemophilia B (HB) patients and to compare them to those in healthy controls. Coagulation factor and inhibitor levels, and TG, were measured in platelet‐poor plasma from 40 patients with HA, 32 patients with HB and 40 healthy subjects. Data were analysed using multiple regression models. In HA patients, factor VIII was a positive determinant of endogenous thrombin potential (ETP) and peak, whereas tissue factor pathway inhibitor (TFPI) and factor V were negative determinants of ETP and peak. In HB patients, FIX was a positive determinant of ETP and peak, FVII being a positive determinant of peak. Antithrombin and protein S (PS) were negative determinants of ETP while FX was a negative determinant of peak. Above all, in HB patients, TFPI was a negative determinant of ETP and peak. In healthy subjects, FVIII was a positive determinant of ETP and peak, whereas FX and protein S were negative determinants of these parameters. TFPI was not a negative determinant of either peak or ETP. In haemophilic patients, the determinant factors of TG are all implicated in FXa generation and inhibition, the crucial determinant factor being TFPI whatever the type of haemophilia, A or B. These findings contribute to the rationale that recently place TFPI as a target for innovative therapies of haemophilia.
The ristocetin cofactor activity assay (VWF:RCo) is the reference method for assessing von Willebrand factor (VWF) activity but remains difficult to perform, and the coefficient of variation of the ...method is high (about 20-30%). This study evaluated and compared the performance for measuring the VWF activity of two newly commercialised assays VWF:Ac Innovance (VWF:Ac) and VWF:RCo Acustar (VWF:RCo Acu) with the reference VWF:RCo aggregation in 123 pathological plasma samples. The correlation and concordance between both new tests (VWF:RCo-Acu and VWF:Ac) and the reference VWF:RCo were good. The results of the VWF activity to VWF antigen ratio were also comparable whatever the method for the classification of VWF deficiency in all patients. Our results showed that both new tests could replace the "gold standard" VWF:RCo in aggregometry with several benefits: they are fully automated, easier and faster to perform, better adapted to emergency situations if necessary.
We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population ...pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.
Introduction
Since June 2021 in France, patients with haemophilia A with anti‐factor VIII inhibitors and patients with severe haemophilia A without anti‐factor VIII inhibitors, and treated with ...emicizumab (Hemlibra), have to choose the dispensing circuit community or hospital pharmacy.
Aim
To evaluate satisfaction of patients whether they choose dispensation from a community pharmacy or retained dispensation from the hospital pharmacy, to understand the main motivation for choosing the community or the hospital pharmacy.
Methods
All patients living in France, regardless of age, were eligible to participate. Between September 13, 2022, and January 9, 2023, 175 respondents answered the satisfaction survey, including 123 in community pharmacy and 52 in hospital pharmacy.
Results
Eighteen months after availability in community pharmacies, treatment accessibility is improved for the benefit of the patient. The door‐to‐door travel times are significantly reduced to the community pharmacy with an average gain of 16.5 min saved from the place of residence. Patients are mostly satisfied with the new dispensing circuit especially concerning the overall satisfaction (p < .0001), the travel time (p < .0001) and the strong relationship with the pharmacist (p = .0022) compared to hospital pharmacy.
Conclusion
Innovation in care pathways is showing its full potential in improving access to medication, made possible by the implementation of a rigorous organization accompanied by training to enable healthcare professionals involved in primary care to provide appropriate management.
No F8 genetic abnormality is detected in approximately 1% to 2% of patients with severe hemophilia A (HA) using conventional genetic approaches. In these patients, deep intronic variation or F8 ...disrupting genomic rearrangement could be causal.
The study aimed to identify the causal variation in families with a history of severe HA for whom genetic investigations failed.
We performed whole F8 gene sequencing in 8 propositi. Genomic rearrangements were confirmed by Sanger sequencing of breakpoint junctions and/or quantitative polymerase chain reaction.
A structural variant disrupting F8 was found in each propositus, so that all the 815 families with a history of severe HA registered in our laboratory received a conclusive genetic diagnosis. These structural variants consisted of 3 balanced inversions, 3 large insertions of gained regions, and 1 retrotransposition of a mobile element. The 3 inversions were 105 Mb, 1.97 Mb, and 0.362 Mb in size. Among the insertions of gained regions, one corresponded to the insertion of a 34 kb gained region from chromosome 6q27 in F8 intron 6, another was the insertion of a 447 kb duplicated region from chromosome 9p22.1 in F8 intron 14, and the last one was the insertion of an Xq28 349 kb gained in F8 intron 5.
All the genetically unsolved cases of severe HA in this cohort were due to structural variants disrupting F8. This study highlights the effectiveness of whole F8 sequencing to improve the molecular diagnosis of HA when the conventional approach fails.
Introduction
The coronavirus disease 2019 (COVID‐19) pandemic has created an unprecedented global health crisis.
Aim
To investigate the impact of the 1st COVID‐19 lockdown on haemophilia patients in ...terms of symptoms, management, medication adherence, mental health and lifestyle behaviours.
Methods
A prospective cross‐sectional phone survey using a two‐part questionnaire was conducted in haemophilia patients (adults and children) followed‐up in a French Haemophilia Comprehensive Care Centre between May 5, 2020 and June 2, 2020 (CLEO CD study: NCT04390126).
Results
Among 284 haemophilia A or B patients with FVIII or FIX < 40% contacted for the study, 239 (84%) including 183 adults and 56 children participated to the survey. In 81% of children and 78% of adults, bleeding episodes remained unchanged or decreased. Medication adherence was 82.0% in adults and 98.2% in children. Non‐adherence concerned haemostatic agents in six patients and analgesics in three. Overall, 67% of adults and 71% of children felt as good as before lockdown. In both adults and children, the three major changes in lifestyle behaviours were: increase in screen time (49% and 57%), decrease in physical activity (43% and 48%), and weight gain (32% and 27%), respectively.
Conclusions
Encouraging results were observed in terms of haemophilia symptoms, medication adherence, and mental health. Conversely, a negative impact was observed on lifestyle behaviours in a cohort of French haemophilia patients during the 1st lockdown.
Bleeding severity in severe haemophilic patients, with low thrombin generation (TG) capacity, can vary widely between patients, possibly reflecting differences in tissue factor pathway inhibitor ...(TFPI) level.
To compare free TFPI (fTFPI) levels in patients with severe haemophilia A (sHA) and severe haemophilia B (sHB) and to investigate in these patients as a whole the relationships between bleeding and TG potential, between TG potential and fTFPI level and between fTFPI level and bleeding tendency.
Data on bleeding episodes retrospectively recorded during follow-up visits over 5-10 years were collected and used to calculate the annualised joint bleeding rate (AJBR). fTFPI levels and basal TG parameters were determined in platelet-poor plasma (PPP) and platelet-rich plasma (PRP) using calibrated automated tomography (CAT).
Mean fTFPI levels did not differ significantly between sHA (n = 34) and sHB (n = 19) patients. Mean values of endogenous thrombin potential (ETP) and thrombin peak (peak) in PPP and PRP were two-fold higher when fTFPI levels < 9.4 versus > 14.3 ng/mL. In patients treated on demand, ETP and peak in PRP were doubled when AJBR was
, AJBR being halved in patients with a low fTFPI level (9.4 ng/mL). In patients on factor prophylaxis, no association was found between TG parameters and either fTFPI level or AJBR.
In patients treated on demand, bleeding tendency was influenced by fTFPI levels, which in turn affected basal TG potential. In patients on prophylaxis, bleeding tendency is probably determined primarily by the intensity of this treatment.
Background
Data are limited on prostate cancer (PC) management in patients with haemophilia (PWH).
Aim
To describe PC screening and diagnosis, treatment modalities and bleeding complications in a ...group of unselected PWH followed at French Haemophilia Treatment Centres (HTCs)
Patients and methods
PC screening, management and bleeding complications were retrospectively investigated at 14 French HTCs between 2003 and 2018.
Results
Among> 1549 > 50‐year‐old PWHs, 73 (4.7%) underwent PC screening (median age 71.1 years; 67/6 HA/HB, 17/56 severe‐moderate/mild). At diagnosis, haematuria was infrequent. Prophylaxis was administered during 76/86 (88%) prostate biopsies (PB) (n = 67 clotting factor concentrates, CFC; n = 9 desmopressin; n = 17 associated with tranexamic acid, TA). Bleeding (11/86, 12.8%) occurred mainly post‐prophylaxis (median delay: 7 days): haematuria (9/11, 81.8%), and rectal bleeding (2/11, 18.2%) including one major (1.2%). PC was confirmed in 50/86 PB and in two prostatectomy specimens (total n = 50 patients, n = 6 with only active surveillance). Surgery (n = 28/44 patients) was managed with CFC. Fifteen patients had radiotherapy/brachytherapy, 10 had hormone therapy; CFC‐based prophylaxis was only prescribed for brachytherapy (n = 2). Major bleedings occurred in 3/28 (10.7%) and 2/15 (13.3%) patients who underwent surgery and radio/brachytherapy, respectively. No bleeding risk factor was found.
Conclusion
Our data indicate that PB requires prophylaxis for atleast 7 days, using CFC, desmopressin or TA in function of haemophilia severity. PC surgery should be considered at high bleeding risk. Long‐term post‐procedural CFC or oral TA could be discussed. Radiotherapy/brachytherapy also should be managed with prophylaxis (CFC or TA).
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