Several innovative drugs liable to lead to changes in healthcare organization are or soon will be available for the management of hemophilia. Analyzing their implementation can shed further light on ...healthcare decision-making, to anticipate changes and risk of breakdown in the patient's care pathway. Multiple criteria decision analysis (MCDA), based on ISPOR recommendations, was used to assess the organizational impact of innovation in hemophilia care management. The MCDA process designed for this specific context involved ten French experts in hemophilia care management (physicians, nurses, pharmacist, physiotherapist and psychologist) in the hemophilia care center of Chambéry, in the Rhône-Alpes Region of France. This pilot study involved seven steps: (i) defining the decision problem; (ii) selecting and structuring criteria; (iii) assessing the relative weight of each criterion with software-assisted simulation based on pairwise comparisons of different organizational change scenarios; (iv) measuring the performance of the selected innovations; (v) scoring alternatives; (vi) calculating aggregate scores; (vii) discussion. The endpoint was to determine the expected overall organizational impact on a 0-100 scale. Seven organizational criteria were selected. "Acceptability for patient/caregiver/association" was the most heavily weighted. Factor VIII by subcutaneous route obtained the highest aggregate score: i.e., low impact on care organization (88.8 out of 100). The innovation with strongest organizational impact was gene therapy (27.3 out of 100). This approach provided a useful support for discussion, integrating organizational aspects in the treatment decision-making process, at healthcare team level. The study needs repeating in a few years' time and in other hemophilia centers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Congenital hypodysfibrinogenemia is a rare fibrinogen disorder, defined by decreased levels of a dysfunctional fibrinogen. We present the functional and structural characterization of two new ...fibrinogen variants. A duplication of 32 bases in FGA exon 5, p.Ser382GlyfsTer50 was identified in a patient (P1) with history of hemoptysis and traumatic cerebral bleeding. A missense mutation in FGG exon 8, p.Ala353Ser was identified in two siblings (P2 and P3) with tendency to bruising and menorrhagia. Fibrin polymerization was studied in plasma and in purified fibrinogen by turbidimetry. Fibrin structure was studied by a permeability assay, laser scanning confocal microscopy (LSCM) and scanning electron microscopy (SEM). In both plasma and purified fibrinogen samples, all patients had an abnormal polymerization characterized by a decreased maximal absorption compared to controls. The permeation constant (Ks) was markedly increased in all patients: 31 ± 9 × 10−9 cm2 in P1, and 20 ± 0.1 × 10−9 cm2 in P2 and P3, compared to 6 ± 2 × 10−9 cm2 in the control (p < 0.05). The presence of very large pores that accounts for the increased Ks was confirmed by LSCM and SEM patients' clots images. By SEM, the patients' fibrin fibers diameters were thicker: 90 ± 25 nm in P1, 162 ± 64 nm in P2 and 132 ± 46 nm in P3 compared to 74 ± 25 nm in control (p < 0.0001). In conclusion, both new causative fibrinogen mutations altered clot structure by forming thick fibers, diminishing fiber branching, and increasing pore filling space. These structural changes to clots explain the patients' bleeding phenotypes.
•The fibrinogen mutations Aα p.Ser382GlyfsTer50 and p.Ala353Ser account for decreased fibrinogen levels.•The FGA exon 5, p.Ser382GlyfsTer50 mutation predicts a truncated Aα chain that not affect the fibrinogen secretion.•The bleeding phenotype could be related to clot morphology such as thick fibers, increased fibrin density and net porosity.
Turbidity analysis is widely used as a quantitative technique in hereditary dysfibrinogenemia. We aimed to compare several coagulation triggers in hereditary dysfibrinogenemia and control plasmas. We ...included 20 patients with hereditary dysfibrinogenemia, 19 with hotspot mutations Aα Arg35His (n = 9), Aα Arg35Cys (n = 2), γ Arg301His (n = 6), γ Arg301Cys (n = 2), and one with Aα Phe27Tyr, and a commercial pooled normal plasma. Fibrin polymerization was activated by bovine or human thrombin or tissue factor (TF), in the presence or absence of tissue type plasminogen activator. The lag time (min), slope (mOD/s), maximum absorbance (MaxAbs, mOD), and area under the curve (AUCp, OD s) were calculated from the fibrin polymerization curves and the time for 50% clot degradation (T50, min), AUCf (OD s) and the overall fibrinolytic potential from fibrinolysis curves. The lag time was significantly shorter and AUC increased in Aα Arg35His patients with bovine thrombin as compared with human thrombin. The MaxAbs and AUCp were significantly higher in γArg301His patients with bovine thrombin compared with human thrombin. Fibrin polymerization parameters of patients' samples were closer to those of control when assessed with TF compared with both human and bovine thrombin. T50 and overall fibrinolytic potential were similar in all samples regardless of the coagulation trigger used, however, with TF the AUCf of Aα Arg35His and γ Arg301His groups were significantly decreased compared with control. Bovine and human thrombin cannot be used equally for studying fibrin polymerization in hotspot hereditary dysfibrinogenemia or control plasmas.
Women with hereditary fibrinogen disorders (HFDs) seem to be at an increased risk of adverse obstetrical outcomes, but epidemiologic data are limited.
We aimed to determine the prevalence of ...pregnancy complications; the modalities and management of delivery; and the postpartum events in women with hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia.
We conducted a retrospective and prospective multicentric international study.
A total of 425 pregnancies were investigated from 159 women (49, 95, and 15 cases of hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia, respectively). Overall, only 55 (12.9%) pregnancies resulted in an early miscarriage, 3 (0.7%) resulted in a late miscarriage, and 4 (0.9%) resulted in an intrauterine fetal death. The prevalence of live birth was similar among the types of HFDs (P = .31). Obstetrical complications were observed in 54 (17.3%) live birth pregnancies, including vaginal bleeding (14, 4.4%), retroplacental hematoma (13, 4.1%), and thrombosis (4, 1.3%). Most deliveries were spontaneous (218, 74.1%) with a vaginal noninstrumental delivery (195, 63.3%). A neuraxial anesthesia was performed in 116 (40.4%) pregnancies, whereas general or no anesthesia was performed in 71 (16.6%) and 129 (44.9%) pregnancies, respectively. A fibrinogen infusion was administered in 28 (8.9%) deliveries. Postpartum hemorrhages were observed in 62 (19.9%) pregnancies. Postpartum venous thrombotic events occurred in 5 (1.6%) pregnancies. Women with hypofibrinogenemia were at an increased risk of bleeding during the pregnancy (P = .04).
Compared with European epidemiologic data, we did not observe a greater frequency of miscarriage, while retroplacental hematoma, postpartum hemorrhage, and thrombosis were more frequent. Delivery was often performed without locoregional anesthesia. Our findings highlight the urgent need for guidance on the management of pregnancy in HFDs.
•There are no epidemiologic data on pregnancy in hereditary fibrinogen disorders (HFDs).•We report an international study of 425 pregnancies in women with hypofibrinogenemia and dysfibrinogenemia.•The prevalence of live birth was high, without differences among the types of HFD.•Retroplacental hematoma, postpartum hemorrhage, and thrombosis were frequent.
Abstract
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.
Essentials
A novel fibrinogen concentrate was evaluated in patients with congenital fibrinogen deficiency.
An open‐label, phase 2–3 trial studied pharmacology, efficacy, and safety in patients ...>6 years.
The product offers safe and effective therapy in the treatment and prophylaxis of bleeding.
Data in recovery show the need of adjusted treatment and further investigation in children.
Summary
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®/CLOTTAFACT® 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®/CLOTTAFACT® showed a pharmacokinetic profile comparable to that of other fibrinogen concentrates and provides safe and clinically effective substitution therapy for fibrinogen‐deficient patients.
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.
Process-of-care studies participate in improving the efficiency of the care pathway for patient with haemophilia (CPPH) and rationalize the multidisciplinary management of patients. Our objective is ...to establish a current overview of the different actors involved in the management of patients with haemophilia and to provide an accurate description of the patient trajectory. This is a qualitative exploratory research based on interviews of the principal health professionals of four haemophilia services, between November 2019 and February 2020, in France. Mapping of the CPPH processes within the different institutions and/or services, as well as the rupture zones, were identified. Treatment delivery and biological analyses were carried out exclusively in healthcare institutions. The main liberal health professionals solicited were nurses, physiotherapists and general practitioner. Obstacles and barriers within the specialized service, with other hospital services and external hospital or private services, community health care providers et community environment and individual one was complex and multiples. Our research identified potential concerns that need to be addressed to improve future studies to identify influential elements. Similarly, other qualitative studies will have to be conducted on the perceptions and literacy of patients with haemophilia to develop a global interactive mapping of their trajectories.
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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