Haemophilia最新文献

Introduction: Patients with Haemophilia A treated with Mim8 may require concomitant Factor VIII (FVIII) replacement; hence, accurate assessment of FVIII activity (FVIII:C) and FVIII inhibitors in the presence of Mim8 is important.

Aim: Assess which chromogenic substrate assays (CSAs) accurately monitor FVIII:C and FVIII inhibitor levels in the presence of Mim8.

Methods: FVIII and Mim8 were spiked into congenital FVIII-deficient plasma to obtain mixtures containing various FVIII:C levels (0-100 IU/dL) and Mim8 concentrations (0, 3, 6 and 12 µg/mL). Five CSAs using different activated Factor IX and X sources (bovine, bovine-human or human) were used to measure FVIII:C. Bovine and bovine-human CSAs were then used to measure FVIII:C of standard half-life (SHL) and extended half-life (EHL) FVIII products. FVIII inhibitor levels were assessed using two different bovine CSAs in congenital FVIII-deficient plasma spiked with various Mim8 concentrations (5, 10, 20 and 40 µg/mL) and FVIII inhibitor levels (0.2, 1.0 and 4.8 BU).

Results: High levels of interference were observed using human CSAs. Bovine CSAs accurately measured FVIII:C of SHL and EHL FVIII products in the presence of Mim8 without interference. In bovine-human CSAs, interference was observed at 5 IU/dL FVIII, increasing up to four-fold with increasing Mim8 levels. FVIII inhibitor levels were accurately measured using bovine CSAs without Mim8 interference.

Conclusion: FVIII:C of SHL and EHL products and FVIII inhibitor levels can be accurately monitored in the presence of Mim8 using bovine CSAs at all FVIII levels, and bovine-human CSAs at FVIII concentrations >20 IU/dL.

Background: Prophylaxis with coagulation factor concentrates is the mainstay of treatment in severe hemophilia A and B. Data on bleeding rates in persons with congenital haemophilia B (PwcHB) receiving prophylaxis are inconsistent.

Aim: This systematic review and meta-analysis were aimed at assessing bleeding outcomes, including annualised bleeding rates (ABR) and the proportion of patients with zero bleeding events, in PwcHB receiving prophylaxis with plasma-derived or recombinant FIX products with standard (rSHL) or extended half-life (rEHL).

Methods: A systematic search was conducted using the bibliographic database Medline, Embase and Cochrane Central Register. The protocol was registered on PROSPERO (registration number: CRD42024592785).

Results: The search yielded 2440 citations and a total of 42 studies (2 randomised and 40 nonrandomised) were included in the final analysis. The pooled estimated mean (95% confidence interval [CI]) ABR was significantly lower in PwcHB treated prophylactically with rEHL FIX than in those receiving rSHL FIX products (1.29 [95% CI: 0.91, 1.66] vs. 3.12 [95% CI: 2.63, 3.62], p < 0.01). The proportion of participants with zero bleeding events was significantly higher in PwcHB treated prophylactically with rEHL FIX than in those receiving rSHL FIX (0.53 [95% CI: 0.37, 0.69] vs. 0.24 [95% CI: 0.14, 0.39], p = 0.01). The ABR did not differ according to age groups (more or less than 12 years).

Conclusion: The results of this meta-analysis suggest that compared to standard half-life FIX concentrates, prophylaxis with rEHL FIX products is associated with a reduction in ABR and a higher proportion of patients with no bleeding episodes.

Introduction: Early prophylaxis is the gold standard of care for severe haemophilia. The development of subcutaneous Factor VIII (FVIII) mimetics, such as emicizumab, has significantly reduced the disease burden and improved protection against bleeding episodes. Despite its benefits, emicizumab does not fully normalize haemostasis, requiring additional FVIII treatment for surgical procedures and management of breakthrough bleeding. In these cases, extended or ultra-extended half-life FVIII products are most commonly used. However, laboratory monitoring of these combinations can be challenging.

Aim: This study investigates the in vitro combined haemostatic activity of emicizumab with efmoroctocog alfa and efanesoctocog alfa using a thrombin generation assay (TGA).

Results and conclusion: TGA can be used to monitor combined treatment with emicizumab and either efmoroctocog alfa or efanesoctocog alfa, which is not possible with currently available FVIII reagents for the latter. As expected, there is no synergistic effect between the mimetic and FVIII at therapeutical doses. Both efmoroctocog alfa and efanesoctocog alfa show similar in vitro procoagulant activity in terms of thrombin generation.

Background: Von Willebrand disease (VWD) is an inherited bleeding disorder caused by deficient or dysfunctional von Willebrand factor (VWF). VWF replacement therapy is indicated in VWD management.

Methods: This systematic review was conducted to evaluate all available evidence of the efficacy, safety, dosing and consumption of pasteurized plasma-derived human coagulation FVIII/human VWF (pdVWF/FVIII; Haemate P/Humate-P) concentrate for on-demand (OD) treatment, surgical prophylaxis and long-term prophylaxis of patients with VWD. A systematic search was performed in MEDLINE and Cochrane Library databases to identify studies (7 June 1982-31 May 2023) reporting the use of pdVWF/FVIII in VWD according to predefined selection criteria. Pharmacovigilance data were also retrieved for the same period.

Results: Fifteen studies were identified, 12 being observational and three interventional. Efficacy and safety assessments and treatment protocols varied across the studies which hindered direct comparisons. Haemostatic efficacy of pdVWF/FVIII was rated excellent/good for OD treatment in 95%-98% of bleeds and in 94%-100% of surgeries. In two separate studies, prophylactic efficacy was rated excellent/good in 100% of treatment cycles. Where reported, median annualized bleeding rates decreased from 3-24 prior prophylaxis to 0.5-6 during prophylaxis. Analysis of pharmacovigilance safety reports showed that pdVWF/FVIII was associated with a low rate of adverse events.

Conclusions: This systematic literature review and analysis of pharmacovigilance data summarize evidence of over 40 years of clinical use of pdVWF/FVIII, supporting its safety and efficacy in VWD.

Background: Haemophilic ankle arthropathy is characterized by chronic pain, loss of strength and proprioception, decreased range of motion (ROM) and impaired functionality.

Objective: To evaluate the safety and efficacy of a manual therapy protocol based on joint and myofascial techniques in patients with haemophilic ankle arthropathy.

Methods: A randomized, single-blind pilot study. Twenty-four patients with haemophilia were randomized to the experimental (manual therapy) and control (no intervention) groups. The intervention lasted for 3 weeks, with one 50-min weekly session. Techniques used: active-passive joint mobilization, articulatory technique, joint decompression and high-speed and short-stroke manipulation, and sustained myofascial induction techniques. The study variables were safety of the intervention (number of hemarthroses), joint pain intensity (visual analogue scale), pressure pain threshold (pressure algometer), range of ankle motion (Leg Motion) and joint condition (Haemophilia Joint Health Score).

Results: None of the patients developed ankle hemarthrosis during the intervention. After the intervention there were intergroup differences in the variables pain intensity (MD = -0.45; p < 0.001), ROM (MD = 0.19; p = 0.003), joint condition (MD = 0.04; p = 0.03) and pressure pain threshold in the internal malleolus (MD = 1.36; p = 0.01). For the interaction time*group after the follow-up period, there were statistically significant differences in pain intensity (F = 6.94; p = 0.01) and dorsal flexion (F = 3.36; p = 0.04) of the ankle.

Conclusions: Manual therapy based on joint and myofascial techniques is safe in haemophilia patients. A protocol implementing joint and myofascial techniques having the dosage and safety parameters established in this study can improve the intensity of pain and dorsal flexion of the ankle in these patients.

Trial registration: ClinicalTrials.gov identifier: NCT05549843.

Introduction: Hemarthrosis, particularly in the knee, accounts for most bleeding episodes in haemophilia. While joint aspiration has proven effective, the role of intra-articular (IA) tranexamic acid (TXA) in managing acute hemarthrosis remains unexplored.

Aim: To assess the efficacy and safety of knee aspiration followed by IA TXA injection in acute haemophilic knee hemarthrosis.

Methods: Forty-four adult haemophilia patients with acute knee hemarthrosis (< 24 h) were randomized to undergo joint aspiration with (TXA group) or without (non-TXA group) IA TXA (1.5 g/15 mL) injection. Both groups received 75 mL injections, including 5 mL of 2% lidocaine and additional 0.9% saline. Ultrasound confirmed hemarthrosis, and standardized factor replacement was given pre-procedure. Primary outcomes included knee range of motion (ROM) and visual analogue scale (VAS) for pain. The significance was set at p < 0.05.

Results: Final analysis included 21 and 17 male patients in the TXA and non-TXA groups, respectively. The TXA group showed a significantly greater knee ROM on days 3, 7, and 14 (p < 0.05), with no differences beyond Day 14. VAS pain scores were significantly lower in the TXA group at 24 h, 3 days, and 7 days post-procedure (p < 0.05). TXA patients reported faster return to work (p = 0.004) and higher satisfaction (p = 0.01). Hemarthrosis recurrence was lower in the TXA group (5.9% vs. 14.3% at 6 weeks; 64.7% vs. 90.5% at 6 months), though differences were not statistically significant. No complications were observed.

Conclusion: Joint aspiration with IA TXA is safe and effective for short-term ROM improvement and pain relief in acute haemophilic knee hemarthrosis.

Introduction: Clinical trials and real-world evidence have demonstrated the efficacy and safety of rVIII-SingleChain in previously treated patients with haemophilia A.

Aim: To investigate the safety and efficacy of rVIII-SingleChain in previously untreated patients (PUPs).

Methods: In an open-label, phase 3, extension study, PUPs with severe haemophilia A (FVIII <1%) received rVIII-SingleChain prophylactically or on-demand. The primary endpoints were incidence of high-titre (HT) inhibitor formation to FVIII, treatment success for major bleeding episodes and annualised spontaneous bleeding rate (AsBR).

Results: Twenty-four PUPs (median age 1 year [range 0-5]) were treated with rVIII-SingleChain; median time on study was 35.0 months (range 2.4-54.0). Overall, six PUPs developed a HT inhibitor (>5 BU/mL) and six developed a low-titre (LT) inhibitor (≤5 BU/mL). The median number of exposure days at inhibitor development was 10 (interquartile range [IQR] 5.0-14.0). Of 11 inhibitor-positive PUPs (five HT, six LT) who continued rVIII-SingleChain therapy, nine (81.8%; three HT, six LT) achieved inhibitor eradication (<0.6 BU/mL). Median time to eradication was 14.3 weeks (IQR 9.8-53.8). Seventeen treatment-emergent adverse events in 12 PUPs (50.0%) were related to rVIII-SingleChain, mainly inhibitor development (14/17 events). Treatment was successful (haemostatic efficacy rated excellent or good) for 290/315 bleeding events (92.1%). During prophylactic therapy, inhibitor-negative PUPs had a median (IQR) AsBR of 0.52 (0.00-4.99) and annualised bleeding rate of 1.98 (0.77-11.23).

Conclusion: RVIII-SingleChain demonstrated a satisfactory benefit:risk profile in PUPs, with a high treatment success rate and a low AsBR during prophylaxis, and was effective at eradicating inhibitors.