Summary
In haemophilia patients, a relationship is usually observed between the clinical expression of the disease and plasmatic factor VIII/factor IX (FVIII/FIX) activity. However, it is known from ...clinical experience, that some haemophilia patients, despite similar FVIII/FIX plasma levels, could exhibit different bleeding phenotype. After determining preanalytical test conditions, we evaluated the thrombin generation capacity from haemophilia plasma samples in various conditions and the potential usefulness of thrombin generation test (TGT) in haemophilia patients. In a series of 46 haemophilia patients (34 haemophilia A and 12 haemophilia B patients), we found a significant correlation between plasmatic FVIII/FIX levels and endogenous thrombin potential (ETP), peak and time to peak obtained by thrombin generation measurement. In addition, a correlation was found between severe clinical bleeding phenotype and ETP. Our results suggest that TGT could be a promising tool to evaluate haemostasis capacity in patients with haemophilia. Our
ex vivo
results, obtained 24 hours after FVIII concentrate administration, showed that in patients presenting similar plasmatic FVIIII levels, thrombin generation capacity may be significantly different. These results suggest that in patients with haemophilia, TGT could be useful for individually tailoring prophylactic regimens as well as for adapting clotting factors infusions in surgical situations, in addition to FVIII/FIX plasma clotting activities.
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.
Clinical response to bypassing agents (BPAs) may vary between patients. Surgery is a particular situation, requiring effective hemostasis during the procedure and for several days postoperatively to ...obtain satisfactory wound healing. However, the optimal dose of BPA in different surgical situations has not been clearly established. We report here a prospective assessment of thrombin generation test (TGT) in monitoring the effectiveness of BPA during 10 elective invasive procedures performed in 6 patients with severe hemophilia and high-titer inhibitors. A standardized 3-step protocol was used in all cases to individually tailor BPA. Thrombin-generating capacity of patients increased after in vitro and ex vivo addition of BPA in a dose-dependent manner. Our results also showed a correlation between in vivo clinical response to BPA and thrombin-generating capacity. These data suggest that TGT may represent a surrogate marker for monitoring bypassing therapies in surgical situations.
Patients with schizophrenia (SZ) often display social cognition disorders, including Theory of Mind (ToM) impairments and communication disruptions. Thought language disorders appear to be primarily ...a disruption of pragmatics, SZ can also experience difficulties at other linguistic levels including the prosodic one. Here, using an interactive paradigm, we showed that SZ individuals did not use prosodic phrasing to encode the contrastive status of discourse referents in French. We used a semi-spontaneous task to elicit noun-adjective pairs in which the noun in the second noun-adjective fragment was identical to the noun in the first fragment (e.g., BONBONS marron "brown candies" vs. BONBONS violets "purple candies") or could contrast with it (e.g., BOUGIES violettes "purple candles" vs. BONBONS violets "purple candies"). We found that healthy controls parsed the target noun in the second noun-adjective fragment separately from the color adjective, to warn their interlocutor that this noun constituted a contrastive entity (e.g., BOUGIES violettes followed by BONBONS violets) compared to when it referred to the same object as in the first fragment (e.g., BONBONS marron followed by BONBONS violets). On the contrary, SZ individuals did not use prosodic phrasing to encode contrastive status of target nouns. In addition, SZ's difficulties to use prosody of contrast were correlated to their score in a classical ToM task (i.e., the hinting task). Taken together, our data provide evidence that SZ patients exhibit difficulties to prosodically encode discourse statuses and sketch a potential relationship between ToM and the use of linguistic prosody.
Aim
For patients with severe haemophilia A, guidelines recommend prophylactic treatment with FVIII, with dose calculations targeting a predetermined FVIII trough level. However, this pharmacokinetic ...(PK) approach is suboptimal, with some patients experiencing breakthrough bleeds. We aimed to improve FVIII dosing by incorporating the thrombin generation assay, a global haemostasis assay whose main pharmacodynamic (PD) parameter, endogenous thrombin potential (ETP), predicts spontaneous bleeding risk.
Methods
We performed post hoc combined PK‐PD modelling using data from 66 adults who received human‐cl rhFVIII (Nuwiq®, Octapharma AG) in a phase IIIb study. Time‐to‐event analyses simulated the probability of spontaneous bleeding for different FVIII exposures and baseline ETPs.
Results
Ninety‐one spontaneous bleeds occurred in 20/66 patients. The relationship between FVIII:C and ETP was non‐linear, and the sigmoid Emax model adequately described the data. Individual PK‐PD Bayesian estimation significantly improved predictive performance. Simulations showed that the mean spontaneous annual bleeding rate decreased with increasing baseline ETP or dosing: with ETP values of 200, 400 and 600 (nmol/L)·min annual bleeding rates were 2.36, 1.25 and 0.66, respectively, on 40 IU/kg human‐cl rhFVIII every 3 days; and annual bleeding rates were 2.09, 1.10, and 0.60, respectively, on 60 IU/kg every 3 days.
Conclusion
Prophylactic FVIII dosing is more clinically meaningful when incorporating ETP alongside FVIII level. For the first time, FVIII dosing can be personalized with the aim of eliminating spontaneous breakthrough bleeds.
Haemophilic arthropathy (HArt) is a serious complication in patients with hemophilia. Early diagnosis and treatment are essential to minimise the development of HArt. The use of biomarkers may ...improve early diagnosis of HArt. Circulating microRNAs (miRNAs) are small, non-coding RNAsthat regulate gene expression, and are being investigated as promising biomarkers due to their role in joint and bone metabolism.
To investigate differential expression of miRNAs and their relationship to arthropathy in patients with hemophilia A.
miRNA expression was examined in a pilot study followed by a validation study (100 hemophilia A patients with n = 83 and without HArt n = 17, 14 controls). Differential miRNA expression was investigated using real-time quantitative PCR.
The pilot study identified 2 miRNAs differentially expressed in patients with Hart (Pettersson score ≥ 1), after adjusting for the false discovery rate (FDR). The validation study evaluated these 2 miRNAs. The results demonstrated that two miRNAs (miR- 208a-3p and 524-3p) were significantly underexpressed in plasma of patients with HArt compared to patients without arthropathy, with FDR <0.05 (Fig. 1). In addition, 3 miRNAs (130a-3p, miR- and 506-3p) were significantly underexpressed in patients with moderate HArt (Pettersson score 4 to 7).
In this proof of concept study we identified a signature of 5 circulating miRNAs associated with Hart with potential as diagnosis tools for HArt. These miRNAs are potential negative regulators of gene expression, suggesting their activity in HArt by interfering with osteoblastic (miR- 208a-3p) and osteoclastic (miR-506-3p) differentiation to impair bone mineralization and remodeling processes, or regulating chondrogenesis (miR-335-5p). miRNAs associated with earlier stages of HArt will be further investigated in a sub-study of the prospective clinical trial PROVE, which will investigate the effects of long-term prophylaxis with simoctocog alfa versus emicizumab in adults with hemophilia A.
•Early diagnosis of hemophilic arthropathy is key to reduce joint damage.•Diagnosis of arthropathy currently relies on joint examination and imaging modalities.•No biomarker has been validated for routine arthropathy screening.•We identified 2 circulating miRNAs associated with hemophilic arthropathy, as diagnostic or prognostic tool for this condition.
Gene therapy for hemophilia is a groundbreaking treatment approach with promising results and potential to reduce the burden of the disease. However, uncertainties remain, particularly regarding the ...liver side effects of AAV gene therapy, which are more common in hemophilia A.
Unlike some other diseases, such as spinal muscular atrophy, where the target cell for gene therapy is different from the one affected by side effects, hemophilia gene therapy operates within the same cellular domain-the hepatocyte. This overlap is challenging and requires a targeted strategy to mitigate the risks associated with liver injury, which often requires temporary immunosuppressive therapy. A comprehensive approach is essential to increase the efficacy of gene therapy and reduce the likelihood of hepatocyte damage. Key components of this strategy include a thorough pre-gene therapy assessment of liver health, careful post-gene therapy liver monitoring, and prompt therapeutic intervention for loss of transgene expression and liver injury. Collaboration between hematologists and hepatologists is essential to ensure a well-coordinated management plan for patients undergoing hemophilia gene therapy.
This review addresses the critical aspect of hepatic comorbidities in patients with hemophilia, emphasizing the need to identify and address these issues prior to initiating gene therapy. It examines the known mechanisms of liver damage and emphasizes the importance of liver monitoring after gene therapy. In addition, the review draws insights from experiences with other AAV-based gene therapies, providing valuable lessons that can guide hemophilia centers in effectively managing liver damage associated with hemophilia gene therapy.
•Patients with hemophilia candidates for gene therapy, require a specific liver health assessment•Proactive MAFLD screening protocols are essential before hemophilia gene therapy•The etiology of AAV-associated transaminitis remains unclear, both innate and acquired immune responses suggested as potential contributors•Patients with hemophilia have an increased risk of developing hepatocellular carcinoma However, the impact of AAV gene therapy on the development of hepatocellular carcinoma remains uncertain.
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