Prophylactic therapy with exogenous clotting factor concentrates in haemophilia A and B aims to achieve levels of circulating FVIII or FIX that are adequate for the prevention or reduction of ...spontaneous joint bleeding. Historically, a minimum trough level of at least 1% of the normal levels of circulating clotting factor has been targeted using standardised protocols. However, clearance of clotting factor varies between products and patients, and other pharmacokinetic (PK) parameters such as the frequency and magnitude of peaks may be important for ensuring optimal coverage. Thus, it is increasingly recognised that an individualised, PK-based approach to prophylaxis is necessary to achieve optimal protection.
This review focuses on the clinical implications of using PK-guided, individualised prophylaxis in haemophilia to improve patient outcomes and considers practical methods of establishing patients’ PK parameters. The most useful PK parameters will depend on the aim of the specific treatment (e.g. preventing activity-related and traumatic bleeds or addressing subclinical bleeding). In clinical practice, lengthy and frequent post-infusion sampling for PK analysis is costly and a significant burden for patients. However, a Bayesian analysis allows for the estimation of different PK parameters (e.g. half-life, factor concentrations over time, etc.) with only a minimum number of samples (e.g. 4, 24 and 48 h for haemophilia A), by using the patient’s data to adjust a relevant population PK value towards the actual value. Numerous tools are available to aid in the practical use of Bayesian PK-guided dosing in the clinic, including the Web-based Application for the Population Pharmacokinetic Service hosted by McMaster University, Canada. The PK data can be used to determine the appropriate prophylaxis regimen for the individual patient, which can be monitored by assessment of the trough level at each clinic visit.
Collection of PK data and subsequent PK-guided dosing should become standard practice when determining treatment strategies for people with haemophilia.
Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX ...activity, thereby protecting against bleeding without burdensome factor IX replacement.
In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×10
genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed.
The annualized bleeding rate decreased from 4.19 (95% confidence interval CI, 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred.
Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile. (Funded by uniQure and CSL Behring; HOPE-B ClinicalTrials.gov number, NCT03569891.).
Acquired haemophilia A (AHA) is a rare and severe haemorrhagic autoimmune disease caused by autoantibodies directed against factor VIII (FVIII). Treatment is based on two principles, including ...haemostatic control to compensate FVIII inhibition and eradication of inhibiting antibodies using immunosuppressive therapy. Rapid recognition and proper management are essential to avoid excess morbidity and mortality. Effective and safe treatments can be challenging, given that AHA patients are often elderly, with multiple comorbidities. Emicizumab, a bispecific antibody that mimics the action of FVIII, has proven effective in managing patients with congenital haemophilia, with or without inhibitors. Likewise, its mode of action suggests theoretical efficacy in AHA patients. We herein describe two AHA cases with comorbidities that were treated effectively using emicizumab combined with immunosuppressive therapy. We have also reviewed the current literature regarding the promising use of emicizumab in this indication.
Platelet membrane glycoprotein VI (GPVI) is increasingly recognized as an important receptor for thrombus formation and growth. Numerous arguments have been published indicating that GPVI plays a ...major role in thrombosis without being essential for physiological hemostasis. In humans, GPVI deficiencies are rarely reported. These are most often deficiencies occurring in the context of autoimmunity and, more rarely, genetic deficits. The purpose of this review is to compile data on the quantitative and qualitative genetic abnormalities of GPVI.
Background
The D-dimer (DD) assay is an essential biological test for the diagnosis and monitoring of thrombotic conditions. DD testing is usually not performed as part of the routine laboratory ...management of patients with hemophilia (PWH). There is an increasing concern about the risk of thrombotic complications in PWH, which is likely related to age, cardiovascular risk factors, invasive thrombogenic procedures, over-correction of Factor VIII (FVIII) or FIX, or administration of new therapeutic agents mimicking FVIII or rebalancing coagulation.
Objective
This retrospective study sought to assess the basal DD levels in PWH treated prophylactically with FVIII, and to evaluate potential changes after switching to emicizumab.
Method
Patients over 18 years of age treated with emicizumab within a single center over the period 2017-2022 were included in the study.
Result
DD levels were measured in 40 adult PWH (37 severe/ three moderate / two with FVIII inhibitor) with a median age of 46 years (range: 19-82; Q1-Q3: 30,25-56,5), before and at least 3 months after emicizumab initiation. No significant changes were revealed, with DD median values of 257 ng/mL (range: 250-2876; Q1-Q3: 250-493,5) before and 250 ng/mL (range: 50-6205; Q1-Q3: 250-380,25) after the switch (p = 0.9).
Conclusion
Most adult PWH on prophylaxis using FVIII display DD levels within the normal range, which remain unchanged after switching to emicizumab. In view of these reassuring results, monitoring of DDs at the start of emicizumab treatment does not appear necessary but could be considered when combined with other bypassing agents or high dose FVIII.
Emicizumab, a bispecific antibody mimicking the action of factor VIII (FVIII), is currently the first and only approved and increasingly accessible disruptive treatment option for hemophilia A, a ...disease so far mainly treated with frequent intravenous infusions of FVIII concentrates or bypassing agents in case of inhibitor development. Other disruptive treatments are expected to follow, such as agents that rebalance coagulation and gene therapy with the ambition of curing hemophilia. While these treatment options represent major achievements or expectations, their adoption and implementation should consider their multiple direct and indirect, immediate or delayed, consequences on hemophilia care globally. It is these multiple changes, present and future, already visible or hypothetical, that this article intends to review and explore.
Regarding the severe forms of the disease in which thromboinflammation is prominent, both endothelial cells and platelets might be affected by autoimmune reactions in addition to direct viral ...infection and cytokine-mediated activation 3,4. ...multiple anti-phospholipid antibodies have been detected in the blood of hospitalized patients in relation with the severity of the disease and the formation of neutrophil extracellular traps known to contribute to thrombotic events 5. ...anti-annexin A2 autoantibodies found in critically ill patients were suggested to contribute to small vessel damage in the lungs 7. Besides endothelial cell damage, activation of platelets is the other cornerstone of the prothrombotic state characteristic of COVID-19 4. Anti-PF4 antibodies would then recapitulate the sequence of events responsible for heparin-induced thrombocytopenia. Besides anti-PF4 autoantibodies, anti-phospholipid antibodies could also contribute to platelet activation as well as antiviral antibodies as observed in other infections 42,43.
Abstract
Introduction
With the increasing complexity of haemophilia care and the advent of numerous therapeutic innovations, there is an unmet need for documentation and data collection tools ...tailored to people with haemophilia (PwH). To date, no fully integrated haemophilia‐specific electronic health record (EHR) has been described in the literature.
Aim
To evaluate the feasibility of integrating a haemophilia‐specific navigator into the Epic EHR.
Methods
Based on clinical experience and registry datasets, we identified key variables describing both PwH and carriers of haemophilia. These were then incorporated into a REDCap database, which served as a starting point for the development of a comprehensive haemophilia flowsheet. We built a dedicated haemophilia navigator within Epic that includes a flowsheet featuring up to 212 variables, as well as customised note templates and patient lists integrating data from the haemophilia flowsheet.
Results
It was feasible to develop a haemophilia navigator within Epic over the course of 12 months. The navigator's flowsheet enables systematic and comprehensive clinical assessment of PwH and carriers, while customised patient lists provide a quick summary of each patient's profile to the haemophilia treatment centre staff and highlight issues that require an intervention. In our clinical practice, patients actively participated in the new documentation process and responded positively to the navigator.
Conclusion
Adapting EHRs to the needs of PwH and carriers promotes holistic care for this population and provides an opportunity for patient empowerment. Such haemophilia‐specific EHRs are expected to promote standardisation of care and facilitate the collection of registry data on a national and international level.
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