Living with an ultra-rare inherited bleeding disorder is challenging. Patients can feel alone and unsure of where to find support because their disorder is so rare. In this paper, a group of ...ultra-rare bleeding disorder experts, including doctors, researchers, regulators, patient advocates, and patients, identify the research that could best improve the lives of people with these disorders. They propose a national network of specialists who can help doctors, who may never have seen these disorders before, to find the right diagnosis faster. A centralized laboratory specialized in ultra-rare bleeding disorders could also improve diagnosis and do research studies. This would help us learn, for example, how symptoms change throughout a patient's life, how effective different treatments are, and what it is like for patients to live with these disorders. A second research priority is to better understand each individual disorder so that the best treatments can be chosen or developed. A pathway showing doctors which treatment options to try, in which order, would help them help their patients. The third research priority is to make it easier to study new treatments for ultra-rare bleeding disorders. This requires designing studies with very small numbers of participants, identifying meaningful outcomes to measure, and convincing pharmaceutical companies to invest in these studies. International agreement on these requirements would allow more patients to participate and benefit from the research. These top-priority research goals should greatly improve knowledge about, and diagnosis and treatment of, ultra-rare inherited bleeding disorders.
Ultra-rare inherited bleeding disorders (BDs) present important challenges for generating a strong evidence foundation for optimal diagnosis and management. Without disorder-appropriate treatment, affected individuals potentially face life-threatening bleeding, delayed diagnosis, suboptimal management of invasive procedures, psychosocial distress, pain, and decreased quality-of-life.
The National Hemophilia Foundation (NHF) and the American Thrombosis and Hemostasis Network identified the priorities of people with inherited BDs and their caregivers, through extensive inclusive community consultations, to inform a blueprint for future decades of research. Multidisciplinary expert Working Group (WG) 3 distilled highly feasible transformative ultra-rare inherited BD research opportunities from the community-identified priorities.
WG3 identified three focus areas with the potential to advance the needs of all people with ultra-rare inherited BDs and scored the feasibility, impact, and risk of priority initiatives, including 13 in systems biology and mechanistic science; 2 in clinical research, data collection, and research infrastructure; and 5 in the regulatory process for novel therapeutics and required data collection.
Centralization and expansion of expertise and resources, flexible innovative research and regulatory approaches, and inclusion of all people with ultra-rare inherited BDs and their health care professionals will be essential to capitalize on the opportunities outlined herein.
Introduction
Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA‐approved recombinant activated human factor VII ...BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (≥12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date.
Aim
To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care.
Methods
Using a randomized crossover design, 27 subjects in PERSEPT 1 (12‐54 years) and 25 subjects in PERSEPT 2 (1‐11 years) treated bleeding episodes with 75 or 225 μg/kg EB initially followed by 75 μg/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2‐56 years) received an initial preoperative infusion of 75 μg/kg (minor procedures) or 200 μg/kg EB (major surgeries) with subsequent 75 μg/kg doses administered intraoperatively and post‐operatively as indicated. Descriptive statistics were used for data analyses.
Results
Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti‐EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee.
Conclusion
Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use.
Men with hemophilia were initially thought to be protected from cardiovascular disease (CVD), but it is now clear that atherothrombotic events occur. The primary objective of the CVD in Hemophilia ...study was to determine the prevalence of CVD and CVD risk factors in US older men with moderate and severe hemophilia and to compare findings with those reported in age-comparable men in the Atherosclerosis Risk in Communities (ARIC) cohort. We hypothesized if lower factor levels are protective from CVD, we would see a difference in CVD rates between more severely affected and unaffected men. Beginning in October 2012, 200 patients with moderate or severe hemophilia A or B (factor VIII or IX level ≤ 5%), aged 54 to 73 years, were enrolled at 19 US hemophilia treatment centers. Data were collected from patient interview and medical records. A fasting blood sample and electrocardiogram (ECG) were obtained and assayed and read centrally. CVD was defined as any angina, any myocardial infarction by ECG or physician diagnosis, any self-reported nonhemorrhagic stroke or transient ischemic attack verified by physicians, or any history of coronary bypass graft surgery or coronary artery angioplasty. CVD risk factors were common in the population. Compared with men of similar age in the ARIC cohort, patients with hemophilia had significantly less CVD (15% vs 25.8%; P < .001). However, on an individual patient level, CVD events occur and efforts to prevent cardiovascular events are warranted. Few men were receiving secondary prophylaxis with low-dose aspirin, despite published opinion that it can be used safely in this patient population.
•CV risk factors are common in older men with hemophilia.•Although older men with hemophilia have less CV disease than comparable unaffected men, CV events do occur and require treatment.
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•Pooled longitudinal efficacy and safety data for rFIXFc demonstrates sustained benefits in hemophilia B.•All evaluable target joints resolved during treatment, and no recurrence was reported in most ...(90%) baseline target joints during follow-up.
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Long-term efficacy and safety of the extended half-life recombinant factor IX Fc fusion protein (rFIXFc) has been established among previously treated patients with severe hemophilia B in 2 phase 3 trials (B-LONG #NCT01027364 and Kids B-LONG #NCT01440946) and a long-term extension study (B-YOND #NCT01425723). In this study, we report post hoc analyses of pooled longitudinal data for up to 6.5 years for rFIXFc prophylaxis. In the B-LONG study, subjects ≥12 years received weekly dose-adjusted prophylaxis (WP; starting dose, 50 IU/kg), individualized interval-adjusted prophylaxis (IP; initially, 100 IU/kg every 10 days), or on-demand dosing. In the Kids B-LONG study, subjects <12 years received 50 to 60 IU/kg every 7 days, adjusted as needed. In the B-YOND study, subjects received WP (20-100 IU/kg every 7 days), IP (100 IU/kg every 8-16 days), modified prophylaxis, or on-demand dosing; switching between treatment groups was permitted. A total of 123 subjects from B-LONG and 30 from Kids B-LONG study were included, of whom 93 and 27, respectively, enrolled in the B-YOND study. The median cumulative duration of treatment was 3.63 years (range, 0.003-6.48 years) in B-LONG/B-YOND and 2.88 years (range, 0.30-4.80 years) in Kids B-LONG/B-YOND group. Annualized bleed rates (ABRs) remained low, annualized factor consumption remained stable, and adherence remained high throughout treatment. Low ABRs were also maintained in subjects with dosing intervals ≥14 days or with target joints at baseline. Complete resolution of evaluable target joints and no recurrence in 90.2% of baseline target joints during follow-up were observed. rFIXFc prophylaxis was associated with sustained clinical benefits, including long-term bleed prevention and target joint resolution, for severe hemophilia B.
Introduction
Haemophilia B (HB) is less well studied than haemophilia A (HA); despite similarities between the two inherited bleeding disorders, important differences remain that require further ...research.
Aim
B‐Natural is a multi‐centre, prospective, observational study of HB, designed to increase understanding of clinical manifestations, treatment, quality‐of‐life (QoL), inhibitor development, immune tolerance induction (ITI) outcome, renal function and create a biorepository for future investigations.
Methods
Participants include sibling pairs/groups without a current/history of inhibitors and singletons or siblings with a current/history of inhibitors followed for six months. Demographics, medical, social history and treatment were recorded. A physical examination including joint range of motion (ROM) was performed; QoL was assessed. Samples were collected for F9 gene mutation, HLA typing, non‐inhibitory antibodies and renal function testing.
Results
Twenty‐four centres enrolled 224 individuals from 107 families including 29 with current/history of inhibitors. Of these, 68, 30.4%, had severe (<1% FIX level of normal); 114, 50.9%, moderate (1%‐5%); and 42, 18.8%, mild (>5‐<40%) disease. At enrolment, 53.1% had 50 + exposure days to exogenous FIX. Comparison of joint scores showed significant (P < .05) differences between those with severe (with/without inhibitors), and those with moderate/mild disease. The majority with severe disease, 80.0% with current/history of inhibitors and 64.3% of those without, were treated with prophylaxis.
Conclusion
B‐Natural provides data supporting an increased understanding of HB and its impact throughout life. The need for optimal disease control to normalize physical and psychosocial outcomes is underscored, and further analyses will contribute to an increased understanding of critical issues in HB.
Prophylactic factor replacement therapy is recommended over on-demand treatment for preserving long-term joint health in hemophilia. Extended half-life products, including efmoroctocog ...alfa/eftrenonacog alfa (recombinant factor VIII FVIII/FIX Fc fusion proteins; herein rFVIIIFc/rFIXFc), have the potential to reduce treatment burden with less frequent administration and improve bleed prevention.
We report post hoc data from patients with hemophilia A or B (HA/HB) who switched from prestudy on-demand FVIII/FIX to rFVIIIFc/rFIXFc prophylaxis at the start of A-LONG/B-LONG or start of/during ASPIRE/B-YOND phase 3 studies.
Patients with ≥6 months rFVIIIFc/rFIXFc prophylaxis were enrolled. Treatment exposure, dosing, annualized bleeding rates, joint health, and health-related quality of life (HRQoL) outcomes were assessed. Results were also stratified by age.
Sixty-seven patients with HA and 50 with HB were analyzed; ≥60% were from regions outside Europe/North America, predominately those aged 12 to 25 years. No subjects returned to on-demand treatment postswitch.
After switch to rFVIIIFc/rFIXFc prophylaxis, median annualized bleeding rates were reduced and sustained at low levels with stable factor usage across age groups (median treatment duration: 4.8/3.6 years). HRQoL outcomes improved for all ages; most pronounced changes were in the sports and leisure and physical health domains. After switch to rFVIIIFc prophylaxis, total modified Hemophilia Joint Health Score and joints with pain decreased in 64.6% and 29.2% of patients with HA. Insufficient data from patients with HB limited joint health evaluation of rFIXFc.
Findings add to existing evidence and demonstrate the clinical and HRQoL benefits of switching patients from on-demand treatment to rFVIIIFc/rFIXFc prophylaxis.
•Prophylactic factor replacement is recommended to preserve long-term joint health in hemophilia.•One hundred seventeen patients switched from on-demand therapy to extended half-life factor VIII/IX prophylaxis.•Postswitch, bleed protection, and health-related quality of life improved across all ages.•Joint health outcomes improved in patients with hemophilia A, with limited data for hemophilia B.
The development of antibodies (inhibitors) to clotting factors compromises the management of hemophilia A and B, resulting in resistance to clotting factor replacement and, in many cases, the need ...for bypassing agents to achieve hemostasis.
To evaluate the association between the presence of inhibitors and achievement of perioperative hemostasis, development of complications, and presurgical plan deviations.
We conducted a retrospective study using data from the Indiana Hemophilia and Thrombosis Center surgical database (1998-2019). Associations between perioperative outcomes and inhibitor status were assessed while controlling for patient and procedural characteristics.
A total of 1492 surgeries were performed in 539 persons with hemophilia, with 72 procedures performed in 20 patients with inhibitors (15 with hemophilia A; 5 with hemophilia B). High-responding inhibitors (>5 BU/mL) were present in 27 procedures, low-responding inhibitors (≤5 BU/mL) were present in in 13 procedures, and 32 procedures were performed in patients with historically persistent inhibitors. Adjusting for age, diagnosis, surgery setting, hemostatic agent, data collection period, and surgery type (major/minor), inhibitors were associated with a higher risk of inadequate perioperative hemostasis (33.4% vs 8.6%; adjusted relative risk adjRR, 3.78; 95% CI, 1.89-7.56; P < .001). Reported complications include hemorrhage, fever, pain, thrombosis, and infections. Complications were not statistically different based on inhibitor status (31.7% vs 14.6%; adjRR, 1.25; 95% CI, 0.63-2.49; P = .526). Presurgical plan deviations (eg, hemostatic medication dose adjustments, procedure rescheduling, and changes in the length of postoperative hospitalization) occurred more frequently in surgeries involving inhibitors (70.8 vs 39.5%; adjRR, 1.47; 95% CI, 1.12-1.93; P = .005).
Inhibitors are associated with higher risks of adverse perioperative outcomes. Strategies to address inhibitor development should be prioritized to avoid undesirable perioperative outcomes.
•The impact of inhibitors on surgical outcomes in hemophilia A and B is yet to be fully explored.•We assessed 1492 surgeries for hemostasis control, complications, and surgical plan deviations.•Inhibitors were associated with reduced bleeding control and increase in surgery plan changes.•Complications were not significantly different based on the presence or absence of inhibitors.
Introduction
Deficiencies of plasminogen and plasminogen activator inhibitor type 1 (PAI‐1) are rare disorders of fibrinolysis. Current laboratory assays for analysis of activity of plasminogen and ...PAI‐1 do not provide an accurate correlation with clinical phenotype.
Methods
The Nijmegen Hemostasis Assay (NHA) was used to simultaneously measure thrombin and plasmin generation in 5 patients with plasminogen deficiency (PLGD) and 10 patients with complete PAI‐1 deficiency. Parameters analysed included: lag time ratio, thrombin peak time ratio, thrombin peak height, thrombin potential (AUC), fibrin lysis time, plasmin peak height and plasmin potential. Parameters were expressed as a percentage compared to a reference value of 53 healthy normal controls.
Results
Patients with PLGD demonstrated a short lag time and thrombin peak time, with normal thrombin peak height but an increased AUC. Plasmin generation was able to be detected in only one (23% plasminogen activity) of the five PLGD patients. All ten PAI‐1 deficient patients demonstrated a short lag and thrombin peak time, low thrombin peak height with normal AUC. Plasmin generation revealed an increased plasmin peak and plasmin potential; interestingly, there was a large variation between individual patients despite all patients having the same homozygous defect.
Conclusion
Patients with either PLGD or PAI‐1 deficiency show distinct abnormalities in plasmin and thrombin generation in the NHA. The differences observed in the propagation phase of thrombin generation may be explained by plasmin generation. These results suggest that disorders of fibrinolysis also influence coagulation and a global assay measuring both activities may better correlate with clinical outcome.
Removal of blood-based additives from recombinant clotting factor concentrates continues to be advocated by the hemophilia community due to the history of infectious disease transmission with ...previous blood-derived clotting factor concentrates. In 2003, octocog-alpha, antihemophilic factor (recombinant), plasma/albumin-free method (ADVATE) was introduced, providing the first third-generation recombinant factor VIII (rFVIII) concentrate. Completed clinical trials have demonstrated ADVATE to be safe and effective in adult and pediatric subjects utilizing both prophylactic and on-demand treatment regimens, and for perioperative hemostatic coverage. In the five completed studies involving more than 200 previously treated patients (PTPs), a single incidence of low-titer, non-persistent inhibitor was reported. Active post authorization safety surveillance (PASS) is being performed to expand the efficacy and safety profile of ADVATE in routine clinical practice. Laboratory studies have documented the storage and post-reconstitution stability of ADVATE, conferring the desired versatility for home treatment. The evolving real-world experience and ongoing studies will provide further insight into ADVATE pharmacokinetics, alternative prophylactic dosing regimens, methods for perioperative hemostatic management, and utility in immune tolerance induction. Experience with ADVATE, and its place in today's treatment paradigm, is the focus of this article.
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