This phase 3 pivotal study evaluated the safety, efficacy, and pharmacokinetics of a recombinant FVIII Fc fusion protein (rFVIIIFc) for prophylaxis, treatment of acute bleeding, and perioperative ...hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms: arm 1, individualized prophylaxis (25-65 IU/kg every 3-5 days, n = 118); arm 2, weekly prophylaxis (65 IU/kg, n = 24); and arm 3, episodic treatment (10-50 IU/kg, n = 23). A subgroup compared recombinant FVIII (rFVIII) and rFVIIIFc pharmacokinetics. End points included annualized bleeding rate (ABR), inhibitor development, and adverse events. The terminal half-life of rFVIIIFc (19.0 hours) was extended 1.5-fold vs rFVIII (12.4 hours; P < .001). Median ABRs observed in arms 1, 2, and 3 were 1.6, 3.6, and 33.6, respectively. In arm 1, the median weekly dose was 77.9 IU/kg; approximately 30% of subjects achieved a 5-day dosing interval (last 3 months on study). Across arms, 87.3% of bleeding episodes resolved with 1 injection. Adverse events were consistent with those expected in this population; no subjects developed inhibitors. rFVIIIFc was well-tolerated, had a prolonged half-life compared with rFVIII, and resulted in low ABRs when dosed prophylactically 1 to 2 times per week. This trial was registered at www.clinicaltrials.gov as #NCT01181128.
Key Points
dental extractions (DEs) in persons with hemophilia A or B (PWH-A or PWH-B) are often associated with bleeding and needing hemostatic therapies (HTs).
to analyze the American Thrombosis and ...Hemostasis Network (ATHN) dataset (ATHNdataset) to assess trends, uses and impacts of HT on bleeding outcomes following DEs.
PWH seen at ATHN affiliates who underwent DEs and opted to share their data with the ATHNdataset between 2013-2019 were identified. The type of DEs, use of HT and bleeding outcomes were assessed.
Among 19,048 PWH ≥2 years of age, 1157 underwent 1301 episodes of DE. Those on prophylaxis experienced a nonsignificant reduction in dental bleeding episodes. Standard half-life factor concentrates were used more often than extended half-life products. PWHA were more likely to undergo DE in the first 30 years of life. Those with severe hemophilia were less likely to undergo DE than those with a mild disease (OR: 0.83; 95% CI: 0.72-0.95). PWH with inhibitors had statistically significantly increased odds of dental bleeding (OR: 2.09, 95% CI; 1.21-3.63).
our study showed that persons with mild hemophilia and younger age were more likely to undergo DE; the presence of inhibitors increased the likelihood of bleeding, while those with prophylaxis and receiving HT experienced a non-statistically significant reduction in bleeding.
Data are needed on minimal factor activity (FA) levels required to prevent bleeding in hemophilia. We aimed to evaluate associations between hemophilia type and FA level and joint bleeding and ...orthopedic procedures using longitudinal data. Data were collected over an 11-year period on males with nonsevere hemophilia A or B without inhibitors who were receiving on-demand factor replacement therapy. Data on the number of joint bleeds in the previous 6 months and data on procedures from clinical records were analyzed using regression models. Data were collected on 4771 patients (hemophilia A, 3315; hemophilia B, 1456) from 19 979 clinic visits. Ages ranged from 2 to 91 years and baseline FA level ranged from 1% to 49% with a mean of 9.4%. Joint bleeding rates were heterogeneous across the FA range and were highest among men age 25 to 44 years. Adjusted for FA level, the mean number of joint bleeds per 6 months was 1.4 and 0.7 for patients with hemophilia A and B, respectively (P < .001). Regression models predicted 1.4 and 0.6 bleeds per year for hemophilia A and B patients, respectively, at an FA level of 15%. Patients with hemophilia B were 30% less likely than those with hemophilia A to have undergone an orthopedic procedure. We conclude that joint bleed rates for any given FA level were higher among hemophilia A than hemophilia B patients, and target FA levels of 15% are unlikely to prevent all joint bleeding in US males with hemophilia.
•Joint hemorrhages and orthopedic procedures are more frequent in patients with hemophilia A than in those with hemophilia B.•FA levels of 20% may be required to prevent all joint hemorrhages.
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Kids B-LONG was a multicentre, open-label, phase 3 study assessing the safety, efficacy, and pharmacokinetics of recombinant factor IX Fc fusion protein (rFIXFc) in previously treated paediatric ...patients younger than 12 years with severe haemophilia B.
The study enrolled 30 previously treated boys younger than 12 years with haemophilia B (≤2 IU/dL ≤2% endogenous coagulation factor IX FIX activity). All patients were initially given rFIXFc prophylaxis (50-60 IU/kg) once per week with adjustments to dose (≤100 IU/kg per infusion) or dosing frequency (up to two times per week) as needed. The primary outcome measure was development of inhibitors (neutralising antibodies). Secondary outcomes were pharmacokinetics, annual bleeding rate (ABR), spontaneous joint ABR, the number of infusions and dose required to resolve a bleed, time from last infusion of rFIXFc to a bleeding episode, assessment of response to treatment, and total annualised rFIXFc consumption for prevention and treatment of bleeding episodes. All patients underwent sequential pharmacokinetic evaluations of their prestudy FIX and rFIXFc. The completed trial is registered with ClinicalTrials.gov, number NCT01440946.
No patients developed inhibitors to rFIXFc; in the 30 enrolled patients the most common adverse events were nasopharyngitis (n=7; 23%) and fall (n=6; 20%); four patients (13%) had serious adverse events. Overall, rFIXFc exhibited a prolonged half-life of 68·6 h (95% CI 61·8-76·0), reduced clearance, and similar recovery compared with prestudy FIX. The median ABR was 2·0 (0·0-3·1) overall and 0·0 (0·0-0·0) for spontaneous joint bleeds; ten (33%) of 30 patients reported no bleeding, and 19 (63%) reported no joint bleeding on-study. The median average prophylactic dose of rFIXFc was 58·6 IU/kg (IQR 52·3-64·8) per week. Throughout the study, 29 (97%) of 30 patients remained on once per week infusions.
Weekly infusions of rFIXFc were well tolerated and resulted in low bleeding rates in children with severe haemophilia B.
Biogen, Sobi.
Women and girls may experience increased bleeding symptoms as carriers of haemophilia. They can also be affected by other hereditary bleeding diatheses such as von Willebrand disease, platelet ...dysfunction defects or deficiencies of coagulation factors (F) such as FI, FII, FV, FVII, FX, FXI and FXIII. In addition to general bleeding symptoms, such disorders pose unique problems for women due to their impact on reproductive health. Women and adolescent girls with undiagnosed bleeding disorders frequently experience heavy menstrual bleeding (HMB; menorrhagia), leading to impairment of daily activities. Other gynaecological and obstetric manifestations, for example miscarriage, bleeding during pregnancy and postpartum haemorrhage (PPH), can occur. Treatment for HMB should consider patient wishes relating to preservation of fertility, and management options include hormonal measures, desmopressin, antifibrinolytics, platelet concentrate transfusions and clotting factor therapy. During pregnancy, monitoring clotting factor levels informs the need for prophylactic therapy; subsequent haemostatic cover can minimise PPH. Under‐recognition of bleeding disorders in females may lead to inappropriate, or lack of, treatment. This may be avoided by increased disease awareness, prompt and accurate diagnosis, and a multidisciplinary approach to patient care. This review considers the range of hereditary bleeding disorders that may affect women and adolescent girls, and their evaluation and management.
Objective The purpose of this study was to determine the usefulness of a simple screening tool for bleeding disorders in a multisite population of women with menorrhagia. Study Design Women with ...menorrhagia between the ages of 18 and 50 years from 6 geographically diverse US centers underwent hemostatic testing for bleeding disorders, complete blood cell count, and ferritin. A questionnaire that contained all elements of the 8-question screening tool was administered. Sensitivity of the screening tool, a screening tool with a pictorial blood assessment chart (PBAC) score of >185, and a screening tool with serum ferritin were calculated for hemostatic disorders. Results Two hundred and seventeen women who were identified with a PBAC score of ≥100 participated in the study. The sensitivity of the screening tool was 89% for hemostatic defects, and sensitivity increased to 93% and 95% with a serum ferritin level of ≤20 ng/mL and a PBAC score of >185, respectively. Conclusion This study confirms the usefulness of a short screening tool for the stratification of women with menorrhagia for hemostatic evaluation.
Abstract Physicians periodically encounter patients with an extraordinarily accelerated course of hypercoagulability who develop thromboses in multiple organ systems over days to weeks. Such patients ...may harbor underlying hypercoagulable clinical conditions, but their clinical course sets them apart from most patients with similar risk factors. Underlying triggers of “thrombotic storm” include pregnancy, inflammation, trauma, surgery, and infection. Aggressive anticoagulant therapy may control thrombotic storm, yet thrombotic storm may resume with even brief interruptions of anticoagulant therapy. The authors of this communication formed the Thrombotic Storm Study Group in order to identify clinical characteristics of such patients, thus constructing preliminary criteria to better define, identify, and study the course of patients deemed to have thrombotic storm. The characteristics culled from these 10 patients are: younger age (oldest was 38 years old at time of presentation); at least 2 arterial or venous (or both) thromboembolic events, typically in unusual sites with or without microangiopathy; unexplained recurrence; and frequently proceeded by a trigger. The following characteristics were not used in defining thrombotic storm: underlying malignancies; use of acute myocardial infarction as a defining arterial event in the setting of established coronary artery disease; use of cocaine; thrombotic complications expected with various intravascular devices; known paroxysmal nocturnal hemoglobinuria or myeloproliferative disorders; severe trauma; and premorbid conditions.
As a result of immunological and nucleic-acid screening of plasma donations for transfusion-transmissible viruses, and the incorporation of viral reduction processes during plasma fractionation, ...coagulation-factor concentrates (CFC) are now judged safe in terms of many known infectious agents, including hepatitis B and C viruses, HIV, and human T-cell lymphotropic virus. However, emerging pathogens could pose future threats, particularly those with blood-borne stages that are resistant to viral-inactivation steps in the manufacturing process, such as non-lipid-coated viruses. As outlined in this Review, better understanding of infectious diseases allows challenges from newly described agents of potential concern in the future to be anticipated, but the processes of zoonotic transmission and genetic selection or modification ensure that plasma-derived products will continue to be subject to infectious concerns. Manufacturers of plasma-derived CFC have addressed the issue of emerging infectious agents by developing recombinant products that limit the need for human plasma during production. Such recombinant products have extended the safety profile of their predecessors by ensuring that all reagents used for cell culture, purification steps, and stabilisation and storage buffers are completely independent of human plasma.
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