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Oldenburg J., Wenning S., Holstein K., Filip J., Miesbach W., Severin K., Eichler H., Halimeh S.
Hamostaseologie 2024 44 Supplement 1 (S58-S59)
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Abstract
Introduction Damoctocog alfa pegol (BAY 94-9027) is an extended half-life PEGylated recombinant factor VIII product approved for treatment of previously treated patients (PTPs) aged ≥ 12 years with haemophilia A. Real-world effectiveness and safety of damoctocog alfa pegol are being assessed in the HEM-POWR study (NCT03932201). Here we present the fourth interim analysis of the HEM-POWR study for a subgroup of PTPs from German study sites. Method HEM-POWR, a Phase IV, open-label, prospective cohort study, included PTPs with mild, moderate or severe haemophilia A receiving damoctocog alfa pegol prophylactically or on demand. Primary endpoint was annualised bleeding rate (ABR); secondary endpoints included joint health and safety. The safety analysis set (SAF) included PTPs with ≥ 1 study dose in the observation period. PTPs fulfilling all inclusion criteria with a documented dose of damoctocog alfa pegol in the study and ≥ 1 documented infusion during the observation period were included in the full analysis set (FAS). Data were captured from patient diaries and physician records. Statistical analyses were explorative and descriptive. Patients provided informed consent and ethical approval was obtained for all study sites. Results At data cut-off (1 August 2023), 73 and 48 PTPs were included in the SAF and FAS of this sub-population, respectively. The median (Q1, Q3) observation periods in the SAF and FAS were 814.0 (482.0, 903.0) and 874.5 (675.5, 933.5) days, respectively. In the FAS, most patients were aged ≥ 18 to < 65 years (40/48, 83.3 %) and had severe disease (39/48, 81.3 %; moderate 9/48, 18.8 %; mild 0.0 %, .Fig. 1). Total median (Q1, Q3), mean (SD) ABR during the observation period was 0.5 (0.0, 1.6), 1.4 (2.4), with a change in ABR of 0.0 (-1.5, 0.5), -0.9 (3.3) compared with prior to damoctocog alfa pegol initiation. Data for bleed subtypes are summarised in .Fig. 2. During the observation period, 21/48 patients (43.8 %) had no bleeds, 37/48 (77.1 %) had no spontaneous bleeds and 29/48 (60.4 %) had no joint bleeds. In the SAF, 27/73 patients (37.0 %) reported treatment-emergent adverse events (TEAEs). Overall, 1 TEAE, a transient inhibitor that resolved, and 1 TEAE-related death (septic shock in aspiration pneumonia and not related to study drug administration) were reported. Conclusion Results from the fourth interim analysis of HEM-POWR continue to provide valuable insights into real-world clinical practice in Germany, inform German stakeholders, and provide evidence of effectiveness and safety of damoctocog alfa pegol in PTPs with mild, moderate or severe haemophilia A.
Other works by authors of this record
Oldenburg J., Wenning S., Holstein K., Filip J., Miesbach W., Severin K., Eichler H., Halimeh S.
Emtree drug index terms
recombinant blood clotting factor 8
Emtree medical index terms
adult, adverse drug reaction, aged, aspiration pneumonia, bleeding, clinical practice, cohort analysis, conference abstract, controlled study, drug administration, female, Germany, hemarthrosis, hemophilia A, human, major clinical study, male, phase 4 clinical trial, septic shock, side effect
Author Address
J. Oldenburg. University Clinic Bonn.
Alesci S., Halimeh S., Olivieri M., Miesbach W., Holstein K., Koenigs C.
Res. Pract. Thromb. Haemost. 2023 7:
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Abstract
Background: Patients with mild hemophilia (residual factor activity > 5 to < 40% represent a very heterogeneous group. Therapeutic approaches are as individual as the bleeding tendency. It is likely that the extent of disease and bleeding risk of patients with mild hemophilia are underestimated, resulting in an undersupply of factor concentrate, e. g. during surgical procedures or trauma. So far, not much data exists on both joint problems of patients, nor on the management of surgical procedures. Aims: To gather insights into the treatment situation of patients (12 years and older) with mild hemophilia A or B and their quality of life. Methods: Using an anonymous cross-sectional patient survey, we documented online patients ’experience with factor concentrates and other treatments. Patients ≥12 years with diagnosed mild hemophilia A or B participated. We evaluated patients ‘satisfaction regarding the therapy situation, support by physicians, and assessed the impact on Quality of Life (EQ-5D-5L). Results: We included 44 patients (35 hemophilia A, 5 hemophilia B, 3 unknown) with a median age at survey of 33 years. The median age at diagnosis was 6.0 years. Median factor activity was 14.0%. 84.2% (n = 32) were treated with factor concentrates in the past. The most frequent reasons for treatment were surgery or joint bleedings (each 65.6%, n = 21). Approximately half of the patients (n = 20) had complications caused by untreated bleeding due to accidents (4), surgical bleeding (11), dental treatment (10), joint bleeding (10) and spontaneous bleeding (2). Only 4 patients (10.3%) were prophylactically treated with factor concentrates. Health state indicates slight problems with mobility, with washing/ dressing, moderate pain and slight anxiety or depression. Conclusion(s): Bleeding complications, especially joint bleeding, seem to be highly underestimated in patients with mild hemophilia A and B. To start an early prophylaxis to avoid joint damage should be discussed even in patients with mild hemophilia. [Table presented]
Non-drug Index Terms
(Based on full text)
anxiety, bleeding, bleeding tendency, clinical article, complication, conference abstract, dental procedure, depression, diagnosis, European Quality of Life 5 Dimensions 5 Level questionnaire, female, Germany, health status, hemarthrosis, hemophilia, hemophilia A, hemophilia B, hemostasis, human, male, operative blood loss, pain, patient satisfaction, prophylaxis, quality of life, special situation for pharmacovigilance, surgery, therapy
Holme P.A., Poulsen L.H., Tueckmantel C., Maas Enriquez M., Alvarez Román M.T., De Cristofaro R.
[Article in Press] [In Process] Haemophilia 2024 :
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Abstract
Introduction: Damoctocog alfa pegol (BAY 94-9027, Jivi®) is an approved extended half-life factor VIII (FVIII) for treatment of previously treated patients with haemophilia A aged ≥12 years. We report the final results of an interventional, post-marketing study of damoctocog alfa pegol prophylaxis in patients with severe haemophilia A. Methods: In this open-label, interventional, post-marketing, phase 4 trial (NCT04085458), previously FVIII-treated patients with severe haemophilia A aged ≥18 years received damoctocog alfa pegol for ≥100 exposure days (EDs). Patients initially received 45 IU/kg every 5 days (recommended) or 40 IU/kg twice-weekly. At Visit 3, patients’ doses could be increased, or treatment frequency adapted. The primary endpoint was FVIII inhibitor development (titter ≥.6 Bethesda units). Secondary endpoints included anti-polyethylene glycol (PEG) antibody development, treatment-emergent adverse events (AEs) and annualized bleeding rate (ABR). Results: Overall, 36 patients were enrolled; 32 patients received treatment, of whom, 27 completed the study. No patients developed FVIII inhibitors; three tested transiently positive for low-titter anti-PEG antibodies without clinical relevance. Three patients reported study-drug-related AEs of mild or moderate intensity. Two patients discontinued the study due to AEs. No deaths occurred. Most patients (70%) were treated with E5D/E7D regimens. The median (Q1;Q3) total ABR (N = 30) was 3.0 (.0;9.0) pre-study and 1.8 (.7;5.9) during the study. Conclusion: Damoctocog alfa pegol individualized prophylaxis regimens were well-tolerated with no immunogenicity concerns. ABRs improved following the switch from pre-study prophylaxis to damoctocog alfa pegol prophylaxis. These results support the favourable safety and efficacy profile of damoctocog alfa pegol prophylaxis.
Drug Index Terms
blood clotting factor 8, macrogol, recombinant blood clotting factor 8
Non-drug Index Terms
adult, aged, article, bleeding, clinical article, clinical significance, controlled study, drug therapy, female, genetic recombination, half life time, hemophilia, hemophilia A, human, immunogenicity, male, marketing, multicenter study, phase 2 clinical trial, phase 3 clinical trial, phase 4 clinical trial, prophylaxis, side effect, special situation for pharmacovigilance
Patient perspective on living with mild hemophilia in Germany: results from a nationwide survey
Alesci R.S., Goldmann G., Halimeh S., Holstein K., Königs C., Miesbach W., Pfrepper C., Olivieri M.
[In Process] Front. Med. 2024 11:
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Abstract
Introduction: The disease burden and bleeding risk of patients with mild hemophilia may be underestimated. Their health-related quality of life (QoL) may be negatively impacted by insufficient treatment and bleed-related joint damage connected to a potentially delayed diagnosis. Aim: This study aims to gain information on the care reality and QoL of patients aged ≥12 years with mild hemophilia in Germany. Methods: An anonymous cross-sectional patient survey using standardized questionnaires was conducted in a validated electronic patient-reported outcome system. Medical specialists, hemophilia centers, patient organizations, and support groups across Germany invited the patients. Results: A total of 43 patients (35 patients with hemophilia A, 5 patients with hemophilia B, and 3 patients for whom the information was missing) with a median age of 33 years were analyzed. The median age at diagnosis was 6.0 years (interquartile range [IQR] 2.0–15.0), and the median factor activity was 14.0% (IQR 12.0–25.0). Nearly 85% of the patients received factor concentrates in the past, and the most common reasons for the treatment were surgery or joint bleeding (each 65.6%). Half of the patients who provided feedback experienced complications during bleeding episodes. Prophylactic treatment with factor concentrates was rare (10.3%). The patients had minor problems regarding their health status. Conclusion: Bleeding complications and joint bleeding, in particular, may be highly underestimated in patients with mild hemophilia, highlighting a medical need in this population. Patients with a potential benefit from prophylaxis need to be identified. Mild hemophilia has a negative impact on patients’ QoL. Hemophilia centers satisfied the patients’ needs. Further research is needed to address the current lack of awareness and improve adequate treatment in the future.
Non-drug Index Terms
adolescent, adult, aged, article, bleeding, child, clinical article, complication, delayed diagnosis, disease management, drug therapy, female, Germany, health status, hemarthrosis, hemophilia, hemophilia A, hemophilia B, human, male, patient-reported outcome, quality of life, questionnaire, special situation for pharmacovigilance, surgery, therapy
Reding M.T., Álvarez-Román M.T., Castaman G., Janbain M., Matsushita T., Meijer K., Schmidt K., Oldenburg J.
Eur. J. Haematol. 2024 112:2 (286-295)
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Abstract
Objectives: To assess effectiveness and safety of damoctocog alfa pegol in interim analyses of the ongoing real-world hemophilia A HEM-POWR study. Methods: HEM-POWR (NCT03932201) is a multinational Phase 4 prospective observational study. The primary objective was annualized bleeding rate (ABR) in previously treated patients (PTPs) with hemophilia A. Secondary objectives included adverse events and number of affected joints. Results: At data cut-off (August 17, 2022), the safety analysis set included 268 patients and the full analysis set (FAS) included 161 patients. The most common dosing regimen during observation period was prophylaxis (FAS = 158/161, 98.1%) every 3–4 days (twice weekly; FAS = 78/158, 49.4%) and a median (min, max) infusion dose of 37.5 (10, 72) IU/kg. PTPs receiving prophylactic damoctocog alfa pegol have fewer infusions compared with prior treatment. Median total ABR (Q1, Q3) was 0.0 (0.0, 1.8) and mean total ABR (SD) was 2.4 (8.2). The proportion of patients with no affected joints increased between initial visit and follow-up. No FVIII inhibitors, treatment-related adverse events, or deaths were reported. Conclusions: Damoctocog alfa pegol shows effectiveness and acceptable safety, as well as consistent utilization, in real-world PTPs with hemophilia A, including in patients with non-severe hemophilia and those with a history of inhibitors. Please see video for a summary of this study.
Drug Index Terms
(Based on full text)
blood clotting factor 8 (endogenous compound), recombinant blood clotting factor 8 (adverse drug reaction, clinical trial, drug therapy, special situation for pharmacovigilance), tumor necrosis factor receptor superfamily member 6 (endogenous compound)
Non-drug Index Terms
(Based on full text)
adolescent, adult, adverse drug reaction, aged, annualized bleeding rate, article, cause of death, child, clinical assessment, clinical effectiveness, clinical evaluation, cohort analysis, comparative effectiveness, connective tissue disease (side effect), controlled study, drug efficacy, drug hypersensitivity (side effect), drug infusion, drug safety, female, follow up, gastrointestinal disease (side effect), half life time, hemophilia A (drug therapy), hepatobiliary disease (side effect), HIV test, human, infection (side effect), infestation (side effect), major clinical study, male, multicenter study, musculoskeletal disease (side effect), observational study, outcome assessment, phase 4 clinical trial, prospective study, skin disease (side effect), subcutaneous tissue, treatment indication
Relapse of Acquired Hemophilia A after COVID-19 Infection
Marumo A., Sugihara H., Omori I., Morishita E.
J Nippon Med Sch 2024 90:6 (474-479)
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Abstract
Acquired hemophilia A (AHA) is a rare disease in which an autoantibody causes bleeding by interacting with and inhibiting the coagulation activity of endogenous factor VIII (FVIII). Most cases of AHA are idiopathic; known causes include autoimmune diseases, malignant tumors, pregnancy, drugs, and viral infections. An 86-year-old man was diagnosed with AHA based on the following results: an activated partial thromboplastin time (aPTT) extension of 130.7 seconds, presence of an inhibitor pattern in a mixing study, an endogenous factor VIII (FVIII) level of <1%, and an FVIII inhibitor titer of >5.1 Bethesda units (BU). The activity of von Willebrand factor (vWF) was diminished (<10%), which was considered a complication of acquired von Willebrand syndrome (AVWS). The patient was started on prednisolone, and the inhibitor level eventually became negative. vWF values also became normal. However, 1 year later, he was hospitalized for treatment of coronavirus disease 2019 (COVID-19). Blood testing showed an aPTT extension of 110.5 seconds, FVIII level of 4%, and FVIII inhibitor titer of 0.8 BU; thus, a relapse of AHA was diagnosed. After administration of corticosteroid and remdesivir, he recovered from COVID-19 and AHA. The inhibitor level became negative on the 9th day of admission. Several studies have implicated COVID-19 infection and vaccination in AHA. We recommend that aPTT be measured when patients with AHA are infected with SARS-CoV2, to confirm AHA relapse.
Drug Index Terms
(Based on full text)
blood clotting factor 8, virus RNA, von Willebrand factor
Non-drug Index Terms
(Based on full text)
case report, chronic disease, complication, coronavirus disease 2019, female, hemophilia A (drug therapy, diagnosis), human, male, pregnancy, recurrent disease, Severe acute respiratory syndrome coronavirus 2, very elderly
Joint bleeds in mild hemophilia: Prevalence and clinical characteristics
Chiari J.B., Prozora S., Feinn R., Louizos E., Gallagher P.G., Bona R.
[Article in Press] Haemophilia 2024 :
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Abstract
INTRODUCTION: Joint bleeds are a common and frequent complication associated with hemophilia, increasing the risk of hemophilic arthropathy. It is important to define and characterize the presence of joint complications in mild hemophilia to develop strategies to mitigate disease burden. AIMS: To characterize the prevalence, clinical characteristics of joint bleeds, and risk factors that may lead to hemarthrosis in people with mild hemophilia. METHODS: Following Institutional Review Board approval, a retrospective chart review was conducted for patients with mild hemophilia seen at the Yale Hemophilia Treatment Center or Classical Hematology Program. RESULTS: The medical records of 70 patients were reviewed. Eighty one percent were male and 19 percent were female. Twenty individuals with mild hemophilia had a history of joint bleeding, 13 were traumatic bleeds, 7 were spontaneous. The age of first joint bleed ranged from 4 to 58 years old, with an average age of 20.8-years old. Ten patients developed joint bleeds between the ages of 10 and 20 years old. The most common locations of joint bleeding were the knee (n = 11) and ankle (n = 7). Eight of 70 patients had hepatitis C (HCV), 6 experienced joint bleeding. CONCLUSIONS: In this study, almost one third of patients with mild hemophilia experienced joint bleeding, often without history of trauma. Joint range of motion was abnormal in more than a third of the patients with mild hemophilia regardless. These data highlight the need for ongoing evaluation and characterization of joint health in individuals with mild hemophilia. HIGHLIGHTS: Twenty-nine percent of individuals with mild hemophilia had history of joint bleed. PwH and mild diseases with previous or current hepatitis C had higher likelihood of joint bleeding. Approximately 15% of PwH and mild diseases had abnormal joint examinations without a confirmed history of joint bleeding.
Non-drug Index Terms
adult, article, bleeding, child, clinical article, cohort analysis, complication, diagnosis, drug therapy, female, hemarthrosis, hemophilia, hemophilic arthropathy, hepatitis C, Hepatitis C virus genotype 6, human, joint examination, major clinical study, male, medical record review, prevalence, range of motion, retrospective study, risk factor
Risk of low bone mineral density in patients with haemophilia: a systematic review and meta-analysis
Zhou H., Chen L., Su H., Chen G., Tong P.
J Orthop Surg Res 2024 19:1 (52)
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Abstract
INTRODUCTION: Patients with haemophilia (PWH) may have lower bone mineral density (BMD). The risk of low BMD in PWH has not been comprehensively analysed. This study aimed to examine the risk of low BMD and changes in BMD in PWH. METHODS: A comprehensive systematic search was performed in 4 databases: PubMed, Embase, Web of Science, and Cochrane Library. The last search was carried out on 11 December 2022. Review Manager 5.4 and Stata 16 were used for meta-analysis. Odds ratios were calculated by the incidence of low BMD between the haemophilia and control groups in each study. A meta-analysis of the odds ratios for each study was performed to estimate pooled odds ratios. Fixed effects models or random effects models were used to assess outcomes. Heterogeneity was evaluated using Higgins' I2. Subgroup analysis and sensitivity analysis were performed to interpret the potential source of heterogeneity. A funnel plot, Egger's regression test, and the trim-and-fill method were used to assess publication bias. RESULTS: 19 of 793 studies, published between 2004 and 2022, that were identified by search strategy were included in this meta-analysis. The risk for low BMD was approximately four times higher compared to controls. PWH have significantly lower lumbar spine, femoral neck, and total hip BMD. Subgroup analysis showed that the risk of low BMD did not increase significantly in developed countries. Very low heterogeneity was observed in the meta-analysis of the risk of low BMD. The result from Egger's regression test suggested that there may be publication bias. However, the meta-analysis results did not alter after the trim-and-fill correction and the findings were robust. CONCLUSION: Haemophilia was associated with an increased risk of low BMD. However, the risk of low BMD did not increase significantly in developed countries. And BMD was reduced in PWH, regardless of age, region, or economic ability. For PWH, our concerns should extend beyond bleeding and osteoarthritis to encompass BMD starting at a young age.
Non-drug Index Terms
(Based on full text)
bone density, complication, femoral neck, hemophilia A, human, meta analysis, metabolic bone disease, osteoporosis
Santagata D., Abenante A., Squizzato A., Dentali F., Donadini M.P., Ageno W., Pabinger I., Tiede A., Ay C.
[Article in Press] J Thromb Haemost 2024 :
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Abstract
BACKGROUND: Venous thromboembolism (VTE) is a well-recognized complication after total-joint replacement (TJR). Persons with hemophilia A or B are considered at low postoperative VTE risk due to their coagulation factor deficiencies and administering pharmacological thromboprophylaxis is often considered contraindicated. However, using factor replacement therapy could increase the postoperative VTE risk. OBJECTIVE: To analyze best available evidences of VTE rates in persons with hemophilia A or B undergoing lower limb TJR and the use of postoperative pharmacological thromboprophylaxis. PATIENTS/METHODS: We systematically screened four online biomedical databases to identify studies reporting VTE rates in patients with hemophilia after TJR. Case reports and case series with less than ten patients were excluded. RESULTS: Twenty-six observational studies were included in this systematic review, reporting 1181 TJRs in patients with hemophilia A or B. Eight studies had VTE rates as the primary outcome. Five studies reported screen-detected VTE, while 21 papers reported symptomatic VTE events. Overall, 17 VTE events were reported (1.4%, 95% CI 0.9%-2.3%); 10 (6.6%) after 151 surgeries with postoperative VTE screening and 7 (0.7%) events in 1080 surgeries without postoperative screening. Thromboprophylaxis protocols were specified in 21 studies; postoperative thromboprophylaxis was used in 15 (1.3%) surgeries. This information was not available for 29.0% of the analyzed population. CONCLUSIONS: Despite the low thromboprophylaxis use in patients with hemophilia, rates of symptomatic VTE after TJR appeared to be low. We also highlighted the need to better report the thrombotic outcome in persons with hemophilia to face the ongoing changes in the hemophilia landscape.
Non-drug Index Terms
arthropathy, article, case report, complication, drug therapy, hemophilia, hemophilia A, human, observational study, orthopedic surgery, prevention, replacement arthroplasty, substitution therapy, surgery, systematic review, therapy, thrombosis, thrombosis prevention, total arthroplasty, venous thromboembolism
A pilot study of US HTC physical therapists' concordance of PT MASAC recommendations and educational needs
Volland L., Nichols C., Santaella M.E., Lambing A., Nammacher K., Frick N.
Haemophilia 2024 30:1 (169-179)
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Abstract
Introduction: Physical therapists (PTs) are essential providers within the Hemophilia Treatment Centers (HTCs) team caring for persons with inherited blood disorders (PWBD). Objective: Little is known regarding PTs understanding and concordance of MASAC PT Recommendations (MASAC#238), educational resources used to maintain competency and support for a mentorship programme. Methods: PTs at federally funded HTCs were eligible to participate in a descriptive non-validated study exploring: (i) demographics, (ii) educational background, (iii) experience in evaluation and treatment of PWBD, (iv) practice patterns indicative of concordance with MASAC#238 and (v) opinion regarding PT mentorship. Results: Respondents experience caring for PWBD ranged 1–36 years, treating both adults and children. Although most acknowledged awareness of MASAC#238, dropout (14/44, 31.8%) was noted; 28/30 (93.3%) who continued were aware of the recommendations. Level of concordance with MASAC#238 varied (range 64.3%–96.2%) regarding: signs/symptoms, treatment of muscle/joint bleeding and pre/post synovectomy and knee replacement treatment. Many PTs identified patients as individual and unique, thus not all recommendations may apply. PTs utilised available educational programmes. No relationships were noted regarding years of practice, education and years caring for PWBD. All respondents favoured a mentorship programme citing benefits, but also outlined barriers. Conclusions: Provision of necessary financial support for optimal function of a full-time PT within the HTC can enhance standards of care for PWBD. Supporting educational opportunities may enhance concordance with current MASAC PT Recommendations. Respondents valued development of a structured, hands-on mentorship programme. MASAC#23 has recently been updated in May 2023 to MASAC#275.
Non-drug Index Terms
(Based on full text)
adult, article, awareness, female, health care facility, hemarthrosis, hemophilia, human, knee replacement, male, medical education, muscle bleeding, physiotherapist, physiotherapy, pilot study, practice guideline, protocol compliance, symptom, synovectomy, United States, work experience
Outcomes of total hip and knee arthroplasty in patients with haemophilia: A meta-analysis of comparative studies and clinical practice recommendations
Challoumas D., Munn D., Jeyakumar G., Bagot C., Rodgers R., Kearns R., Jones B.
Haemophilia 2024 30:1 (180-194)
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Abstract
Aim: We aimed to compare the outcomes of total hip and knee arthroplasty (THA, TKA) in haemophilic patients compared to matched controls. Methods: Through a literature search we identified all cohort studies comparing perioperative complications and other outcomes of THA and TKA in haemophilic patients and matched controls without haemophilia. Results of the same outcome measure assessed by two or more studies were pooled in meta-analyses; odds ratios (ORs) with 95% confidence intervals (CI) were calculated. The risk of bias in included studies and certainty of evidence of each result were assessed using the Newcastle-Ottawa scale and the GRADE tool respectively. Results: A total of five retrospective studies with matched controls were included; four of them were of good and one of fair quality. Based on moderate certainty evidence, compared to matched controls, patients with haemophilia had a significantly higher incidence of the following complications after a) TKA: periprosthetic joint infection [PJI; OR 1.6 CI (1.3, 1.9)], 1-year revision/re-operation [OR 1.4 CI (1.2, 1.8)] and b) THA: major and minor 90-day complications [major OR 2.2 CI (1.7, 2.9); minor OR 1.4 CI (1.1, 1.8)], venous thromboembolism [OR 3.1 CI (2.1, 4.6)]. PJI incidence in THA was not different in haemophilia compared to controls [OR 1.5 CI (.9, 2.6)]. Conclusion: Our results can be used by healthcare professionals counselling patients with haemophilia considering a THA or TKA as part of the informed consent process. We provide detailed clinical recommendations for the perioperative management of THA and TKA in haemophilic patients.
Non-drug Index Terms
(Based on full text)
article, blood transfusion, clinical practice, comparative study, GRADE approach, health care personnel, hemophilia, human, incidence, informed consent, meta analysis, mortality, Newcastle-Ottawa scale, patient counseling, perioperative care, perioperative complication (complication), periprosthetic joint infection (complication), postpartum hemorrhage (complication), publication, revision arthroplasty, total hip replacement, total knee arthroplasty, treatment outcome, venous thromboembolism
Impact of inherited bleeding disorders on maternal bleeding and other pregnancy outcomes: A population-based cohort study
Alam A.U., Wu C., Kaul P., Jain V., Sun H.
[Article in Press] Haemophilia 2024 :
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Abstract
Introduction: Increasing rate of postpartum haemorrhage (PPH) has been observed between 2003 and 2010 in Canada. Inherited bleeding disorders contribute to the risk of PPH. Aim: To identify the trend in PPH in the last decade, assess the impact of bleeding disorders on pregnancy outcomes and evaluate their coagulation workup during pregnancy. Methods: We conducted a population-based retrospective cohort study using the Alberta Pregnancy Birth Cohort from 2010 to 2018. We included women with von Willebrand disease (VWD) and haemophilia, identified by previously validated algorithm and matched with controls. Logistic regression was used to compute odds of PPH and other pregnancy outcomes. Results: We identified 311,330 women with a total of 454,400 pregnancies with live births. The rate of PPH did not change significantly from 10.13 per 100 deliveries (95% CI 10.10–10.16) in 2010–10.72 (95% CI 10.69–10.75) in 2018 (p for trend =.35). Women with bleeding disorders were significantly more likely to experience PPH (odds ratio [OR] 2.3; 95% CI 1.5–3.6), antepartum haemorrhage (OR 2.9; 95% CI 1.5–5.9) and red cell transfusion (OR 2.8; 95% CI 1.1–7.0). We observed a nonsignificant rise in the rate of PPH in women with VWD and haemophilia. Only 49.5% pregnancies with bleeding disorders had third trimester coagulation factor levels checked. Higher odds of PPH and antepartum haemorrhage were observed even with factor levels ≥0.50 IU/mL in third trimester. Conclusion: Despite comprehensive care in women with bleeding disorders, they are still at higher risk of adverse pregnancy outcomes compared to population controls.
Drug Index Terms
blood clotting factor
Non-drug Index Terms
adult, algorithm, antepartum hemorrhage, article, birth cohort, bleeding disorder, blood clotting, Canada, cohort analysis, complication, controlled study, drug therapy, female, hemophilia, hemophilia A, heredity, human, live birth, major clinical study, obstetric hemorrhage, population dynamics, postpartum hemorrhage, pregnancy, pregnancy outcome, retrospective study, therapy, third trimester pregnancy, von Willebrand disease
Minimum factor VIII levels to prevent joint bleeding in mild hemophilia A
Agosti P., Siboni S.M., Scardo S., Torri A., Gualtierotti R., Peyvandi F.
Blood Adv. 2023 7:23 (7209-7215)
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Abstract
The severity of the bleeding phenotype in patients with hemophilia A (HA) broadly correlates with the degree of coagulation factor VIII (FVIII) deficiency in plasma. However, the FVIII level necessary to achieve the goal of zero joint bleeds remains unclear. This study aimed to identify the minimum FVIII level necessary to prevent joint bleeds in patients with HA. In this retrospective study, patients with congenital mild HA treated on demand, aged ≥16 years, with no history of FVIII inhibitors, followed at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, were enrolled. We investigated 270 male patients with a median age of 45 years (16-88) and median lifelong FVIII of 21 IU/dL. One hundred patients (37%) had a lifelong history of at least 1 joint bleed. The mean annualized joint bleeding rate (AJBR) and spontaneous AJBR were 0.016 (standard deviation [SD], 0.032) and 0.001 (SD, 0.010), respectively. After adjusting for age, for each IU/dL increase in FVIII, there was a 6% reduction in AJBR and an 11% reduction in spontaneous AJBR. The minimum FVIII levels needed to prevent lifelong any joint bleeds and spontaneous joint bleeds resulted to be 19.2 IU/dL and 17.7 IU/dL, respectively. In this large cohort of persons with mild HA, we identified the minimum FVIII levels needed to prevent total and spontaneous joint bleeds (19.2 IU/dL and 17.7 IU/dL, respectively). These findings could suggest important implications for the accurate design of prophylactic therapies for persons with moderate and severe HA, including gene therapy.
Drug Index Terms
(Based on full text)
blood clotting factor 8 (endogenous compound)
Non-drug Index Terms
(Based on full text)
adolescent, aged, article, cohort analysis, disease association, disease severity, follow up, hemarthrosis (complication, prevention), hemophilia A, human, major clinical study, male, medical history, phenotype, prevention study, protein blood level, retrospective study
Fornari A., Antonazzo I.C., Rocino A., Preti D., Fragomeno A., Cucuzza F., Ceresi N., Santoro C., Ferretti A., Facchetti R., Cozzolino P., Biasoli C., Cassone C., Coppola A., Cortesi P.A., Mantovani L.G.
[Article in Press] [In Process] Haemophilia 2023 :
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Abstract
Backgroud: A huge amount of data about psychosocial issues of people with haemophilia (PwH) are available; however, these materials are fragmentary and largely outdated, failing to reflect the impact of current treatment strategies. Aim: Describing the influence of illness on psychosocial aspects of adult PwH (≥18 years) and caregivers of children with haemophilia (CPwH) without inhibitors, in Italy. Methods: Surveys (for adult PwH, CPwH and haemophilia specialists) were developed by a multidisciplinary working group and conducted from November 2019 to June 2020. Results: A total of 120 PwH without inhibitors and 79 CPwH completed the survey. Adult patients reported a significant impairment in many psychosocial aspects, including working activities, relations with family members and social relations. Caregivers generally reported better scores in all aspects of the survey. Mobility, Pain and Mental health domains of EQ-5D were the most frequently impaired in both patients and caregivers, reducing the perceived quality of life. Genetic counselling was an important issue, 53% of CPwH declaring unawareness of their carrier status, as well as the psychological support offered by the reference center, 67.0% of respondents reporting that no psychological support was provided at the time of diagnosis communication. Conclusion: This study provides information about PwH's and CPwH's point of view in the current scenario of continuous innovations in haemophilia treatment and management furthermore, updated insights on psychosocial problems faced by patients and caregivers are reported.
Non-drug Index Terms
adult, article, caregiver, child, cross-sectional study, daily life activity, drug therapy, European Quality of Life 5 Dimensions questionnaire, female, genetic counseling, hemophilia, hemophilia A, human, interpersonal communication, Italy, major clinical study, male, medical specialist, mental health, pain, psychological care, psychosocial disorder, quality of life, social interaction, social psychology, unconsciousness
Oomen I., Verhagen M., Miranda M., Allacher P., Kaijen P., Hassan S., Meijer D., Rijpma S., Schweiger H., Fijnvandraat K., Voorberg J., Schols S., Gouw S.
Res. Pract. Thromb. Haemost. 2023 7:
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Abstract
Background: It is known that anti-factor VIII (FVIII) antibodies may have neutralizing as well as non-neutralizing characteristics. We hypothesize that FVIII-binding antibodies form a spectrum consisting of non-neutralizing antibodies (NNA), low-titer neutralizing antibodies below the detection limit of the widely used Nijmegen Bethesda assay (NBA), and low and high responding inhibitors detectable with the NBA (figure 1). Aims: We aim to assess the prevalence and characteristics of FVIII-specific antibodies in an unselected cross-sectional cohort of persons with hemophilia A. Methods: All persons with hemophilia A (mild/moderate/severe) who participated in the nationwide multicenter Hemophilia in the Netherlands-6 study with an available plasma sample were included. Presence of FVIIIbinding antibodies of immunoglobulin (Ig) A, M, and G isotypes and IgG subclasses, and titers were assessed using direct-binding ELISAs. FVIIIspecificity was assessed using a competition-based ELISA approach. Presence of low-titer neutralizing antibodies below the detection limit of the NBA was assessed using the novel Nijmegen ultra-sensitive Bethesda assay (NusBA), with detection limit of ≥0.1 Nijmegen ultra-sensitive Bethesda units (NusBU/mL). The NBA was used as described earlier. Results: In total, 788 persons with congenital hemophilia A were included (336 (42.6%) mild, 123 (15.6%) moderate, 329 (41.8%) severe). FVIII-specific antibodies were detected in 158 (20.1%) persons. IgG1 was the most abundant antibody, present in 95 (12.1%) individuals. Highest titer levels were found for IgG1 and IgG4. As hypothesized a spectrum of FVIII-specific antibodies was present in our population: 621 (78.8%) persons with no detectable FVIII-specific antibodies, 137 (17.4%) with FVIII-specific NNA, 4 (0.5%) with low-titer neutralizing antibodies measured by NusBA, 3 (0.4%) with low-titer inhibitors or inhibitors (NBA data pending), and 5 (0.6%) with Nijmegen Bethesda positive inhibitors (figure 2). Conclusion(s): This cross-sectional nationwide cohort study reveals the full spectrum of FVIII-specific NNA, low-titer inhibitory antibodies and inhibitors, in a cohort of 788 persons with hemophilia of all severities. [Figure presented] [Figure presented]
Drug Index Terms
(Based on full text)
blood clotting factor 8, immunoglobulin A, immunoglobulin G, immunoglobulin G1, neutralizing antibody
Non-drug Index Terms
(Based on full text)
adult, cohort analysis, conference abstract, controlled study, cross-sectional study, drug therapy, ELISA kit, enzyme linked immunosorbent assay, female, hemophilia, hemophilia A, hemostasis, human, limit of detection, major clinical study, male, Netherlands, population research, prevalence
Real-World Effectiveness and Safety of Damoctocog Alfa Pegol in Canadian Patients with Hemophilia A: Interim Results from the HEM-POWR Study
Matino D., Iorio A., Chan A., Samji N.
Res. Pract. Thromb. Haemost. 2023 7:
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Abstract
Background: Damoctocog alfa pegol is an extended half-life PEGylated recombinant Factor VIII product approved in Canada for previously treated patients (PTPs) aged ≥12 years with hemophilia A. Its efficacy and safety have been demonstrated previously (Reding, 2017; Reding ISTH 2022). HEM-POWR is an ongoing international study of real-world effectiveness and safety of damoctocog alfa pegol. Aims: To explore effectiveness and safety of damoctocog alfa pegol in a subgroup of Canadian patients from the HEM-POWR study (NCT03932201). Methods: In these subgroup analyses, primary endpoint was annualized bleeding rate (ABR). Secondary endpoints included joint health and safety. PTPs with hemophilia A receiving damoctocog alfa pegol with any treatment modality were eligible. Statistics were descriptive. Data were collated from patient e-diaries and physician records. Ethical approval was obtained for all sites. Results: At data cut-off (17 August 2022), the full analysis set included 19 patients, including 1/19 (5.3%) pediatric patient. Patients were observed for a mean (SD) 345.9 (131.0) days. A total of 18/19 patients received prophylactic treatment prior to the study (1 missing); 14/19 (73.7%) were pre-treated with damoctocog alfa pegol (Table 1). Median (mean, SD) number of bleeds in the overall population (N = 19) was 1.0; (0.6, 0.6). Total ABR, median (mean, SD) was 1.5 (1.8, 1.1) for the 6 patients available at assessment time point; overall change in ABR during the observation period compared with prior to damoctocog alfa pegol initiation was −1.9 (−5.1, 9.9) (Table 2). Treatment-emergent adverse events (TEAEs) occurred in 8/19 (42.1%) patients; 3/19 (15.8%) had serious TEAEs. There was 1 serious TEAE that led to change of treatment regimen. No study drug-related TEAEs or discontinuations were reported. Conclusion(s): This interim analysis of HEM-POWR in Canadian patients demonstrates the real-world effectiveness of damoctocog alfa pegol prophylaxis in reducing ABR compared to prior prophylactic treatment with an acceptable safety profile. Funded by Bayer. [Table presented] [Table presented]
Drug Index Terms
(Based on full text)
recombinant blood clotting factor 8
Non-drug Index Terms
(Based on full text)
adverse drug reaction, aged, bleeding, Canada, Canadian, clinical trial, conference abstract, controlled study, drug therapy, female, hemophilia A, hemostasis, human, major clinical study, male, multicenter study, pediatric patient, phase 3 clinical trial, phase 4 clinical trial, side effec
Comorbidities - An Additional Burden in the Real Life of Patients with Haemophilia
Ursu C., Serban M., Serban P., Traila A., Andrei D., Vaide I., Jinca C., Boeriu E., Arghirescu T.
Res. Pract. Thromb. Haemost. 2023 7:
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Abstract
Background: In a world without adequate therapy, haemophilia-related morbidity presents a deleterious impact on the quality of life of persons with hemophilia (PwH). Hemophilia-independent comorbidities are certainly increasing the burden of disease. Aims: Our objective was to analyze the dimension and profile of comorbidities in PwH, in terms of epidemiological evaluation, cumulative assessment of concomitant diseases, and severity. Methods: Our cross-sectional observational survey was conducted on a group of 122 PwH over a period of three years (2019–2021), divided according to the age of birth (after and prior to the introduction of the National Haemophilia Program-related therapy), in group 1 (<23 years, 11.91 ± 6.82) and group 2 (˃23 years, 40 ± 10.69). The epidemiological and cumulative assessment and severity of concomitant diseases were realized by establishing 14 disease-researched areas, evaluating their severity, and calculating the cumulative illness rating scale (CIRS). Results: Patients in group 1 had only one comorbidity, underweight being present in 33.3% of cases. The patients in the 2nd group were overweighed in 33,73%, with obesity in 21.68% of cases; cardiovascular comorbidities affected 26,5%, arterial hypertension ranking first (10.84%); osteoporosis was recorded at 15.66%, diabetes, epilepsy, chronic hepatitis, kidney failure, and psoriasis affecting 1,2–2,4% of them. The cumulative prevalence of comorbidities was impressive, with an evocative CIRS index of 373 in group 2, and 64 in group 1. Surgical interventions for comorbidities were needed in 5 (4,1%) of all patients, one (2,56%) from the first and 4 (4,82%) from the second group. Conclusion(s): Comorbidities dependent on the age of PwH (r = 0.66), unfortunately, started to develop early in adulthood, presenting a multidisciplinary profile. A comprehensive approach with specialists in other fields (cardiology, oncology, psychiatry) is mandatory to provide optimal care for PwH.
Non-drug Index Terms
(Based on full text)
adult, adulthood, chronic hepatitis, comorbidity, conference abstract, cross-sectional study, Cumulative
Tomschi F., Hmida J., Herzig S., Ransmann P., Brühl M., Schmidt A., Herzig M., Goldmann G., Strauß A.C., Oldenburg J., Richter H., Hilberg T.
[Article in Press] Haemophilia 2024 :
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Abstract
INTRODUCTION: Regular physical activity (PA) is recommended for patients with haemophilia (PwH). For PwH it is crucial to ensure a sufficient factor level to prevent PA-induced bleedings. However, there is a gap in the literature dealing with specific factor levels, which are needed when performing specific types of PA. AIM: To provide data on factor VIII (FVIII) levels at the start of PA performed by PwH. METHODS: In this prospective 12-month real-world observational study, 23 PwH recorded every PA they performed and the FVIII levels at the start of the PA using a pharmacokinetic application. PA types were clustered according to the collision and injury risk into three categories (Cat I = low, Cat II = medium, Cat III = high risk). Haemophilia Joint Health Scores (HJHS) were performed at baseline, after 6 and 12 months. RESULTS: 795 PA sessions of Cat I, 193 of Cat II, and 23 of Cat III were documented. FVIII levels at the start of PA were different between categories (Cat I: 29.8 ± 32.1%, Cat II: 38.3 ± 33.4%, Cat III: 86.6 ± 29.2%). Out of all PA sessions, 145 (14%) were performed at a factor level of ≤3%. Three PA-induced bleeding occurred. Baseline HJHS was 14.5 ± 13.6 points and did not change throughout the study. CONCLUSION: This study provides real-life data on FVIII levels at the start of 1011 PA sessions. PwH are mainly active in low-risk sports with higher FVIII levels observed in Cat II and III, respectively. Only three PA-induced bleeding occurred, even though several PA were started with low FVIII levels.
Drug Index Terms
blood clotting factor 8
Non-drug Index Terms
adult, arthropathy, article, bleeding, cat, female, hemophilia, hemophilia A, human, male, observational study, pharmacokinetics, physical activity, rare disease
Potential Predictive Biomarkers for the Development and Outcomes of Inhibitors in Hemophilia A Patients
Fan M.-N., Shen T., Cai X., Chao T.-Y., Manco-Johnson M., Xiao W., Konkle B.A., Li L., Miao C.H.Blood 2023 142: (2621)
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Abstract
Introduction Inhibitor development poses a significant challenge in the treatment of hemophilia A (HA). Approximately 30% of HA patients develop inhibitors in response to FVIII infusion therapy. While the risk is highest early in treatment days, patients are at risk throughout their lifetime. Regardless of certain known risk factors, the lack of biomarkers for inhibitor development hampers efforts to prevent their occurrence. Since inflammation is a well-known risk factor, one of our goals is to identify potential biomarkers among inflammatory cytokines. Another focus is glycosylation-related biomarkers, which has drawn great attention in biomarker discovery of various diseases including cancers. By analyzing the association of cytokines and plasma glycosylation with inhibitor formation, this research aims to provide valuable references for clinical care. Methods Plasma samples from 60 HA patients, and 23 healthy donors were analyzed to detect the levels of G-CSF, IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10, IL12p70, IP-10 and TNF. The HA samples were divided into inhibitor negative (InhNeg, BU < 0.6, n = 26) and inhibitor positive (InhPos, BU ≥ 0.6, n = 34) groups. A predictive model of inhibitor development was established using logistic regression analysis. To investigate the correlation between cytokine levels and high inhibitor titers, the inhibitor-positive samples were further categorized into good risk (< 10 BU, n = 14) and poor risk (≥ 10 BU, n = 20) groups based on immune tolerance induction therapy prognosis. Total plasma N-glycans were released, methylated, and analyzed by using MALDI-TOF MS/MS. A synthesized N-glycan was spiked in to quantify each glycoform. The study evaluated the correlation between HA sample groups and various glycosylation ratios, including for sialylation, core-fucosylation, galactosylation and galactose. The cut-off value of each glycosylation ratio was based on the median of the inhibitor-negative group. Results The adjusted odds ratio of inhibitor development for elevated G-CSF, IL-6 and decreased IL-10 were 2.84 (95% CI: 1.45-8.48; p = 0.021), 1.50 (95% CI: 1.14-2.42; p = 0.069), and 0.28 (95% CI: 0.10-0.61; p = 0.006), respectively in HA patients. Among InhPos HA patients, the levels of G-CSF, IL-2, IL-6, IL-8, and IL-10 in poor risk group were significantly higher than in good risk group (p-value < 0.05, ANOVA). Since aging also causes glycosylation changes, we analyzed adult (≥ 18 years old, n = 31) and pediatric (< 18 years old, n = 17) HA patients separately. Among analyzed glycan ratios, 80% of adult HA patients with inhibitors had a higher core-fucosylation ratio. All pediatric patients with inhibitors had significant lower sialylation and higher galactosylation ratios. Strikingly, pediatric patients with inhibitors exhibited around 2-fold higher core-fucosylation than those without inhibitor. Conclusion Our finding of elevated levels of G-CSF and IL-6 along with decreased levels of IL-10 associated with the presence of inhibitors, suggests the potential for prediction of inhibitor development. Moreover, high levels of G-CSF, IL-2, IL-6, IL-8 and IL-10 in patients with high inhibitor titers (≥ 10 BU, poor risk group) but not in good risk group imply they could be explored in future studies as prognostic factors in immune tolerance therapy. Glycan ratios can also hold promise as biomarkers including higher core-fucosylation in adult patients. Additionally, significant lower sialyation, higher galactosylation and core-fucosylation ratios indicate higher possibility of inhibitor development in pediatric patients.
Drug Index Terms
(Based on full text)
biological marker, galactose, gamma interferon, glycan, granulocyte colony stimulating factor, interleukin 10, interleukin 1beta, interleukin 2, interleukin 6, interleukin 8
Non-drug Index Terms
(Based on full text)
adult, aging, conference abstract, controlled study, diagnosis, drug therapy, female, fucosylation, glycosylation, hemophilia A, high risk population, human, immunological tolerance, infusion therapy, major clinical study, matrix assisted laser desorption ionization time of flight mass spectrometry, pediatric patient, prediction, predictive model, risk factor, sialylation
Chandler M., Charlet J., Moulton T., Recht M.
Blood 2023 142: (5479)
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Abstract
Background: The ATHNdataset is sponsored by the American Thrombosis and Hemostasis Network, including 17,109 hemophilia A people as of the cutoff date, 4/30/22. Patients with Hemophilia A are transitioning more and more from standard half-life (SHL) products to extended half-life (EHL) recombinant factor VIII (rFVIII) products Objective: To evaluate the effect of Hemophilia A patients transitioning from BAY 81-8973 (Kovaltry ®) to BAY 94-9027 (Jivi ®) and from BAY 14-2222 (Kogenate FS ®) to BAY 81-8973 and then to BAY 94-9027 in a real-world setting. Methods: The ATHNdataset was queried for patients treated with BAY 94-9027 that had BAY 81-8973 as a prior medication as well as for the latter that had BAY 14-2222 as a prior medication. Data included demographic data, treatment history, and bleed rates. Query dates were between January 1, 2010 and April 30, 2022. Summary: A total of 205 patients were treating with BAY 94-9027 and 354 with BAY 81-8973 at data cut-off. Thirty patients that treated with BAY 94-9027 had BAY 81-8973 listed as one of their prior medications. Of these, 90% had severe Hemophilia A, while 7% had moderate and 3% had mild disease. All were male, with an average age of 37 years at data cut-off; 80% being White and 90% not Hispanic, Latino or of Spanish origin. Overall, 24/30 patients were consistently treated prophylactically with BAY 81-8973 and with BAY 94-9027. The mean annualized total bleed rate (Total ABR) on BAY 81-8973 was 0.47 and 0.42 on BAY 94-9027, while the annualized joint bleed rate (Joint ABR) was 0.28 on both products and the annualized spontaneous bleed rate (Spontaneous ABR) was 0.17 and 0.30, respectively. The most frequent dosing regimen on BAY 81-8973 was 3x/week or more often, while on BAY 94-9027 more than 80% of patients were using a less frequent regimen than 3x/week, with 2x/week being the most common. (Figure 1) In addition, a sub-analysis was performed on the same patients that transitioned from BAY 81-8973 to BAY 94-9027, to include those patients that also used BAY 14-2222 as a prior medication to BAY 81-8973. A total of 12 patients transitioned from BAY 14-2222 to BAY 81-8973 and then to BAY 94-9027. Of these, all (100%) had severe Hemophilia A and were male. The average age was 33 years at data cut-off; 83% being White and 92% not Hispanic, Latino or of Spanish origin. Overall, 8/12 patients were treating consistently prophylactically with BAY 14-2222, BAY 81-8973 and BAY 94-9027. For these patients, the mean Total ABR on BAY 14-2222 was 3.59, on BAY 81-8973 it was 1.10 and 0.72 on BAY 94-9027, while the Joint ABR was 0.30 on BAY 14-2222, 0.64 on BAY 81-8973 and 0.34 on BAY 94-9027. The Spontaneous ABR was 0.14, 0.35 and 0.67, respectively. (Figure 2) The most frequent dosing regimen on BAY 14-2222 and BAY 81-8973 was 3x/week, while on BAY 94-9027 nearly 90% of patients were using a less frequent regimen than 3x/week, with 2x/week being the most common. Conclusions: The data show that hemophilia A patients who transitioned to BAY 94-9027 from BAY 81-8973, or those that transitioned from BAY 14-2222 to BAY 81-8973 and then to BAY 94-9027 did experience similar or decreased total annual bleed rates with a decrease in their prophylaxis regimen frequency when transitioning to BAY 94-9027 in the real world. The therapeutic burden of frequent infusions can be reduced when patients transition between rFVIII product classes (SHL to EHL), without change in their annual bleed rate. These data should be interpreted with caution owing to limitations of real-world studies and further studies are needed to confirm the impact of switching to BAY 94-9027 and BAY 81-8973 in real-world settings. Additional studies are needed to expand on these results.
Drug Index Terms
(Based on full text)
recombinant blood clotting factor 8
Non-drug Index Terms
(Based on full text)
adult, bleeding, Caucasian, clinical trial, conference abstract, drug therapy, hemarthrosis, hemophilia A, hemostasis, Hispanic, human, major clinical study, male, prophylaxis, Spaniard, thrombosis, young adult
Dix C., Dolan G., Hunt B.J.
[Article in Press] Journal of Thrombosis and Haemostasis 2024
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Abstract
Revolutionary advances in the treatment of hemophilia has led to a significant improvement in life expectancy. Associated with this has been an increase in age-related diseases especially atherosclerotic cardiovascular disease (CVD). While people with hemophilia (PWH) develop atherosclerosis at rates similar to those of the general population, rates of atherothrombosis and mortality related to CVD have been much lower, due to their hypocoagulable state. Changing treatment paradigms, aimed at reducing the risk of bleeding by improving hemostasis to levels approaching normality, has meant that the protection they are thought to have had may be lost. CVD risk factors are just as common in PWH as in the general population, but appear to be undertreated. In particular, primary prevention of CVD is vital in all individuals, but particularly in PWH as treatment of established CVD can be difficult. Active identification and management of CVD risk factors, such as obesity, physical inactivity, hypertension, and hypercholesterolemia, is required. In particular, statins have been shown to significantly reduce cardiovascular and all-cause mortality with few adverse events and no increased risk of bleeding in the general population, and their use needs urgent assessment in PWH. Further longitudinal research into preventing CVD in PWH, including accurate CVD risk assessment, is required to optimize prevention and management.
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Emtree drug index terms
anticoagulant agent, hydroxymethylglutaryl coenzyme A reductase inhibitor
Emtree medical index terms
adult, all cause mortality, atherosclerosis, bleeding, cardiovascular disease, cardiovascular risk, coronary atherosclerosis, drug therapy, exercise, hemophilia, hemostasis, human, hypercholesterolemia, hypertension, hypocoagulability, life expectancy, male, middle aged, mortality, obesity, physical inactivity, prevention, primary prevention, review, risk assessment, risk factor
Author Address
B.J. Hunt. Guy's & St Thomas’ NHS Foundation Trust.
Author Email
Miesbach W., Boban A., Chowdary P., Coppens M., Crato M., Jimenez-Yuste V., Klamroth R., Makris M., Mulders G., Peyvandi F.
[Article in Press] [In Process] Haemophilia 2024
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Miesbach W., Boban A., Chowdary P., Coppens M., Crato M., Jimenez-Yuste V., Klamroth R., Makris M., Mulders G., Peyvandi F.
Emtree drug index terms
Emtree medical index terms
gene therapy, hemophilia, hemophilia A, human, letter
Author Address
W. Miesbach. Medical Clinic 2, Institute of Transfusion Medicine, University Hospital Frankfurt.
Author Email
Radiosynovectomy in haemophilic synovitis and arthropathy of the knee: A scoping review
Ray A., Rowbotham E.
[Article in Press] [In Process] Haemophilia 2024
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Abstract
Introduction: Radiosynovectomy is an established treatment for chronic synovitis in patients with haemophilia. Although its role in rheumatological diseases has diminished, it remains an accepted therapy for haemophilic synovitis. Aim: The aim of this scoping review was to map and summarise the evidence surrounding radiosynovectomy in haemophilic knees, identify gaps in the literature and inform future research. Results: Forty-three manuscripts and abstracts were identified for this review. Evidence was limited to observational studies and Yttrium-90 was the most studied licensed radioisotope. Radiosynovectomy was associated with a reduction in bleeding frequency and pain, improvements in range of motion and a reduction in the use of factor replacement. Conclusion: The literature reviewed lacks studies of sufficient methodological quality to permit systematic review and meta-analysis. Systematic review using risk of bias assessment for observational studies should be undertaken to better evaluate the efficacy and safety of radiosynovectomy. A causal relationship between RSV and key clinical outcomes remains undetermined.
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Emtree drug index terms
Emtree medical index terms
adverse drug reaction, arthropathy, bleeding, clinical outcome, drug therapy, hemophilia, hemophilia A, human, meta analysis, observational study, pain, range of motion, review, scoping review, side effect, synovitis, systematic review, therapy
Author Address
A. Ray. Department of Radiology, York Hospital.
Author Email
Menier C., Meunier S., Porcheddu V., Romano L., Correia E., Busato F., Tost J., Maillère B.
[Article in Press] European Journal of Immunology 2024
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Abstract
Tolerance to self-proteins involves multiple mechanisms, including conventional CD4+ T-cell (Tconv) deletion in the thymus and the recruitment of natural regulatory T cells (nTregs). The significant incidence of autoantibodies specific for the blood coagulation factor VIII (FVIII) in healthy donors illustrates that tolerance to self-proteins is not always complete. In contrast to FVIII-specific Tconvs, FVIII-specific nTregs have never been revealed and characterized. To determine the frequency of FVIII-specific Tregs in human peripheral blood, we assessed the specificity of in vitro expanded Tregs by the membrane expression of the CD137 activation marker. Amplified Tregs maintain high levels of FOXP3 expression and exhibit almost complete demethylation of the FOXP3 Treg-specific demethylated region. The cells retained FOXP3 expression after long-term culture in vitro, strongly suggesting that FVIII-specific Tregs are derived from the thymus. From eleven healthy donors, we estimated the frequencies of FVIII-specific Tregs at 0.17 cells per million, which is about 10-fold lower than the frequency of FVIII-specific CD4+ T cells we previously published. Our results shed light on the mechanisms of FVIII tolerance by a renewed approach that could be extended to other self- or non-self-antigens.
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Menier C., Meunier S., Porcheddu V., Romano L., Correia E., Busato F., Tost J., Maillère B.
Emtree drug index terms
autoantibody, autoantigen, blood clotting factor 8
Emtree medical index terms
adult, article, blood, CD4+ T lymphocyte, controlled study, demethylation, diagnosis, hemophilia A, human, human cell, in vitro study, male, middle aged, normal human, regulatory T lymphocyte, thymus
Author Address
C. Menier. CEA Paris-Saclay, DRF / DMTS / SIMoS.
Author Email
The underevaluated impacts of the therapeutic revolution of hemophilia on women and girls
Hermans C., Krumb E., Rotellini D., Pierce G.F.
Journal of Thrombosis and Haemostasis 2024 22:4 (915-918)
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Abstract
The advent of new treatment options over the last decades has markedly improved the lives of male persons with hemophilia (PwH). However, this therapeutic revolution has not benefited women and girls with hemophilia (WGH) and symptomatic carriers of the disease to the same extent as their male counterparts. This inequity is primarily due to the exclusion of WGH from clinical trials and a failure to fully recognize their specific treatment needs. Additionally, the indirect impact of innovative therapies, when used for male PwH, on the lives of mothers, other relatives, and partners of these individuals has been largely overlooked until now. In addition to improving access of WGH and carriers to new hemostatic treatments and comprehensive hemophilia care, it is imperative to strive for alleviating the mental burden imposed on them by this chronic disease. The recently proposed concept of a “hemophilia-free mind,” primarily focused on male PwH, should therefore also be applied to WGH, symptomatic carriers, and the predominantly female support network of PwH.
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Hermans C., Krumb E., Rotellini D., Pierce G.F.
Emtree drug index terms
Emtree medical index terms
asymptomatic carrier, disease burden, experimental therapy, female, gender inequality, health care access, hemophilia, hemostasis, human, patient care, review, support group
Author Address
C. Hermans. Haemostasis and Thrombosis Unit/Division of Adult Haematology, Cliniques universitaires Saint-Luc, Université catholique de Louvain.
Author Email
A rare twist: COVID-19 infection masquerading as IgA vasculitis in a hemophilia a patient
Alnaqbi K.A., Abunamous N., Saleem T.
Clinical Rheumatology 2024 43:4 (1393-1399)
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Abstract
Hemophilia A and B are one of the most common hereditary bleeding disorders. Patients are predisposed to bleeding spontaneously or after minor trauma in different areas such as the skin, gastrointestinal, or joints. COVID-19 infection has been associated with various clinical manifestations and complications including rarely triggering IgA vasculitis. We report a 23-year-old man who was previously diagnosed with severe hereditary hemophilia A. He presented to our hospital with classic symptoms of IgA vasculitis, complaining of petechiae and purpura in his limbs, fatigue, body aches, poor oral intake, abdominal pain, and watery non-bloody diarrhea. He did not present with respiratory symptoms or fever typical of COVID-19 infection. Abnormal blood tests were mildly elevated C-reactive protein, elevated d-dimers, and low Factor VIII activity. Extensive immunological tests were negative. CT abdomen with contrast was unremarkable. A skin biopsy strongly indicated IgA vasculitis. COVID-19 test came back positive. The patient was managed symptomatically and with glucocorticosteroids which significantly improved his symptoms. The available literature on clinical features, laboratory tests, and management of COVID-19-associated IgA vasculitis is discussed. However, there is no case reported on the associations between hemophilia, COVID-19 infection, and IgA vasculitis. This is the first case of atypical COVID-19 infection masquerading as de novo IgA vasculitis in an adult patient with underlying hemophilia. Our case contributes to the growing body of literature about hemophilia being a possible predisposing factor that a COVID-19 virus relies on to amplify immune dysregulation resulting in IgA vasculitis.
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Alnaqbi K.A., Abunamous N., Saleem T.
Emtree drug index terms
blood clotting factor 8 (endogenous compound), C reactive protein (endogenous compound), D dimer (endogenous compound), methylprednisolone (drug therapy), methylprednisolone (intravenous drug administration), pantoprazole, paracetamol, prednisolone (drug therapy), prednisolone (oral drug administration), recombinant blood clotting factor 8 (drug therapy), recombinant blood clotting factor 8 (intravenous drug administration)
Emtree medical index terms
abdominal pain (drug therapy), adult, anaphylactoid purpura (drug therapy), ankle disease, blood analysis, case report, clinical article, clinical feature, coronavirus disease 2019, diarrhea, drug dose reduction, family history, fatigue, fluid therapy, follow up, hemophilia A (congenital disorder), hemophilia A (drug therapy), human, human tissue, laboratory test, male, nausea, pain, palliative therapy, petechia, physical examination, punch biopsy, purpura, rash, review, skin biopsy, young adult
Author Address
K.A. Alnaqbi. Division of Rheumatology, Tawam Hospital.
Author Email
Álvarez-Román M.T., Jiménez-Yuste V., Martín-Salces M., De la Corte-Rodríguez H., Bonanad S., Núñez R., Fernández-Mosteirín N., García-Frade L.J., Martinoli C., Kim H.K.
Haemophilia 2024 30:2 (513-522)
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Abstract
Aim: Joint damage due to haemarthrosis can be effectively monitored with point-of care ultrasound using the Haemophilia Early Arthropathy Detection with US (HEAD-US) scoring system. A post hoc comparative analysis of the joint status of patients with severe haemophilia A (HA) or B (HB) was performed. Methods: The databases of two observational, cross-sectional studies that recruited patients with HA or HB from 12 Spanish centres were analysed to compare the status of the elbows, knees and ankles in patients with severe disease according to treatment modality. The HEAD-US score was calculated in both studies by the same trained operators. Results: Overall, 95 HA and 41 HB severe patients were included, with a mean age of 35.2 ± 11.8 and 32.7 ± 14.2 years, respectively. The percentage of patients who received prophylaxis, over on-demand (OD) treatment, was much higher in HA (91.6%) than in HB (65.8%) patients. With a similar number of target joints, the HEAD-US score was zero in 6.3% HA and 22.0% HB patients (p <.01), respectively. The HA population showed significantly worse HEAD-US scores. Whilst osteochondral damage occurred more frequently in patients OD or tertiary prophylaxis, our data suggest that articular damage is less prominent in primary/secondary prophylaxis, regardless of the type of haemophilia. These latter treatment modalities were also associated with a lower prevalence of synovial hypertrophy, particularly in HB patients. Conclusion: This post hoc analysis indicates that joint status seems to be significantly influenced by haemophilia type (HA or HB) and treatment modality in these severe Spanish populations with severe disease. Continuing HEAD-US monitoring for the early detection and management of intra-articular abnormalities, as well as more efficiently tailored therapies should be warranted.
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Álvarez-Román M.T., Jiménez-Yuste V., Martín-Salces M., De la Corte-Rodríguez H., Bonanad S., Núñez R., Fernández-Mosteirín N., García-Frade L.J., Martinoli C., Kim H.K.
Emtree drug index terms
Emtree medical index terms
adolescent, adult, ankle, article, child, comparative study, controlled study, cross-sectional study, disease severity, early diagnosis, echography, elbow, female, hemophilia A, hemophilia B, Hemophilia Early Arthropathy Detection with Ultrasound score, hemophilic arthropathy (diagnosis), hemophilic arthropathy (prevention), human, knee, major clinical study, male, MyLabAlpha, observational study, post hoc analysis, preschool child, prevalence, primary prevention, real time ultrasound scanner, school child, scoring system, secondary prevention, Spain, Spaniard, synovitis, tertiary prevention
Author Address
M.T. Álvarez-Román. Hospital Universitario La Paz.
Author Email
