Für Sie Recherchiert 1/2023
Franchini M., Focosi D.
[In Process] Thromb. Res. 2023 222: (7-11)
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Matino D., Decker K., Iserman E., Keepanasseril A., Germini F., Chan A., Walsh L., Iorio A.
Res. Pract. Thromb. Haemost. 2022 6:
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Abstract
Background: In Canada, as yet, there are no reports on real-world safety, effectiveness and patient satisfaction outcomes when switching from a previous factor (F)VIII product to the extended half-life recombinant FVIII, damoctocog alfa pegol (BAY 94-9027/ Jivi®). Aims: To report on changes in effectiveness, utilization, and patient satisfaction when switching to damoctocog alfa pegol prophylaxis from previous standard half-life octocog alfa (BAY 81-8973/ Kovaltry®) treatment in patients with severe hemophilia A aged ≥12 years in a Canadian real-world setting. Methods: This observational, retrospective, intra-patient comparison study uses real-world data collected at the Hamilton-Niagara Regional Hemophilia Treatment Centre. Patients with severe hemophilia A (FVIII:C <0.01 IU/ml) aged ≥12 years receiving octocog alfa prophylaxis for ≥9 months and willing to switch to damoctocog alfa pegol were included and were observed for 9 months pre-and post-switch. Clinical outcomes included annualized bleeding rate and quality-of- life (QoL) evaluations (Patient Reported Outcomes, Burdens and Experiences [PROBE]). Results: Clinical outcomes data were available for 18 patients. Median annualized bleeding rates following the switch to damoctocog alfa pegol are shown in Table 1. For damoctocog alfa pegol vs octocog alfa, the median (Q1;Q3) number of infusions per week was 2.20 (2.01;2.98) vs 2.67 (2.09;2.93), respectively and the median annualized recorded FVIII utilization was 3819.6 (2980.9;4564.8) vs 4348.7 (3769.0;5156.5) IU/kg/year, respectively. QoL was maintained following the switch: Median (Q1;Q3) improvement in PROBE score was 0.02 (-0.08;0.07, n = 12). Conclusion(s): These data provide real-world evidence supporting the use of damoctocog alfa pegol as an effective alternative therapy for patients with severe hemophilia A currently receiving octocog alfa. Improved clinical outcomes were observed following this switch even when patients' QoL and bleeding control were well-maintained with octocog alfa. Long-term observation of patients on damoctocog alfa pegol prophylaxis may reveal progressive improvement in clinical outcomes and/or QoL. Study sponsored by Hemalytic, Inc.
Santoro C., Fuh B., Le P.Q., Maes P., Berrueco R., Mingot-Castellano E.M., von Mackensen S., Tueckmantel C., Cabre-Marquez J.F., Wang M.
Eur. J. Haematol. 2023 110:1 (77-87)
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Abstract
Objectives: To report the final results of the 2-year TAURUS study, assessing weekly prophylaxis dosing regimens of octocog alfa (Kovaltry®/BAY 81–8973) used in standard clinical practice in patients with moderate-to-severe haemophilia A. Methods: TAURUS (NCT02830477) is a phase 4, multinational, prospective, non-interventional, single-arm study in patients of any age with moderate or severe haemophilia A (≤5% factor [F]VIII activity). TAURUS was designed to primarily investigate weekly prophylaxis dosing regimens used in standard clinical practice. Annualised bleeding rates (ABRs), treatment satisfaction and adherence, and safety were also assessed. Results: Of 302 patients included in the full analysis set, 84.4% (n = 255) maintained their octocog alfa prophylaxis baseline regimen throughout the study, with a majority of patients (76.5%, n = 231) on two times or three times weekly regimens at the end of the observation period (≥1–≤2 years). ABRs, treatment satisfaction, and adherence remained stable during the observation period. Octocog alfa was well tolerated and there were no new or unexpected adverse events. Conclusions: These data show that a smooth transition is observed when switching to octocog alfa from a previous FVIII treatment, with no safety issues and stable bleeding rates in a real-world setting of patients with moderate-to-severe haemophilia A.
Moreno-Segura N., Pérez-Alenda S., García-Dasí M., Carrasco J.J., Marqués-Sulé E., Querol F., Bonand S., Aguilar-Rodríguez M.
[Article in Press] Haemophilia 2022 :
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Abstract
BACKGROUND: Haemophilic arthropathy is one of the main causes of morbidity in people with haemophilia (PWH), inducing pain and reduced functionality. Therefore, PWH are complex patients and must be approached from a multidisciplinary perspective. OBJECTIVES: To evaluate the effectiveness of a therapeutic exercise and cognitive-behavioural therapy (CBT) combined protocol on functionality, pain, and joint health of PWH, arthropathy and chronic pain. Treatment satisfaction was also evaluated. METHODS: A single-blinded clinical trial with 21 PWH in prophylactic regimen was carried out. Participants were divided into an experimental group (EG, n = 11) and a control group (CG, n = 10). The EG underwent a 4-month programme of home-based therapeutic exercise plus CBT, whilst CG performed their daily activities. Patients were evaluated at baseline, post-intervention and after 12 additional weeks. Measures of functionality (Haemophilia Activities List, Timed Up and Go Test, 2-Minutes-Walking-Test and Sit-to-Stand Test), pain (PainDETECT and Visual Analogue Scale) and joint health (Haemophilia Joint Health Score) were taken. Related dimensions of the A36 Haemophilia Quality of Life Questionnaire were calculated. Effects were calculated using a two-factor ANOVA. RESULTS: The EG showed significant improvements in function (p < .001), pain (p < .001), joint damage (p = .006), and satisfaction with the treatment (p = .006) dimensions of the A36 Haemophilia Quality of Life Questionnaire, as well as in pain measured with the Visual Analogue Scale (p = .008) and PainDETECT (p = .035). CONCLUSIONS: The combined physiotherapy and CBT protocol showed a partial improvement in functionality, pain and joint health of PWH, arthropathy and chronic pain. In addition, participants were satisfied with the treatment.
Miesbach W., Oldenburg J., Klamroth R., Eichler H., Koscielny J., Holzhauer S., Holstein K., Hovinga J.A.K., Alberio L., Olivieri M., Knöfler R., Male C., Tiede A.
[Article in Press] Hamostaseologie 2022 :
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Original (Non-English) Title
Gentherapie der Hämophilie: Empfehlung der Gesellschaft für Thrombose- und Hämostaseforschung (GTH)
Anti-FVIII antibodies in Black and White hemophilia A subjects: do F8 haplotypes play a role?
Pratt K.P., Gunasekera D., Vir P., Tan S., Pierce G.F., Olsen C.H., Butenas S., Mann K.G.
[Article in Press] Blood Adv 2022 :
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Abstract
The most common complication in hemophilia A (HA) treatment, affecting 25-30% of severe HA patients, is the development of alloimmune inhibitors that foreclose the ability of infused factor VIII (FVIII) to participate in coagulation. Inhibitors confer significant pathology on affected individuals and present major complexities in their management. Inhibitors are more common in African American patients, and it has been hypothesized that this is a consequence of haplotype (H)-treatment product mismatch. F8 haplotypes H1-H5 are defined by nonsynonymous single-nucleotide polymorphisms encoding sequence variations at FVIII residues 1241, 2238 and 484. Haplotypes H2-H5 are more prevalent in individuals with black African ancestry, while 80-90% of the white population has the H1 haplotype. This study used an established multiplex fluorescence immunoassay to determine anti-FVIII antibody titers in plasma from 394 HA subjects (188 black, 206 white), measuring their binding to recombinant full-length H1 and H2 and B-domain-deleted (BDD) H1/H2, H3/H5 and H4 FVIII proteins. Inhibitor titers were determined using a chromogenic assay and linear B-cell epitopes characterized using peptide microarrays. FVIII-reactive antibodies were readily detected in most HA subjects, with higher titers in those with a current inhibitor, as expected. Neither total nor inhibitory antibody titers correlated with F8 haplotype mismatches, and peptides with D1241E and M2238V polymorphisms did not comprise linear B-cell epitopes. Interestingly, the BDD-FVIII proteins were markedly more reactive than the full-length FVIII products with plasma antibodies. The stronger immunoreactivity of BDD-FVIII suggests that B-domain removal may expose novel B-cell epitopes, perhaps through conformational rearrangements of FVIII domains.
Gallastegui N., Steiner B., Aguero P., Bailey C., Kruse-Jarres R., Quon D., Hanacek C., Volland L., Barnes R., von Drygalski A.
BMC Musculoskelet. Disord. 2022 23:1
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Abstract
Background: The use of musculoskeletal ultrasound (MSKUS) for point-of-care (POC) evaluation of hemophilic arthropathy is growing rapidly. However, the extent to which MSKUS influences clinical treatment decisions is unknown. Methods: We conducted a three-year, prospective, multi-center study at three hemophilia treatment centers in the United States to evaluate the utilization of POC-MSKUS for routine clinical decision-making in adult persons with hemophilic arthropathy. Bilateral elbows, knees and ankles were assessed clinically [Hemophilia Joint Health Score (HJHS)] and with POC-MSKUS by the Joint TissueActivity and Damage Exam (JADE) protocol at baseline and approximately annually for two additional times. Treatment decisions, including physical therapy (PT) and “medical” (joint injections/aspirations, referrals to orthopedics, changes/adjustments of hemostatic plans, and use of oral anti-inflammatory medications) were recorded in relation to POC-MSKUS. Results: Forty-four persons [median age 37 years (IQR 29, 51)], mostly with severe Hemophilia A on clotting factor prophylaxis, completed 129 visits, yielding 792 joint exams by POC-MSKUS and HJHS [median at baseline 27 (IQR 18, 42)] over a median follow up of 584 days (range: 363 to 1072). Among 157 management decisions, 70% were related to PT plans (n = 110) and 30% were “medical”. Point-of-care MSKUS influenced 47/110 (43%) PT plans, mostly informing treatment of specific arthropathic joints (45/47 plans) in patients with high HJHS. Physical therapy plans influenced by POC-MSKUS directed more manual therapy/therapeutic exercises, while plans based on physical exam were focused more on global exercises and wellness. Treatment decisions were mostly based on the identification of specific musculoskeletal abnormalities visualized by POC-MSKUS. Of note 20/47 (43%) POC-MSKUS plans included de-escalation strategies, thereby reducing exercise intensity, mostly for joint instability and subclinical hemarthroses. Point-of-care MSKUS also informed 68% (32/47) of “medical” decisions, surprisingly mostly for injections/aspirations and referrals to orthopedics, and not for adjustments of hemostatic treatment. Although not formally studied, ultrasound images were used frequently for patient education. Conclusion: Routine joint evaluations with POC-MSKUS resulted in few changes regarding medical management decisions but had a profound effect on the formulation of PT plans. Based on these findings, new studies are essential to determine the benefit of MSKUS-informed management plans on joint health outcomes.
Chaves D.G., Fonseca F.M.L., Araújo H.C.B., De Oliveira L.M.M., Amorim M.V.D.A., Assis Neto C.C., Carvalho M.D.G.
Blood Coagul. Fibrinolysis 2022 33:8 (463-467)
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Abstract
Hemophilia A is a bleeding disorder caused by deficiency or low activity of circulating factor VIII characterized by prolonged blood coagulation time and often spontaneous bleeding. Patients with the severe form of the disease may present considerable heterogeneity in the occurrence of bleeding episodes and some of them have a mild hemophilia A phenotype. This study aimed to evaluate the association of biomarkers and coagulation parameters to the differential hemorrhagic profile of severe hemophilia A patients. Polymorphisms in the genes of proteins C and S, factors V and VII and prothrombin were evaluated in a group of severe hemophilia A patients with a broad spectrum of bleeding profile. Plasma levels of coagulation factors and thrombin generation were also analyzed. This study included 59 Brazilian hemophilia A patients who were allocated into low bleeding profile (LBP; n = 33) and high bleeding profile (HBP; n = 26) groups based on their joint and muscle bleeding episodes requiring treatment in the 5 years before inclusion in the study. Results evidenced that endogenous thrombin potential (ETP) and plasma factor VII levels were significantly higher in the LBP group. Results indicate a prominent importance of FVII plasma activity and endogenous thrombin potential on the differential bleeding phenotype of hemophilia A patients.
Pezeshkpoor B., Oldenburg J., Pavlova A.
Hamostaseologie 2022 42:6 (390-399)
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Abstract
Hemophilia A and hemophilia B are rare congenital, recessive X-linked disorders caused by lack or deficiency of clotting factor VIII (FVIII) or IX (FIX), respectively. The severity of the disease depends on the reduction of coagulation FVIII or FIX activity levels, which is determined by the type of the pathogenic variants in the genes encoding the two factors (F8 and F9, respectively). Molecular genetic analysis is widely applied in inherited bleeding disorders. The outcome of genetic analysis allows genetic counseling of affected families and helps find a link between the genotype and the phenotype. Genetic analysis in hemophilia has tremendously improved in the last decades. Many new techniques and modifications as well as analysis softwares became available, which made the genetic analysis and interpretation of the data faster and more accurate. Advances in genetic variant detection strategies facilitate identification of the causal variants in up to 97% of patients. In this review, we discuss the milestones in genetic analysis of hemophilia and highlight the importance of identification of the causative genetic variants for genetic counseling and particularly for the interpretation of the clinical presentation of hemophilia patients.
Area under the curve: Comparing the value of factor VIII replacement therapies in haemophilia A
Persson S., Berndt C., Engstrand S., Trinczek A., Carlsson K.S., Berntorp E.
[Article in Press] Haemophilia 2022 :
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Abstract
Introduction: In factor VIII (FVIII) prophylaxis for haemophilia A, cost comparisons have used price per international unit (IU) based on the once reasonable assumption of equivalent outcome per IU. Now, with several extended half-life (EHL) products available, new outcome-oriented ways to compare products are needed. Area under the curve (AUC) quantifies FVIII levels over time after infusion providing comparable data. Aim: To develop a decision analytical model for making indirect comparisons of FVIII replacement products based on AUC. Methods: A literature search identified 11 crossover studies with relevant pharmacokinetic data. A common comparator FVIII level curve was calculated using pooled data from selected studies. Absolute curves for other products were estimated based on relative differences to the common comparator (% difference vs the anchor). Three scenarios were investigated: (1) Kogenate® versus Kovaltry® and Jivi®; (2) Advate® versus Elocta®, NovoEight®, Kovaltry, Adynovate®, Afstyla®, and ReFacto®; and (3) Jivi versus Elocta, Adynovate, and Kogenate. Sensitivity analyses investigated effects of assay type and dose. Results: In scenario 1, Jivi (+50%) and Kovaltry (+14%) showed larger AUCs versus Kogenate. In scenario 2, EHL products, Elocta and Adynovate, had the largest AUC (+64% and +58%, respectively) versus Advate. Compared with all other products in scenario 3, Jivi had the largest AUC by +13%–28%. Conclusion: This analysis concludes that EHL products differ in relative AUC, have a larger AUC compared with standard half-life, and thus, different FVIII levels over time after infusion. This model may aid decision makers in the absence of head-to-head data.
Haemophilia A and B – evaluation of the Swedish prophylactic regimen by magnetic resonance imaging
Lundin B., Baghaei F., Holmström M., Petrini P., Müller G., Månsson S., Ljung R.
[Article in Press] Haemophilia 2022 :
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Abstract
Introduction: Sweden has been a pioneer in the prophylactic treatment of haemophilia. Magnetic resonance imaging (MRI) can detect small changes in joints and can therefore give an indication of a risk of developing arthropathy. Aim: To use MRI to evaluate the outcome of the Swedish ‘high-dose regimen’ and correlate the findings to age, bleeds, joint score and physical activity. Methods: The study group comprised 48 Swedish male patients, mean age 25 years (range 12–33 years), with severe or moderate haemophilia A or B. Data on the Haemophilia Joint Health Score (HJHS) were available and physical activity was evaluated by a self-reported questionnaire. Results: MRI score was recorded in 188 joints. Twenty out of 48 patients had a score of ≥1 (range 1–13) in 31 joints of which 3/31 scores were in the knees and 28/31 in the ankles. No correlation was found between the number of recorded bleeds and the MRI score or between HJHS and MRI score. There was no correlation between the physical activity and the number of joint bleeds per se, but a trend (OR 3.0) that those most physically active (19/48; 39.6%), more frequently had an MRI score of ≥1 with an overweight for the right ankle. Conclusion: The Swedish prophylactic model offers protection against haemophilia joint arthropathy but will still not prevent osteochondral changes in some patients at young age. MRI of the ankles can signal risk of future arthropathy and indicate need to modify the prophylactic regimen.
The impact of ankle haemarthropathy in patients with moderate haemophilia
Wilkins R.A., Siddle H.J., Chapman G.J., Horn E., Walwyn R., Redmond A.C.
[Article in Press] [In Process] Haemophilia 2022 :
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Abstract
Introduction: Moderate haemophilia has traditionally been associated with less complications than severe haemophilia. Changes in treatment recommendations have highlighted the burden of moderate haemophilia with a subset of patients with a severe bleeding phenotype. The ankle joint is disproportionally affected by ankle haemarthropathy however the impact has not been evaluated in moderate haemophilia, nor the effect on health related quality of life (HRQoL) or foot and ankle outcomes. Aims: To establish the impact of ankle haemarthropathy in patients with moderate haemophilia. Methods: A multicentre questionnaire study recruited patients from 11 haemophilia centres in England, Scotland and Wales. The HAEMO-QoL-A and Manchester-Oxford foot and ankle questionnaire (MOXFQ) with total and domain scores measured impact. Measures of pain and ankle haemophilia joint health (HJHS) scores were also collected. Results: Twenty-nine participants were recruited. HAEMO-QoL A mean (SD) total scores of 10.8 (5.2) of 100 (best health) and foot and ankle specific MOXFQ total scores of 45.5 (24.7) above zero (best outcome) indicate poor HRQoL and foot and ankle outcomes. Average ankle pain over past 6 months of (0–10) 5.5 (SD2.5) was reported and median (IQR) ankle HJHS of 3.0 (1;12.5) to 4.5 (0;9.5) for the left and right ankles. Conclusion: HRQoL and foot and ankle specific outcomes are poor in patients with moderate haemophilia and ankle haemarthropathy, driven by chronic levels of ankle joint pain. Despite moderate haemophilia being considered less affected by haemarthrosis and haemarthropathy, patients with a bleeding or haemarthropathy phenotype are clinically similar to patients with severe haemophilia A.
Acquired Haemophilia A in four north European countries: survey of 181 patients
Lindahl R., Nummi V., Lehtinen A.-E., Szanto T., Hiltunen L., Olsson A., Glenthoej A., Chaireti R., Vaide I., Funding E., Zetterberg E.
[Article in Press] [In Process] Br. J. Haematol. 2022 :
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Abstract
Acquired haemophilia A (AHA) is a rare bleeding disorder caused by acquired antibodies against coagulation factor VIII. In the Nordic countries, treatment and outcomes have not been studied in recent times. To collect retrospective data on patients diagnosed with AHA in the Nordic countries between 2006 and 2018 and compare demographic data and clinical outcomes with previously published reports, data were collected by six haemophilia centres: three Swedish, one Finnish, one Danish and one Estonian. The study included 181 patients. Median age at diagnosis was 76 (range 5–99) years, with even gender distribution. Type and severity of bleeding was comparable to that in the large European Acquired Haemophilia Registry study (EACH2). Bleedings were primarily treated with activated prothrombin complex concentrate (aPCC) with a high success rate (91%). For immunosuppressive therapy, corticosteroid monotherapy was used most frequently and this may be the cause of the overall lower clinical remission rate compared to the EACH2 study (57% vs. 72%). Survey data on 181 patients collected from four north European countries showed similar demographic and clinical features as in previous studies on AHA. aPCC was used more frequently than in the EACH2 study and the overall remission rate was lower.
Hoppe A., Rupa-Matysek J., Gil L.
Acta Haematol. Pol. 2022 53:5 (303-315)
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Abstract
Acquired hemophilia A (AHA) is a rare bleeding disorder, caused by the development of autoantibodies (inhibitor) against endogenous clotting factor VIII (FVIII). A common clinical manifestation is subcutaneous bleeding, but soft tissue hematomas and excessive post-operative hemorrhages may also occur. A diagnosis of AHA is made in patients presenting with an isolated prolonged activated partial thromboplastin time without correction in a mixed plasma study, and decreased FVIII activity. Multiple myeloma (MM) is a hematological malignancy of terminally differentiated plasma cells producing monoclonal protein (M protein). Although malignancy is found as an underlying disorder in 6–18% of AHA cases, MM seems to be a very rare cause of AHA. MM is associated with an increased risk of thrombotic complications, while AHA leads to bleeding in up to 95% of cases (although one third of patients do not require hemostatic treatment) and therefore management of patients with concomitant AHA and MM is a clinical challenge. For bleeding control and therapy of AHA, the by-passing agents activated prothrombin complex concentrate and recombinant activated factor VII, as well as porcine recombinant factor VIII, are efficient. However, for inhibitor eradication, immunosuppressive treatment can beinsufficient, and therefore intensive myeloma-aimed treatment is required. Disease- and therapy-related coagulation alterations in MM patients carry the risk of both thrombosis and bleeding, complicating the treatment of AHA in this group of patients.
Association between sports participation, factor VIII levels and bleeding in hemophilia A
Bukkems L., Versloot O., Cnossen M., Jonsson S., Karlsson M., Mathôt R.A., Fischer K.
[Article in Press] Thromb. Haemost. 2022 :
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Abstract
Background Little is known how sports participation affects bleeding risk in hemophilia. This study aimed to examine associations between sports participation, factor VIII (FVIII) levels and bleeding in persons with hemophilia A. Methods In this observational, prospective, single-center study, persons with hemophilia A who regularly participated in sports were followed for 12 months. The association of patient characteristics, FVIII levels, and type/frequency of sports participation with bleeding were analyzed by repeated time-to-event (RTTE) modelling. Results One hundred twelve persons (median age 24 years [IQR:16 - 34], 49% severe, 49% on prophylaxis) were included. During follow-up, 70 bleeds of which 20 sports-induced were observed. FVIII levels were inversely correlated with the bleeding hazard; a 50% reduction of the baseline bleeding hazard was observed at FVIII levels of 3.1 and a 90% reduction at 28.0 IU/dL. The bleeding hazard did not correlate with sports participation. In addition, severe hemophilia, pre-study annual bleeding rate and presence of arthropathy showed a positive association with the bleeding hazard. Conclusions This analysis showed that FVIII levels were an important determinant of the bleeding hazard, but sports participation was not. This observation most likely reflects the presence of adequate FVIII levels during sports participation in our study. Persons with severe hemophilia A exhibited a higher bleeding hazard at a similar FVIII levels than non-severe, suggesting that the time spent at lower FVIII levels impacts overall bleeding hazard. These data may be used to counsel persons with hemophilia regarding sports participation and the necessity of adequate prophylaxis.
Postoperative bleeding adversely affects total knee arthroplasty outcomes in hemophilia
Goker B., Caglar O., Kinikli G.I., Aksu S., Tokgozoglu A.M., Atilla B.
Knee 2022 39: (261-268)
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Abstract
Background: Hemophilic arthropathy can result in severe degenerative arthritis and functional limitations in the knees of relatively young patients. Total knee arthroplasty (TKA) provides pain relief and gain of function in advanced-stage hemophilic arthropathy cases. However, little is known about the long-term effects of early major postoperative bleeding (MPOB) in people with hemophilia (PWH). The aim of this study was to evaluate the effects of early MPOB on the final functional outcome, complications, and implant survival of TKA in a single-center hemophilia cohort. Method: PWH who underwent TKA between 1998 and 2019 in a single center were reviewed. Demographic data, clinical data, and radiographic images were evaluated. Hospital for Special Surgery (HSS), Knee Society Score (KSS), and Knee Society Function Score (KSS-F) scores were used to determine function. Patients with early bleeding complications (wound dehiscence, ecchymosis, hemarthrosis, hematoma formation, prolonged or recurrent bleeding attacks) were defined as the bleeding group. Patients who did not experience these complications were assigned to the control group. The bleeding group was compared with controls. Survival of the primary arthroplasty was analyzed by Kaplan–Meier curves. Results: Forty-five TKAs in 29 patients were included in the study. TKA led to an increase in the mean range of motion from 46.08° to 84.59° (P < 0.01). HSS scores increased from 48.33 preoperatively to 82.67 postoperatively (P < 0.01). There were improvements in both KSS and KSS-F scores from 34.22 and 53.3 preoperatively to 82.00 and 84.63 (P < 0.01), respectively. Ten patients (10 TKAs) (34%) experienced major bleeding during the postoperative period. Six of these patients had moderate hemophilia, and four had severe hemophilia. Three of these patients had hemarthroses (10.2%), one patient had a hematoma (3.4%), one patient had hemorrhagic bullae formation (3.4%), and five had excessive/prolonged bleeding from the wound (17%). The bleeding group (34%) had significantly worse HSS (63.78 vs 92.75, P < 0.001), KSS (61.78 vs 93.25, P < 0.001), and KSS-F (60.71 vs 96.25, P = 0.005) scores compared with controls. Preoperative and postoperative flexion contractures were positively correlated (+0.33, P = 0.003). One of the patients with postoperative hemarthrosis also had an accompanying transient common peroneal nerve palsy, and one patient (3.4%) had a periprosthetic fracture. Three knees (6.6%), two of whom were in the bleeding group, developed periprosthetic infections. Four knees (8.8%) in three patients underwent revision surgery, and two knees (4.4%) ended up in arthrodeses. Kaplan–Meier analysis revealed a mean survival duration of 17.04 years for the bleeding group and 22.15 years for the control group (P = 0.83). Survival rates were 80.0% for the bleeding group and 96.4% for the control group (P = 0.83). Conclusions: In this study, MPOB after TKA in PWH was common and led to significantly worse function. MPOB after TKA in PWH was associated with a higher rate of complications and lower survival rates, although the differences were not statistically significant. Efforts must be made to avoid MPOB after TKA in PWH.
Immune tolerance against infused FVIII in hemophilia A is mediated by PD-L1+ Tregs
Becker-Gotot J., Meissner M., Kotov V., Jurado-Mestre B., Maione A., Pannek A., Albert T., Flores C., Schildberg F.A., Gleeson P.A., Reipert B.M., Oldenburg J., Kurts C.
J. Clin. Invest. 2022 132:22
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Abstract
A major complication of hemophilia A therapy is the development of alloantibodies (inhibitors) that neutralize intravenously administered coagulation factor VIII (FVIII). Immune tolerance induction therapy (ITI) by repetitive FVIII injection can eradicate inhibitors, and thereby reduce morbidity and treatment costs. However, ITI success is difficult to predict and the underlying immunological mechanisms are unknown. Here, we demonstrated that immune tolerance against FVIII under nonhemophilic conditions was maintained by programmed death (PD) ligand 1–expressing (PD-L1–expressing) regulatory T cells (Tregs) that ligated PD-1 on FVIII-specific B cells, causing them to undergo apoptosis. FVIII-deficient mice injected with FVIII lacked such Tregs and developed inhibitors. Using an ITI mouse model, we found that repetitive FVIII injection induced FVIII-specific PD-L1+ Tregs and reengaged removal of inhibitor-forming B cells. We also demonstrated the existence of FVIII-specific Tregs in humans and showed that such Tregs upregulated PD-L1 in patients with hemophilia after successful ITI. Simultaneously, FVIII-specific B cells upregulated PD-1 and became killable by Tregs. In summary, we showed that PD-1–mediated B cell tolerance against FVIII operated in healthy individuals and in patients with hemophilia A without inhibitors, and that ITI reengaged this mechanism. These findings may impact monitoring of ITI success and treatment of patients with hemophilia A.
Long-term joint outcomes in adolescents with moderate or severe haemophilia A
Schmidt D.E., Michalopoulou A., Fischer K., Motwani J., Andersson N.G., Pergantou H., Ranta S.
Haemophilia 2022 28:6 (1054-1061)
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Abstract
Introduction: Favourable joint outcomes are expected with modern haemophilia A (HA) management. Evaluation of long-term treatment outcomes is hampered by the delay between bleeding episodes during childhood and resulting joint outcomes in adulthood. Aim: To measure the long-term joint health of adolescents with moderate and severe HA, according to severity and inhibitor status. Methods: Pilot cross-sectional study of five European PedNet centres in moderate and severe HA patients aged 10–19 years. Structured assessment of joint status by physical examination (HJHS) and ultrasound (HEAD-US). Results: In total, 141 HA patients were evaluable, 100 without inhibitors (81 severe, 19 moderate HA), and 41 severe HA with current/past inhibitors. On physical examination, 12/81 (15%) of severe HA without inhibitors, 3/19 (16%) of moderate HA, and 13/41 (32%) of severe HA patients with inhibitors exhibited joint abnormalities. Inhibitor persistence, longer inhibitor duration, and a high peak inhibitor level were associated with impaired joint health. Ultrasound showed joint damage (bone or cartilage) in 13/49 (27%) of severe HA without inhibitors, 1/12 (8%) of moderate HA, and 10/28 (36%) of severe HA patients with inhibitors. A discordant ankle evaluation by ultrasound versus physical examination was present in 53/169 joints (31%). Conclusions: Most adolescents with severe or moderate HA show favourable joint health. Future research with combined ultrasound and/or MRI is needed to better understand joint outcomes in the remaining patients. Patents with inhibitors showed a two-fold increased proportion with joint deterioration. Ultrasound paired with physical examination increases sensitivity for detection of joint damage.
Reding M., Alvarez-Román M., Sanabria M., Castaman G., Janbain M., Matsushita T., Meijer K., Schmidt K., Oldenburg J.
Res. Pract. Thromb. Haemost. 2022 6:
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Abstract
Background: Damoctocog alfa pegol is an extended half-life PEGylated recombinant Factor VIII product for previously treated patients (PTPs) aged ≥12 years with haemophilia A. Efficacy and safety of damoctocog alfa pegol was demonstrated in the pivotal Phase 3 PROTECT VIII trials and their extensions. Aims: HEM-POWR (NCT03932201) is an ongoing, multicentre Phase IV study to demonstrate the real-world effectiveness and safety of damoctocog alfa pegol in PTPs aged ≥12 years with haemophilia A. Second interim effectiveness analyses are presented. Methods: PTPs aged ≥12 years with haemophilia A receiving damoctocog alfa pegol with any kind of treatment modality (prophylaxis, intermittent prophylaxis or on-demand) are eligible. Primary endpoints are total bleeding events and annualised bleeding rate (ABR). Data were recorded electronically and patients provided informed consent. Ethical approval was obtained for all sites. Results: At data cut-off (31 August 2021), 162 patients were enrolled, with 78 patients included in the full analysis set (FAS; 3 mild, 9 moderate, 66 severe disease). In the FAS, mean (standard deviation [SD]) age at enrolment was 35.4 (13.6) years; 71/78 (91.0%) received prophylaxis before enrolment. The median (mean, SD) difference in ABR between the observation period and prior to damoctocog alfa pegol initiation was -0.11 (-1.01, 9.94). Additional data are summarised in Table 1. Joint health was assessed by the number of pre-treatment joint bleeds compared with the number of bleeds at the first follow-up. The number of patients with any affected joint decreased from 37/62 (59.7%) to 8/56 (14.3%). Additional data are presented in Figure 1. Conclusion(s): These second interim data support the conclusions from the PROTECT clinical trials, demonstrating the effectiveness of damoctocog alfa pegol for reducing ABR and improving joint health in patients with mild, moderate and severe haemophilia A. This study was funded by Bayer.
Cruz E., Coutinho M., Leite F., Moreira L., Pinho N., Seidi N., Morais S.
Res. Pract. Thromb. Haemost. 2022 6:
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Background: Severe hemophilia A is a serious condition and is even more critical in women. Besides common haemorrhagic symptoms (hemarthrosis and/or hematomas), women may have increased risk of developing gynaecological bleedings. Also challenging is the management of gestation and delivery. Aims: Here we describe the clinical case of a severe haemophilia A female. Methods: Sporadic severe haemophilia A female, homozygous for the F8 intron 22 inversion resulting from a maternally inherited distal inversion and a paternally inherited de novo, also distal inversion. Furthermore, the maternally inherited F8 was transcriptionally inactive. Results: Since the diagnosis, she had several bleeding episodes, including hemarthrosis (knees and elbows) and muscle hematomas. She started regular prophylaxis at age of 11 before menarche to prevent gynecological bleedings. Besides symptoms of severe haemophilia, she also had life-threatening gynaecological bleeding (ovarian hemorrhagic cysts that resulted in right oophorectomy and annexectomy). When she decided to be a mother, she was oriented to preimplantation diagnosis with gender selection and transfer of female embryos. After two unsuccessful procedures, she decided accepting the risk of giving birth to an affected child. She had two pregnancies without bleeding complications, under 3x/week prophylaxis in the first, and 2x/week in the second pregnancy, and was submitted to two caesareans. Pharmacokinetic (PK) studies performed at 28-years- old revealed a FVIII half-life of 15.1 h and FVIII in-vivo recovery of 3.2 (IU/dl per IU/kg). During first pregnancy, PK studies, at 12, 31 and 35 weeks of gestation, revealed FVIII half-lives of 17.8, 19.9 and 17.7 h and FVIII in-vivo recovery of 2.36, 3.58 and 3.26 (IU/ dl per IU/kg), respectively. Conclusion(s): This report underlines the difficulties in management of gynecological bleedings in women with severe haemorrhagic disease and the management of successful pregnancies and deliveries with a multidisciplinary approach. Additionally it shows an increase of FVIII half-life, during pregnancy.
Bernardo A., Soto I., Gutiérrez L., Caro A., Martínez-Carballeira D., Corte Buelga J., Vázquez S., Palomo-Antequera C., Andreu A., Fernández-Pardo A., Oto J., Medina P.
Res. Pract. Thromb. Haemost. 2022 6:
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Background: Hemophilia A (HA) is a rare bleeding disorder caused by factor VIII (FVIII) deficiency due to mutations in the F8 gene. Disease severity inversely correlates with plasma FVIII (FVIII:C) concentration. Unaccountably, a subgroup of severe HA patients scarcely bleed and do not require prophylactic FVIII administration, while moderate HA patients bleed frequently, despite their FVIII:C levels. Aims: To evaluate the capacity of the ST Genesia® Thrombin Generation System (TGT) to ascertain the hemostatic status of the entire cohort of HA outpatients, treated and non-bleeding, in Asturias (Spain) and to compare it with FVIII performance. Methods: We recruited 55 HA patients (18 severe, 7 moderate and 30 mild; FVIII:C< 40%) following treatment and without inhibitors, and 25 healthy controls. HA patients were monitored assessing FVIII activity (and vWF levels) at diagnosis and follow-up, and screened for F8 mutations. The TGT BleedScreen was evaluated during follow-up. Results: Patients with severe/moderate HA had lower FVIII:C at diagnosis and a higher annual bleeding rate (ABR) than mild HA patients (p < 0.001) (Table 1). Importantly, on the day of the TGT and despite having lower FVIII:C, severe/moderate patients had a similar thrombin potential than mild patients, reflecting better the non-bleeding phase of our patient cohort (Figure 1). Additionally, a correlation of the F8 mutation type was observed with HA severity, ABR and hemostatic status. Conclusion(s): The hemostatic status of HA patients measured with ST Genesia® correlates more precisely with their bleeding risk than classical FVIII:C. The F8 mutation type may indicate a worse prognosis, higher ABR and worse hemostatic status. The TGT may represent a more suitable tool than classical FVIII:C determination to identify HA patients that may require a closer follow-up and a tailored therapeutic adjustment in high-risk situations. MINECO (RYC-2013- 12587), MICIU (SAF2017-85489- P), Roche (SP200221001), GVA (ACIF/2017/138) and Sociedad Española de Trombosis y Hemostasia. (Table Presented).
Reschke M., Königs C., Marquardt N., Sigl-Krätzig M., Holzhauer S.
Res. Pract. Thromb. Haemost. 2022 6:
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Background: Treatment options for children with hemophilia have greatly improved, new treatment options, including gene therapy, emerged throughout the last years protecting from premature arthropathy and allowing an active life. Ultrasound scoring systems have been established1,2,3 as point of care methods for routine assessment of joint health to guide therapy or assess outcomes in clinical trials. Aims: To gain information on techniques currently available and used to assess joint health including standardized physiotherapeutic examinations, MRI or ultrasound. To understand what prevents physicians to use ultrasound to regularly screen for arthropathy. Methods: We electronically sent 17 questions to all members of the Pediatric working group of the Society of Thrombosis and Hemostasis (GTH). Results: 24 physicians of at least 19 different pediatric hemophilia centers answered all questions. All physicians used several examination methods to assess joint health, 54% used standardized physiotherapist exams, 50% performed ultrasound and/or MRI. Most physicians performed those examinations based on clinical symptoms (n = 13; 54%), not on a regular basis. The most commonly used ultrasound score was HEADUS (n = 10/12 performing ultrasound; 83%). 50% of physicians do not use standardized ultrasound examinations. Ultrasound examinations are mostly carried out by radiologists or treating physicians (n = 12; 50%) and (n = 11; 46%) respectively. Reasons limiting use of ultrasound were incomplete training and limited resources (time, space, physicians). 50% of physicians see a need for more education on the subject. Symptoms were rated most influential for making therapy decisions, ultrasound and MRI examinations were deemed less important. Conclusion(s): Standard of care to monitor joint health in children with hemophilia in GAS is still physical examination. Up to now, implementation of ultrasound as a regular screening tool is hampered by lack of training.
Effect of PK assessment on clinical outcomes for patients with moderate to severe hemophilia A
Young G., Callaghan M., Balasa V., Soni A., Ahuja S., Roberts J., Simpson M., Frick A., Mokdad A., Xing S., Caicedo J.
Res. Pract. Thromb. Haemost. 2022 6:
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Background: Individualized pharmacokinetic (PK)-guided prophylaxis has been shown to improve outcomes in patients with hemophilia A (PWHA) in clinical trials; however, PK-guided testing in real-world settings is poorly understood. Aims: This retrospective chart review examined clinical outcomes for patients before and after PK testing in US hemophilia treatment centers (HTC). Methods: This study included 132 male PWHA from 7 HTCs with moderate or severe disease, ≥3 months prior FVIII prophylaxis and up to 12 months FVIII prophylaxis after PK-guided prescription change (index date), no inhibitors prior to index date, and no concurrent participation in clinical trials. Change in mean annualized bleed rate (ΔABR) and confidence intervals (CIs) were calculated using patient bleed logs. (Table Presented) Results: Of the 132 patients (age: Median = 13, range: 2-43; severe disease: 93.2%), 58 (44%) remained on the same FVIII (non-switchers) and 74 (56%) switched FVIII therapy (switchers) after PK assessment. The majority (95%) of switchers had transitioned from a standard half-life (SHL) to extended half-life (EHL) product. ABR decreased for the entire cohort post-index [-0.97 (95% CI: -1.54, -0.42)], driven by a decrease in joint bleeds [-0.77 (-1.23, -0.34)]. Decrease in ABR was larger among non-switchers [-1.93 (-3.14, -0.78)], similarly driven by a decrease in joint bleeds [-1.43 (-2.45, -0.54)]. Although switchers did not have a significant decrease in ABR [-0.35 (-0.78, 0.06)], switchers had lower ABRs before PK-guided prophylaxis vs non-switchers (1.23 vs 3.85, respectively) and maintained lower ABRs after index date (0.88 vs 1.93). Conclusion(s): Individualized pharmacokinetic-guided prophylaxis was associated with an overall reduction in ABR in both FVIII switchers and non-switchers, with results more pronounced among non-switchers. Dose adjustments based on PK testing could be a useful strategy for optimizing treatment for those remaining on same SHL or EHL therapy and maintaining proper trough levels in patients switching from SHL to EHL.
Khair K., Nissen F., Ferri-Grazzi E., O'Hara J., Ofori-Asenso R., Aizenas M., Zhang H., Moreno K., Burke T., Nolan B.
Res. Pract. Thromb. Haemost. 2022 6:
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Background: Hemophilia A (HA) is a congenital bleeding disorder caused by a deficiency in clotting factor (F)VIII and can cause uncontrolled bleeding and musculoskeletal dysfunction. Published data on the unmet clinical need in moderate and mild HA are limited. Aims: To assess bleed outcomes in people with moderate or mild HA. Methods: CHESS II and CHESS PAEDs are retrospective, burden-of- illness studies. CHESS II was conducted in adults (≥18 years), with hemophilia of any severity, across eight European countries. CHESS PAEDs focused on children (0-17 years), with moderate or severe hemophilia, across five European countries. Both studies obtained informed consent and ethical approval for data use. Data were captured by specialists via web-based forms. Twelve months of retrospective data on all bleeding episodes, target joints and pain were examined. Results: In CHESS II, 174/190 adults (91.6%) with moderate HA and 92/94 adults (97.9%) with mild HA did not receive routine prophylaxis (Table 1). Of those not receiving prophylaxis: 147/174 (84.5%) with moderate HA had ≥1 bleed/year, including 60/174 (34.5%) who had ≥3 bleeds/year; 69/92 (75.0%) with mild HA had ≥1 bleed/year, including 7/92 (7.6%) who had ≥3 bleeds/year. In CHESS PAEDs, of the 282 children with moderate HA included, 146/282 (51.8%) did not receive routine prophylaxis (Table 2); of those, 108/146 (74.0%) had ≥1 bleed/year, including 59/146 (40.4%) who had ≥3 bleeds/ year. In those not receiving prophylaxis, the number of target joints and pain severity increased with a higher number of bleeds. Conclusion(s): Most adults with moderate or mild HA in CHESS II and more than half of children with moderate HA in CHESS PAEDs did not receive routine prophylaxis; more than one third of adults and ∼40% of children with moderate HA not receiving prophylaxis experienced ≥3 bleeds/year. Additional research is warranted to investigate potential reasons for limited use of prophylaxis in these populations. (Table Presented).
Pain as a determinant of the quality of everyday functioning of persons with haemophilia
Marinić M., Rihtar S., Boban A.
Res. Pract. Thromb. Haemost. 2022 6:
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Background: Pain has been described commonly in persons with haemophilia, however, the effect of pain on various aspects of their everyday functioning is still underexplored. Aims: The aim of this study was to analyse the frequency and intensity of pain among persons with haemophilia, its effect on daily activities, and correlation with disease severity and sociodemographic and psychological characteristics. Methods: The data were obtained by a survey conducted in 2021 among adults with haemophilia in Croatia. The questions included sociodemographic data (age and education), details on haemophilia (type, severity, and frequency of bleeding), pain scales evaluating frequency, intensity, and the effect of pain on daily activities, and psychological characteristics (depression, optimism, happiness, and feeling of physical safety). Table 1 Top sub-concepts by Hemo-TEM domain Results: A total of 98 patients responded to the survey. 24.7% of them reported that they suffer from pain daily, and 25.8% frequently. Pain was reported as moderately intensive in 45.4%, intensive in 13.4% and very intensive in 2.1% of the respondents. The influence of pain on daily activities demonstrated interaction with recreational activities (M = 2.73), walking (M = 2.63), working (M = 2.42), and sleeping (M = 2.16), when using the scoring scale (range 1-5). Pain significantly correlated with haemophilia severity, frequency of bleeding, age, and was related to depression, optimism, and feelings of happiness and physical safety. Regarding the concurrent effect of pain intensity and/or frequency on these psychological variables, regression analysis shows that in both cases pain is a significant predictor only if it has a negative impact on daily activities as a mediator. Conclusion(s): Pain is present in many persons with haemophilia, particularly the older ones with severe disease, and affects various aspects of their everyday functioning. It is necessary to raise awareness of this problem, to continue working on pain prevention and treatment, and to provide effective mechanisms of psychological support.
Real-world efficacy of extended half-life Factor VIII in patients with haemophilia A on prophylaxis
White K., Alamelu J., Ling G.
Res. Pract. Thromb. Haemost. 2022 6:
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Background: Standard half-life Factor VIII (FVIII) products were previously the standard of care as prophylaxis in Haemophilia A with requiring alternate day administration. Recently, extended half-life (EHL) FVIII has been licensed to improve adherence and convenience for patients. Two products available in the United Kingdom are 1. Esperoct (turoctocog alfa pegol), a PEGylated recombinant FVIII, and 2. Elocta (efmoroctocog alfa), a rFVIII-Fc fusion protein. While the ASPIRE trial (Elocta) and Pathfinder (Esperoct) trial demonstrated ABR of <1 and 1.2 respectively, evidence in the real-world setting are useful to validate the findings. Aims: To review the management, real-world outcomes and concordance of patients receiving EHL FVIII outside of the clinical trial setting. Methods: A single centre, retrospective audit of clinical notes and laboratory results for all patients (children and adults) currently receiving EHL FVIII. Data were collected on patient demographics, annualised bleed rates (ABR), surgery and the presence of FVIII inhibitors. Results: 44 patients are on EHL FVIII at St Thomas' Hospital Haemophilia comprehensive care centre, which treats a total of 370 patients with Haemophilia A of any severity. 18 patients use Esperoct and 26 use Elocta with an average age of 41.5 years and 21 years respectively. Treatment time on Esperoct was 25 months (stdev 25.8) and Elocta 45.2 months (stdev 25.9), with the majority infusing twice weekly. The ABR for Esperoct was 1.2 and for Elocta 0.92. Major and minor surgical procedures were performed with no bleeding. Pharmacokinetic studies have been difficult during the pandemic but 14/18 (77.8%) troughs were done with Esperoct and 26/26 with Elocta. No inhibitors were identified with either EHL FVIII. Conclusion(s): In a large cohort, EHL FVIII have demonstrated good efficacy data at minimising ABRs in the real-world setting, providing adequate haemostasis during surgical procedures whilst reducing the infusional burden for patients.
Role of activated platelets in compensation of bleeding severity in hemophilia A
Laha Roy C., Maharana S., Kishor K., Ranjan R., Mahapatra M., Saxena R., Kannan M.
Res. Pract. Thromb. Haemost. 2022 6:
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Background: Hemophilia A (HA) is an X linked bleeding disorder which is due to the deficiency of factor VIII (FVIII). Severity of the disease is categorized based on the FVIII level and the HA patients with factor level <1% are characterized ad severe. Majority of these patients tend to have major hemorrhages. However, in general, 10% of severe patients compensate major bleeding. We hypothesize that activated platelets may have a role in compensation of bleeding severity in these patients. Aims: To investigate the role of activated platelets in severe HA with mild hemorrhages. Methods: Twelve severe HA patients and equal number of age matched normal were included after obtaining informed consent. Clinical details such as bleeding type, frequency and number of transfusions were recorded. 10 ml whole blood was collected and subjected for flow cytometry analyses to study the activated platelets. For this purpose, platelets were incubated with CD62P, PAC-1 and Annexin V and a minimum of 10,000 events were recorded for the analysis. Results: All HA patients had <1% FVIII and their age ranged between 7 and 39 years. Two of these patients never had muscle bleed and FVIII was infused to them only on demand. In addition to this, one of these two patients never developed any joint bleed. Based on bleeding and FVIII infusion, these patients were categorized as mild bleeders. When examined their platelets using flow cytometry, the PAC-1 binding were higher in both the patients (3.64% and 2.91% respectively) compared to that of normal (0.95%). However, the CD62P and AV binding in these patients were within the normal. Conclusion(s): Patients with mild bleeding had higher expression of integrin receptor complex αIIbβ3 which indicates the activated status of platelets in them. Thus, it is possible that activated platelets may contribute to mild hemorrhage in these patients.
Annualized bleeding rates in severe hemophilia on prophylaxis in a real-world setting
Kraemmer D., Bauer B., Ay C., Pabinger I.
Res. Pract. Thromb. Haemost. 2022 6:
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Background: Therapeutic options for hemophilia have expanded considerably with the introduction of extended half-life products (EHL). Aims: We investigated prophylaxis with standard (SHL) and EHL in a real-world setting. Methods: In our center, patient diaries used to self-document infusions and bleeding episodes are collected within the framework of the Austrian Haemophilia Registry. We included all recorded infusions of adult patients with hemophilia A (HA) or B (HB) receiving prophylaxis with SHL or EHL (albutrepenonacog-alfa, damoctocog-alfa- pegol, efmoroctocog-alfa, eftrenonacog-alfa, lonoctocog-alfa, nonacog-beta- pegol, rurioctocog-alfa- pegol) for ≥6 months between 2018-01- 01 and 2020-12- 31. Since switching between products could occur, we analyzed the data using mixed-effects models allowing for random intercepts and adjusting for age and hemophilia type. Results: Fifty HA (median age 35 years; interquartile range 25-41) and 7 HB patients (42 years; 29-59) recorded a total of 31.3 million IU over 13,820 infusions for a median of 730 days (range 190-1,095). Median annualized bleeding rate (ABR) and joint ABR of the whole cohort was 4.74 (0.67-14.15) and 3.01 (0-8.36), respectively. Twenty-five patients were treated with EHL, eight of which documented a switch during the observation period. Summary statistics of ABR, joint ABR, infusion frequency, and factor consumption are presented in Table 1. Prophylaxis with EHL was associated with an incidence total and joint ABR ratio of 0.55 (95% CI 0.42, 0.73) and 0.73 (95% CI 0.53, 1.01), respectively; and a difference in weekly factor usage of 386.6 IU (95% CI -480.9, 1,254.1). Weekly infusions were lower on EHL (-0.43; 95% CI -0.76, -0.08). Conclusion(s): ABR and joint ABR during prophylaxis with EHL, albeit lower when compared to SHL, were still high overall, which might partly be explained by preferential switching of patients with more complicated bleeding phenotypes. Patients with high bleeding rates despite prophylaxis require an individualized approach such as an increase in their infusion frequency, a switch to non-factor treatments, or gene therapy.
Oleshko O., Klingberg A., Curth U., Werwitzke S., Tiede A.
Res. Pract. Thromb. Haemost. 2022 6:
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Background: Acquired hemophilia A (AHA) is a bleeding disorder due to neutralizing autoantibodies against FVIII. Its clinical presentation significantly differs from that in congenital hemophilia A (CHA) with or without alloantibody inhibitors, but the underlying reason remains unknown. We have previously shown that anti-FVIII antibodies form immune complexes (IC) when FVIII protein concentration exceeds the normal range, which is expected in AHA but not CHA. These complexes incorporate von Willebrand factor (VWF) and might therefore disturb primary hemostasis. Aims: To explore the functional impact of VWF-containing FVIII-IC on hemostasis. Methods: IC were detected and characterized by analytical ultracentrifugation (AUC). FVIII-depleted normal plasma was supplemented with VWF, washed fluorescently-labeled platelets from healthy volunteers, and a mix of 7 monoclonal anti-FVIII IgG antibodies (Ab1-7) with or without FVIII. A Bioflux flow chamber model under high shear rates and calibrated automated thrombography were used to assess the primary and secondary hemostasis, respectively. Results: Formation of IC by Ab1-7 was observed in the presence of FVIII, but not in its absence. VWF was incorporated into FVIII-IC as shown by AUC. VWF-dependent platelet adherence and aggregation under high shear stress was significantly impaired (by 20 to 100%), depending on platelet donor and experimental conditions, in the presence of FVIII-containing IC as compared to Ab1-7 alone. In contrast, thrombin generation capacity was not impaired by FVIII-IC. Conclusion(s): Our data demonstrate that FVIII-IC contain vWF and disturb platelet function in an ex vivo model of primary hemostasis. We suggest that FVIII-IC occurring in AHA disturb hemostasis more severely than just the absence of FVIII in CHA with or without inhibitors. The severe impairment of primary hemostasis, combined with the suppression of FVIII activity, could contribute to the unique bleeding pattern of AHA.
Timmer M.A., Kuijlaars I.A.R., Kloek C., de Kleijn P., Schutgens R.E.G., Veenhof C., Pisters M.F.
[Article in Press] [In Process] Haemophilia 2022 :
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Background: Regular physiotherapy with a physiotherapist experienced in the field is not feasible for many patients with haemophilia. We, therefore, developed a blended physiotherapy intervention for persons with haemophilic arthropathy (HA) (e-Exercise HA), integrating face-to-face physiotherapy with a smartphone application. Aim: The aim of the study was to determine proof of concept of e- Exercise HA and to evaluate feasibility. Methods: Proof of concept was evaluated by a single-case multiple baseline design. Physical activity (PA) was measured with an accelerometer during a baseline, intervention and post-intervention phase and analysed using visual inspection and a single case randomisation test. Changes in limitations in activities (Haemophilia Activities List [HAL]) and a General Perceived Effect (GPE) were evaluated between baseline (T0), post-intervention (T1) and 3 months post-intervention (T2) using Wilcoxson signed rank test. Feasibility was evaluated by the number of adverse events, attended sessions and open-ended questions. Results: Nine patients with HA (90% severe, median age 57.5 (quartiles 50.5–63.3) and median HJHS 32 (quartiles 22–36)) were included. PA increased in two patients. HAL increased mean 15 (SD 9) points (p =.001) at T1, and decrease to mean +8 points (SD 7) (p =.012) at T2 compared to T0. At T1 and T2 8/9 participants scored a GPE > 3. Median 5 (range 4–7) face-to-face sessions were attended and a median 8 out of 12 information modules were viewed. No intervention-related bleeds were reported. Conclusion: A blended physiotherapy intervention is feasible for persons with HA and the first indication of the effectiveness of the intervention in decreasing limitations in activities was observed.
Germini F., Noronha N., Abraham Philip B., Olasupo O., Pete D., Navarro T., Keepanasseril A., Matino D., de Wit K., Parpia S., Iorio A.
J. Thromb. Haemost. 2022 20:6 (1364-1375)
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Background: Knowledge about the risk for bleeding in patients with hemophilia (PWH) would be relevant for patients, stakeholders, and policy makers. Objectives: To perform a systematic review of the literature on risk assessment models (RAMs) and risk factors for bleeding in PWH on regular prophylaxis. Methods: We searched Medline, Embase, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews from inception through August 2019. In duplicate, reviewers screened the articles for inclusion, extracted data, and assessed the risk for bias using the Quality in Prognostic Studies (QUIPS) tool. A qualitative synthesis of the results was not performed due to high heterogeneity in risk factors, outcomes definition and measurement, and statistical analysis of the results. Results: From 1843 search results, 10 studies met the inclusion criteria. No RAM for the risk for bleeding in PWH was found. Most studies included only PWH A or both PWH A and B and were conducted in North America or Europe. Only one study had a low risk for bias in all the domains. Eight categories of risk factors were identified. The risk for bleeding was increased when factor levels were lower and in people with a significant history of bleeding or who engaged in physical activities involving contact. Conclusions: Our findings suggest that plasma factor levels, history of bleeds, and physical activity should be considered for the derivation analysis when building a RAM for bleeding in PWH, and the role of other risk factors, including antithrombotic treatment and obesity, should be explored.
Cortesi P.A., Di Minno G., Zanon E., Giuffrida G., Santoro R.C., Marino R., D’angiolella L.S., Antonazzo I.C., Squassabia G., Clemente F., Di Laura D., Cimino E., Pasca S., Nicolosi D., Mantovani L.G.
J. Clin. Med. 2022 11:12
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Abstract
(1) Background: new generations of rFVIII products offered the possibility to improve personalized therapeutic approaches, reducing the number of infusions or increasing the protection against bleeding risk. The aim of this study was to assess the effectiveness of prophylaxis with BAY 81-8973 (octocog alfa, Kovaltry®, Bayer Pharma AG) in the real-world setting and its impact on FVIII consumption compared to previous standard half-life treatments. (2) Methods: a retrospective observational study was conducted in five Italian Haemophilia Centers. Patients with haemophilia A under prophylactic treatment with BAY 81-8973 for at least one year, and previously on prophylaxis with a different product were included in the study. Annual bleeding rate (ABR) and annual FVIII consumption were compared. (3) Results: forty-four patients were included in the study. After switching to BAY 81-8973, ABR was significantly reduced (1.76 vs. 0.23; p = 0.015), the percentage of patients with zero bleeds increased from 54.6% to 84.1% (p = 0.003), and the overall FVIII consumption decreased by 25,542 (−7.2%, p = 0.046) IU per patient-year. Patients treated every 3 days or 2 times per week increased from 0% to 27.3%. (4) Conclusion: our results suggest that prophylaxis with BAY 81-8973 can improve clinical outcomes and reduce FVIII consumption, in the real-world practice, compared with the previous prophylaxis regimen with standard half-life products.
Cortesi P.A., Di Minno G., Zanon E., Giuffrida G., Santoro R.C., Marino R., D’angiolella L.S., Antonazzo I.C., Squassabia G., Clemente F., Di Laura D., Cimino E., Pasca S., Nicolosi D., Mantovani L.G.
J. Clin. Med. 2022 11:12
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Abstract
(1) Background: new generations of rFVIII products offered the possibility to improve personalized therapeutic approaches, reducing the number of infusions or increasing the protection against bleeding risk. The aim of this study was to assess the effectiveness of prophylaxis with BAY 81-8973 (octocog alfa, Kovaltry®, Bayer Pharma AG) in the real-world setting and its impact on FVIII consumption compared to previous standard half-life treatments. (2) Methods: a retrospective observational study was conducted in five Italian Haemophilia Centers. Patients with haemophilia A under prophylactic treatment with BAY 81-8973 for at least one year, and previously on prophylaxis with a different product were included in the study. Annual bleeding rate (ABR) and annual FVIII consumption were compared. (3) Results: forty-four patients were included in the study. After switching to BAY 81-8973, ABR was significantly reduced (1.76 vs. 0.23; p = 0.015), the percentage of patients with zero bleeds increased from 54.6% to 84.1% (p = 0.003), and the overall FVIII consumption decreased by 25,542 (−7.2%, p = 0.046) IU per patient-year. Patients treated every 3 days or 2 times per week increased from 0% to 27.3%. (4) Conclusion: our results suggest that prophylaxis with BAY 81-8973 can improve clinical outcomes and reduce FVIII consumption, in the real-world practice, compared with the previous prophylaxis regimen with standard half-life products.
Cardiovascular disease in hereditary haemophilia: The challenges of longevity
Shapiro S., Benson G., Evans G., Harrison C., Mangles S., Makris M.
Br. J. Haematol. 2022 197:4 (397-406)
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The development of effective and safe treatments has significantly increased the life expectancy of persons with haemophilia (PWH). This has been accompanied by an increase in the comorbidities of ageing including cardiovascular disease, which poses particular challenges due to the opposing risks of bleeding from haemophilia and antithrombotic treatments versus thrombosis. Although mortality secondary to coronary artery disease in PWH is less than in the general population, the rate of atherosclerosis appears similar. The prevalence of atrial fibrillation in PWH and risk of secondary thromboembolic stroke are not well established. PWH can be safely supported through acute coronary interventions but data on the safety and efficacy of long-term antithrombotics are scarce. Increased awareness and research on cardiovascular disease in PWH will be crucial to improve primary prevention, acute management, secondary prevention and to best support ageing PWH.
Invisible bleeds: Lived experiences and barriers to care for men with hemophilia
Arya S., Siad F.M., Wilton P., Page D., Boma-Fischer L., Floros G., Winikoff R., Teitel J., Sholzberg M.
J. Thromb. Haemost. 2022 20:2 (296-306)
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Introduction: Guidelines of the World Federation of Hemophilia support the provision of equitable, optimal care for people with hemophilia (PWH). However, limited research exists examining the lived experiences of PWH or the barriers to care they may encounter. The primary objective of this exploratory study was to describe the experiences of men with hemophilia in Canada. Methods: We conducted a qualitative descriptive study using a semistructured interview guide and analyzed transcribed interviews using inductive thematic content analysis. Inclusion criteria were: age ≥18 years, English-speaking, and confirmed diagnosis of inherited hemophilia A or B. Results: A total of 11 participants were interviewed. Median age was 39 years old (29–73 years old), and diagnoses included severe hemophilia A (n = 5), mild hemophilia A (n = 2), and severe hemophilia B (n = 4). Three primary themes arose: (1) impact on identity and daily life; (2) dynamic changes in treatment; and (3) barriers to care and identified needs. Major subthemes included chronic pain and activity limitation, psychosocial burden, and symptom normalization. Multidisciplinary care, coordinated surgical care, improved emergency care, and clear care plans were identified as ongoing needs. Discussion: Men with hemophilia described significant symptom burden and areas of ongoing need. Collaborative efforts between hematologists, emergency room physicians, and surgeons to establish hospital-specific testing, treatment and referral guidelines, and regular hemophilia treatment center audits may help address these care gaps, providing more person-centered, equitable care. Future work is required to implement these strategies and monitor their effects.
Minno M.N.D.D., Martinoli C., Pasta G., la Corte-Rodriguez H.D., Samy I., Stephensen D., Timmer M.A., Winburn I.
[Article in Press] Haemophilia 2022 :
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Background: Patients with haemophilia experience recurring hemarthroses, mainly involving knees, elbows and ankles, which lead to haemophilic arthropathy, the major chronic complication of haemophilia. With new approaches to haemophilia treatment leading to fewer joint bleeds and, in some cases, no bleeding events, assessing whether current outcome assessment tools provide adequate sensitivity and specificity for management and care of patients with haemophilia is needed. Methods: An overview of current imaging tools for monitoring joint health, novel osteochondral damage and synovial proliferation biomarkers, and the relationship between assessments for functionality and imaging modalities is provided. Usefulness and sensitivity of point-of-care ultrasound (POCUS) to complement other assessments and use of ultrasound to monitor haemophilic arthropathy are also examined. Results: This review provides rationale for haemophilia teams to move beyond traditional outcomes in joint imaging, as well as guidance and evidence on assessment of joint health for potential new treatment modalities, such as gene therapy. The role of POCUS in the existing paradigm for haemophilia care and management along with the use of ultrasound as a complement to other outcome assessment tools are also discussed. Finally, the clinical effects of subclinical bleeding on joint function are described, to motivate screening for synovial proliferation. Conclusion: POCUS can facilitate the early detection of joint damage and can monitor disease progression while providing insights into the efficacy of treatment regimens, and should be considered as an essential assessment tool for managing the care of patients with haemophilia.
Acute-type acquired hemophilia A after COVID-19 mRNA vaccine administration: A new disease entity?
Hosoi H., Tane M., Kosako H., Ibe M., Takeyama M., Murata S., Mushino T., Sonoki T.
J. Autoimmun. 2022 133:
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Abstract
Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder. Various autoimmune diseases, including AHA, have been reported to occur after the administration of mRNA COVID-19 vaccines. However, the characteristics of these AHA cases remain unclear. We report a case in which AHA arose in a young patient after the administration of an mRNA COVID-19 vaccine, but improved rapidly. The patient's factor VIII (FVIII) inhibitor titer spontaneously decreased to less than half of that seen at diagnosis. One week after the initial immunosuppressive therapy, the FVIII inhibitor had disappeared. Our case suggests that AHA that arises in young patients after COVID-19 vaccination may resolve spontaneously, and the levels of FVIII inhibitors may decrease more rapidly in such cases than in idiopathic AHA. Unlike for immune thrombocytopenic purpura (ITP), no acute type of AHA has been recognized. This case suggests that just as there is an acute type of ITP that develops in children/after vaccination, there may be an acute type of AHA that arises in young patients that receive mRNA COVID-19 vaccines.
Usefulness of anti-factor VIII IgG ELISA in acquired hemophilia A follow-up
Chansavang A., Philippe A., Bozinovic I., Ben Hadj Ali K., Smadja D., Helley D., Darnige L., Mauge L.
Ann. Hematol. 2022 101:11 (2453-2460)
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Abstract
Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder due to the presence of neutralizing autoantibodies directed against the coagulation factor VIII (FVIII). The reference method to detect and quantify anti-FVIII antibodies is the Bethesda assay (BA), but it presents some limitations such as a lack of sensitivity for low titers of inhibitor and the need for experienced laboratory. A commercially available ELISA detecting anti-FVIII antibodies has demonstrated excellent sensitivity and specificity. The aim of our study was to assess the performance of this ELISA for the detection of anti-FVIII IgG in AHA patients during the follow-up. In total, 11 acquired hemophilia A patients were recruited, and anti-FVIII antibody levels were monitored by BA and ELISA. Anti-FVIII IgG ELISA showed 100% sensitivity and 100% specificity, and it correlated with the BA. Discrepancies observed in 13.3% of cases were consistent with patients’ biological evolution. All these data suggest the possible use of anti-FVIII IgG ELISA for both diagnosis and follow-up of AHA patients.
Plut D., Kotnik B.F., Pusnik L., Slak P., Snoj Z., Salapura V.
[Article in Press] Radiol Oncol 2022 :
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Abstract
BACKGROUND: Ultrasound (US) has been proven to be reliable in the assessment of early haemophilic arthropathy in the adult haemophilic population, however few studies so far focused on the reliability of US specifically in the paediatric haemophilic population. We were interested if the changing appearance of the growing bone hinders the ultrasonographic evaluation of the pathologic processes caused by haemophilic arthropathy. The aim of the study was to assess the reliability of US for evaluation of haemophilic arthropathy in children in comparison to magnetic resonance imaging (MRI). PATIENTS AND METHODS: The study included all children aged 6 years or more with severe haemophilia in the country (n = 10). We assessed their elbows, knees, and ankles bilaterally by US and compared the results to the MRI as the reference standard. Pearson correlation coefficient (r) was used to analyse correlation. RESULTS: The correlation with MRI for the US for the total score was excellent for all joints (r = 0.849 for the elbows, r = 1 for knees, r = 0.842 for ankles). The correlation of scores for specific joint components showed fair, moderate, or excellent correlation for all joint components in all joints. The correlation was the lowest for the evaluation of cartilage and bone in the ankles (r = 0.546 and r = 0.478) and bone in the elbows (r = 0.499). CONCLUSIONS: Our study proved that US using the HEAD-US method performed by paediatric radiologists is a reliable tool for detection and quantification of haemophilic arthropathy in children in comparison to MRI.
The potential role of protease systems in hemophilic arthropathy
Hauw W.W.S., Chia J.S.J., Nandurkar H.H., Sashindranath M.
Blood Adv 2022 6:18 (5505-5515)
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Abstract
Hemophilic arthropathy (HA) is characterized by joint damage following recurrent joint bleeds frequently observed in patients affected by the clotting disorder hemophilia. Joint bleeds or hemarthroses trigger inflammation in the synovial tissue, which promotes damage to the articular cartilage. The plasminogen activation system is integral to fibrinolysis, and the urokinase plasminogen activator, or uPA in particular, is strongly upregulated following hemarthroses. uPA is a serine protease that catalyzes the production of plasmin, a broad-spectrum protease that can degrade fibrin as well as proteins of the joint extracellular matrix and cartilage. Both uPA and plasmin are able to proteolytically generate active forms of matrix metalloproteinases (MMPs). The MMPs are a family of >20 proteases that are secreted as inactive proenzymes and are activated extracellularly. MMPs are involved in the degradation of all types of collagen and proteoglycans that constitute the extracellular matrix, which provides structural support to articular cartilage. The MMPs have an established role in joint destruction following rheumatoid arthritis (RA). They degrade cartilage and bone, indirectly promoting angiogenesis. MMPs are also implicated in the pathology of osteoarthritis (OA), characterized by degradation of the cartilage matrix that precipitates joint damage and deformity. HA shares a number of overlapping pathological characteristics with RA and OA. Here we discuss how the plasminogen activation system and MMPs might exacerbate joint damage in HA, lending insight into novel possible therapeutic targets to reduce the comorbidity of hemophilia.
Bogachev-Prokophiev A., Sharifulin R., Karadzha A., Larionova N., Shmyrev V., Kornilov I., Mamaev A., Afanasyev A., Pivkin A.
Clin. Case Rep. 2022 10:8
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Abstract
Minimally invasive mitral valve repair and ablation of atrial fibrillation, combined with FVIII level-controlled replacement therapy, can be safely performed in patients with severe hemophilia.
Risk of diabetes in haemophilia patients compared to clinic and non-clinic control cohorts
Pandey B., Barnes R.F.W., Sun H., Jackson S., Kruse-Jarres R., Quon D.V., von Drygalski A.
Haemophilia 2022 28:3 (445-452)
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Abstract
Introduction: Ageing patients with haemophilia (PWH) develop cardiovascular risk factors impacting care. Little is known about the prevalence of diabetes in PWH and its relation to other comorbidities. Aim: To examine the risk of diabetes for adult PWH compared to men from the general United States population (National Health and Nutrition Examination Surveys [NHANES]) and outpatients attending a Veterans Affairs Medical Center (VAMC) clinic. Methods: Retrospective cross-sectional design. PWH from four haemophilia centres (n = 690) were matched with random samples from NHANES and VAMC. Diabetes (yes/no) was the outcome, while age, body mass index (BMI), race and Hepatitis C (HCV; by serology) and human immunodeficiency virus (HIV) positivity were covariates. We fitted semiparametric generalized additive models (GAMs) in order to compare diabetes risk between cohorts. Results: Younger PWH were at lower risk of diabetes than NHANES or VAMC subjects irrespective of BMI. However, the risk of diabetes rose in older PWH and was closely associated with HCV. For HCV-negative subjects, the risk of diabetes was considerably lower for PWH than NHANES and VAMC subjects. The difference persisted after controlling for BMI and age, indicating that the low risk of diabetes in PWH cannot be explained by lean body mass alone. Conclusion: Since many ageing PWH are HCV positive and therefore at heightened risk for diabetes, it is important to incorporate diabetes screening into care algorithms in Haemophilia Treatment Centers, especially since PWH are not always followed in primary care clinics.
