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Eichler H., Albisetti M., Halimeh S., Knöfler R., Königs C., Langer F., Miesbach W., Oldenburg J., Scholz U., Streif W., Klamroth R.
[Article in Press] Hamostaseologie 2024 :
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Abstract
Since the 1970s, specialized hemophilia centers have been established to optimize the complex and costly treatment of patients with severe bleeding disorders. In 2019, the first GTH guidelines on the structural and process quality of hemophilia centers were published. On this basis, a procedure for the certification of hemophilia centers has been established under the technical leadership of the GTH. These GTH guidelines are essentially based on the European Guidelines for the Certification of Haemophilia Centers published in 2013, created by the European Haemophilia Network (EUHANET). In 2023, this European guideline was revised by the EAHAD Accreditation and Audit of Haemophilia Centers Working Group. On this background, the GTH guidelines have now been revised to take relevant updates to the European guidelines into account.
Original (Non-English) Title
Leitlinie der Gesellschaft für Thrombose-und Hämostaseforschung (GTH) zur Struktur-und Prozessqualität von Hämophilie-Zentren
Non-drug Index Terms
accreditation, article, bleeding disorder, certification, clinical audit, drug therapy, hemophilia, human, multicenter study, therapy
Chandler M., Moulton T., Charafi L., Charlet J., Recht M.
[Article in Press] [In Process] Eur. J. Haematol. 2024 :
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Abstract
Objectives: Health information for 17 109 people living with hemophilia A (PLwHA) is contained within the ATHNdataset. We aimed to evaluate the real-world effectiveness of damoctocog alfa pegol (BAY 94-9027, Jivi®) for hemophilia A. Methods: The ATHNdataset was queried for PLwHA receiving damoctocog alfa pegol between January 1, 2010 and April 30, 2022. Data captured via patient charts were analyzed. Results: At data cutoff, 205 PLwHA were treated with damoctocog alfa pegol: 150 (73.2%) severe (1 female [0.5%]) and 55 (26.8%) mild/moderate (3 [1.5%] female). In total, 32/205 (25.9%) PLwHA received on-demand treatment; 172 (83.9%) received prophylaxis—161 (93.6%) continuous prophylaxis. Documented bleed rates were available for 187 (91.2%) PLwHA, including those on prophylaxis and on-demand regimens, with 150 (80.2%) treated for > 12 months. Overall annualized bleeding rates and proportion of PLwHA with zero bleeds, receiving prophylaxis during the observation period, were mean (SD) 0.26 (1.03) and 138/157 (87.9%), respectively. No new or recurring inhibitors were reported. Conclusion: A low number of bleeds were observed with damoctocog alfa pegol in the real world in both male and female PLwHA. Data should be interpreted with caution owing to limitations of real-world studies and insubstantial data for female PLwHA.
Drug Index Terms
recombinant blood clotting factor 8
Non-drug Index Terms
aged, article, bleeding, child, cohort analysis, controlled study, drug therapy, female, genetic recombination, half life time, hemophilia A, human, major clinical study, male, prophylaxis
The influence of severity of hemophilia on bone mineral density and fracture risk
Ransmann P., Hmida J., Brühl M., Schildberg F.A., Goldmann G., Oldenburg J., Jaenisch M., Tomschi F., Hilberg T., Strauss A.C.
Res. Pract. Thromb. Haemost. 2024 8:8
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Abstract
Background: Evidence states that persons with hemophilia are frequently affected by low bone mineral density (BMD). Data assessing the relationship between severity of hemophilia and occurrence of osteoporosis are lacking. Objectives: This prospective cohort study aimed to assess the impact of hemophilia severity on BMD and to investigate trabecular bone score (TBS) and fracture risk (FRAX). Methods: This prospective cohort study evaluated the BMD, TBS, and FRAX in 255 persons with hemophilia using dual x-ray absorptiometry. The International Society for Clinical Densitometry guidelines were used for classification: osteoporosis (T-score <−2.5), osteopenia (T-score <−1.0), normal (T-score >−1.0). Patients younger than 50 years of age with a Z-score of <−2.0 were considered below the expected range for age. Results: Of 255 persons with hemophilia (mild: n = 52, moderate: n = 53, severe: n = 150) aged 43 ± 15 years (mean ± SD), 63.1% showed reduced BMD. Even 11.9% of persons with hemophilia aged <50 years were classified as below the expected range for age. Neck BMD decreased linearly with severity (mild: 0.907 ± 0.229, moderate: 0.867 ± 0.131, severe: 0.799 ± 0.143; P = .01). TBS was classified as “normal” in n = 178 (81.3%) with a mean value of 1.403 ± 0.136, and there were no differences between severity levels (P = .54). The FRAX was 4.4% ± 3.0%. After adjustment of TBS, it was 2.8% ± 3.7%. Conclusion: The present study shows that BMD is decreased in 63.1% of persons with hemophilia also depending on the severity of hemophilia. However, the largely normal TBS implies that the microarchitecture of the bone does not seem to be affected. It is recommended to include osteoporosis screening, including TBS analysis, in the comprehensive diagnostic work-up of persons with hemophilia, especially as they age.
Drug Index Terms
(Based on full text)
calcium (special situation for pharmacovigilance), cortisone (special situation for pharmacovigilance), vitamin D (special situation for pharmacovigilance)
Non-drug Index Terms
(Based on full text)
acute hepatitis C, adult, aged, alcohol consumption, article, body height, body mass, body weight, bone density, cohort analysis, data analysis software, densitometry, disease severity, dual energy X ray absorptiometry, fracture risk assessment, hemophilia, hemophilia A, hemophilia B, human, hypogonadism, major clinical study, osteopenia, osteoporosis, phenotype, physical activity, prevalence, prospective study, range of motion, smoking, trabecular bone
Ljung R., Chan A.K.C., Ahuja S.P., Mancuso M.E., Marquez J.F.C., Volk F., Blanchette V., Kerlin B.A., Trakymiene S.S., Glosli H., Kenet G.
[Article in Press] [In Process] Eur. J. Haematol. 2024 :
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Abstract
Objectives: To report the long-term safety and efficacy of BAY 81-8973 in the LEOPOLD Kids extension phase. Methods: Patients received BAY 81-8973 (25–50 IU/kg) at least twice weekly. The primary endpoint was safety, assessed in all patients who entered the extension phase (n = 82). Efficacy endpoints were assessed in patients without high-titre inhibitors/immune tolerance induction (n = 67). Results: Children (n = 82) received BAY 81-8973 for a median of 3.1 years per patient and a median of 405 exposure days per patient. Long-term BAY 81-8973 treatment was well tolerated, with no cases of de novo inhibitor development in the extension phase. Annualised bleeding rates (ABRs) within 48 h of prophylaxis were low for all bleeds (median [IQR], 0.7 [0–1.9]; mean, 1.4 [SD, 2.1]) and for joint bleeds (median [IQR], 0 [0–0.7]; mean, 0.5 [SD, 1.1]) (n = 67). Twenty-one of 67 patients (31.3%) had zero bleeds within 48 h of prophylaxis; the treatment response was ‘good’/‘excellent’ in 87.9% of bleeds, and most bleeds resolved with ≤ 2 BAY 81-8973 infusions (83.5%). Conclusion: Long-term BAY 81-8973 treatment is well tolerated and maintains low ABRs for all bleeds and joint bleeds in children with severe haemophilia A. Trial Registration: ClinicalTrials.gov identifier: NCT01311648.
Drug Index Terms
blood clotting factor 8, recombinant blood clotting factor 8
Non-drug Index Terms
adolescent, article, bleeding, child, clinical trial, drug therapy, hemarthrosis, hemophilia A, human, immunological tolerance, major clinical study, male, multicenter study, phase 2 clinical trial, phase 3 clinical trial, prophylaxis, special situation for pharmacovigilance, treatment response
Joint reaction and simulated muscle forces during squatting and walking in persons with hemophilia
Mah J., Robertson C., Mah N., Roybal J., Thornhill D., Funk S., Manco-Johnson M.J., Carollo J., Gaffney B.M.M., Warren B.B.
[In Process] Clin. Biomech. 2024 120:
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Abstract
Background: Persons with hemophilia experience joint bleeding that can lead to debilitating arthropathy, most commonly seen in ankles, knees, and elbows. Arthropathy can hinder participation in daily and athletic activities. We explored how hemophilic arthropathy impacts movement patterns in walking and bilateral squatting tasks in persons with hemophilia compared to healthy controls. Methods: Persons with hemophilia and healthy controls completed walking and squatting tasks while kinematic and kinetic motion capture data were collected. The Hemophilia Joint Health Score exam was performed to measure hemophiliac arthropathy. OpenSim was used to model muscle and joint reaction forces and calculate moments and angles. Peak values were compared using Cohen's d to estimate effect sizes of hemophilia on movement parameters. Findings: Nine persons with hemophilia and eight age-matched controls were analyzed. Temporal-spatial metrics were similar between hemophilia and control groups in both tasks. In walking, persons with hemophilia had higher peak ankle dorsiflexion angles, vertical ground reaction force weight acceptance peaks, and hip extension and flexion moments compared to controls. In squatting, persons with hemophilia had lower knee extension moments, ankle joint reaction force, and knee extensor forces, but had higher hip extension moments. Interpretation: Temporal-spatial metric similarity between hemophilia and controls suggests that kinetic and kinematic analyses are needed to identify movement pattern differences. These data identify potential compensatory strategies at the hip that may be used by persons with hemophilia to mitigate impact on the knee and ankle. Future work will confirm these data in a larger sample size and be used to develop physical therapy strategies.
Non-drug Index Terms
adult, ankle, ankle dorsiflexion angle, ankle joint, arthropathy, article, benchmarking, case control study, clinical article, cohort analysis, controlled study, diagnosis, effect size, elbow, female, gait, ground reaction force, hemarthrosis, hemophilia, hemophilia A, hemophilic arthropathy, human, male, motion capture, muscle strength, physiotherapy, simulation, walking
Pardos-Gea J., Benítez O.
Eur. J. Haematol. 2024 113:5 (685-692)
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Abstract
Aim: To assess risk factors of retroperitoneal and lower extremity musculoskeletal bleed in acquired haemophilia (AHA) and perform an objective assessment of disability and influence on survival. Methods: We included 49 patients with AHA from November 2017 to May 2023. The occurrence of any retroperitoneal or/and lower extremities bleeding manifestation was investigated. On clinical follow-up, we search for compressive femoral neuropathy and quadriceps amyotrophy. The lower extremity functional scale (LEFS) was carried out one year after the last bleeding event in all AHA patients. Results: A 61.2% of patients in our AHA cohort presented with any retroperitoneal and/or lower extremities musculoskeletal manifestation. Those patients had higher percentage of major bleeding EACH2/ISTH criteria (90% vs. 57%, p =.01), needs of blood transfusions (86% vs. 57% of patients, p =.03), and haemostatic by-pass products (90% vs. 63%, p =.02). Hypertension (HR 2.6, 95% CI 1.1–5.9, p =.02), presence of autoimmune disease (HR 13, 95% CI 1.7–99, p =.01), and inhibitor level > 20 BU (HR 2.6 95% CI 1.0–6.8, p =.04) significantly predicted retroperitoneal/lower extremities clinical manifestations. Most frequent sequelae were quad atrophy (30.6%) and femoral nerve palsy (20.4%). Quad atrophy and LEFS scores under 50 were associated with increased mortality (HR 3, 95% CI 1.1–8.6 and HR 12, 95% CI 3.3–45, respectively). Conclusion: AHA with retroperitoneal/lower extremities bleeding involvement is of greater severity and shows high disability and worst survival outcomes. Quadriceps atrophy and LEFS scale scoring under 50 predicted mortality in our AHA patients.
Drug Index Terms
(Based on full text)
anticoagulant agent (special situation for pharmacovigilance), antithrombocytic agent (special situation for pharmacovigilance), blood clotting factor 8 inhibitor (special situation for pharmacovigilance), corticosteroid (special situation for pharmacovigilance), hemoglobin (endogenous compound)
Non-drug Index Terms
(Based on full text)
acquired haemophilia a (diagnosis), adult, aged, angiography, article, artificial embolization, autoimmune disease, blood transfusion, Charlson Comorbidity Index, clinical article, clinical feature, clinical significance, cohort analysis, comparative study, digestive system hemorrhage, disability (diagnosis), disability assessment, disease severity, ecchymosis, ECOG Performance Status, female, femoral nerve compression (diagnosis), femoral nerve palsy, hemoglobin blood level, hemophilia A (diagnosis), human, hypertension, iliopsoas hematoma, immunosuppressive treatment, leg disease (diagnosis), Lower Extremity Functional Scale, male, mortality, muscle atrophy (diagnosis), muscle bleeding (diagnosis), muscle hematoma (diagnosis), overall survival, quadriceps femoris muscle, retroperitoneal disease (diagnosis), risk factor, sensitivity and specificity, skin disease, survival, tomography
TREATMENT SATISFACTION AND JOINT HEALTH OUTCOMES WITHIN A REAL-WORLD HAEMOPHILIA B POPULATION: THE ADELPHI DISEASE SPECIFIC PROGRAMMESURVEY
Jiméne-ZYuste V., Percier C., Porstmann T., Ball N., Castaman G., Fabbron G.G., Okuma M.G.A.
Hematology, Transfusion and Cell Therapy 2024 46: (S569-S570)
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Abstract
Background: While haemophilia care continues to improve, People with Haemophilia B (PwHB) may still experience disease and treatment burden. Aims: To describe physician-reported treatment satisfaction and joint health outcomes in a real-world population of PwHB. Methods: The Adelphi Real World haemophilia Disease Specific Programme™is a retrospective, cross-sectional survey gathering data on treatment satisfaction and joint health via physician-completed patient record forms. Data were obtained from France, Germany, India, Italy, Japan, Spain, the UK and USA. Physician inclusion criteria were: (1) Haematology or haematology-oncology specialist; (2) treats ≥5 patients with haemophilia A/B per month. PwHB inclusion criteria were: (1) males with moderate-to-severe HB; (2) Receiving Extended Half-Life (EHL) or Standard Half-Life (SHL) therapy prophylactically. Results: In this interim analysis, 85 physicians provided data on 232 PwHB receiving prophylaxis with EHL (n = 199 [86%]) or SHL therapy (n = 33 [14%]). Demographics were similar between the two treatment groups, although a greater proportion of people with severe HB received EHL therapy. Physicians reported that 84% of PwHB receiving EHL and 73% receiving SHL therapy were fully compliant (received > 80% of prescribed dose). Physicians were not completely satisfied with the current treatment for 57% of patients receiving EHL and 70% receiving SHL therapy, for reasons including treatment schedules and lack of effectiveness for specific bleed types. Physicians reported 42% (n = 83/199) of PwHB receiving EHL and 36% (n = 12/33) receiving SHL therapy had joint problems due to haemophilia. In the overall PwHB group, physicians reported that 28% (n = 64) had problems in ≥ 1 target joint and 36% (n = 83) had joint pain. Conclusion: Although physicians reported good adherence to therapy among PwHB, most were not completely satisfied with treatment outcomes, and reported joint problems for more than one-third of PwHB. With this evaluation revealing scope for improvement, future analysis will provide detail regarding treatment satisfaction from the patients'perspective.
Non-drug Index Terms
(Based on full text)
adult, arthralgia, bleeding, child, conference abstract, cross-sectional study, drug therapy, hemophilia, hemophilia A, hemophilia B, human, Italy, Japan, major clinical study, male, observational study, patient compliance, prophylaxis, retrospective study, Spain, therapy, therapy effect, treatment outcome, United Kingdom
PEOPLE WITH MILD HEMOPHILIA ARE AT RISK OF JOINT DISEASE: THE NATIONWIDE COHORT HIN-6 STUDY
Camelo R.M., Smit C., Eikenboom J., Rosendaal F., van Vulpen L.F.D., Beckers E.A.M., Hooimeijer L., Coppens M., Schols S.E.M., Leebeek F.W.G., Driessens M.H., Bom J.G.V.D., Rezende S.M., Gouw S.C.
Hematology, Transfusion and Cell Therapy 2024 46: (S561-S562)
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Abstract
Clinical data on people with mild hemophilia (mPwH) is important to guide their treatment but remains scarce worldwide. In addition, since modern hemophilia therapies can turn severe phenotypes into mild or normal ones, knowing the clinical, therapeutical, and outcomes data of mPwH becomes essential as a proxy of these treatments. We described mPwH who participated in the 6th version of the Hemophilia in the Netherlands (HiN-6) cross-sectional nationwide study. Male mPwH (lowest plasmatic factor activity 5.1%‒40.0%) answered a questionnaire about their disease, treatment, and outcomes, in 2019. Questionnaires were elaborated according to age: younger than 12-years (children and responded by their parents/caregivers), between 12- and 17.9-years (adolescents), and 18-years or older (adults). A total of 387 mPwH responded to the questionnaires. Their median (Interquartile Range; IQR) age was 49.0-years (26.0‒62.0), 340 (87.8%) were adults, 29 (7.5%) had past or current inhibitors, 197 (50.9%) had ever been treated with any clotting product, and 12 (3.1%) were currently on prophylaxis. Approximately 74% reported they perceived their disease was not serious or not serious at all, and the different activity groups responded similarly. Recent bleed at any site was reported by 24/47 (51.1%) non-adults, related to the previous quarter, and 96/340 (28.2%) adults, related to the previous year. Joint impairment was reported for 180 joints (22 perceived as severe) by 50/387 (12.9%) mPwH. Age at first hemarthrosis was 10.0 years [5.0‒16.0] among 97 (25%) mPwH. Lifetime hospitalization due to joint surgery was reported by 31/358 (8.7%) mPwH. The analyses of PROMIS29 and RAND-26 (quality of life), and HAL (functional abilities) indicated good quality of life and functional abilities. mPwH who participated in the HiN-6 Study reported good social functioning and a non-impactant disease in their lives, although bleeds, joint impairment, and need for joint surgeries still occur.
Non-drug Index Terms
(Based on full text)
adolescent, adult, arthropathy, bleeding, caregiver, child, conference abstract, female, functional status, hemarthrosis, hemophilia, hospitalization, human, joint surgery, major clinical study, male, Netherlands, phenotype, prophylaxis, quality of life, questionnaire, school child, social interaction
Biomarkers Involved in the Pathogenesis of Hemophilic Arthropathy
Badulescu O.V., Scripcariu D.-V., Badescu M.C., Ciocoiu M., Vladeanu M.C., Plesoianu C.E., Bojan A., Iliescu-Halitchi D., Tudor R., Huzum B., Frasinariu O.E., Bararu-Bojan I.
Int. J. Mol. Sci. 2024 25:18
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Abstract
Hemophilia, which is a rare disease, results from congenital deficiencies of coagulation factors VIII and IX, respectively, leading to spontaneous bleeding into joints, resulting in hemophilic arthropathy (HA). HA involves complex processes, including synovial proliferation, angiogenesis, and tissue remodeling. Despite ongoing research, factors contributing to HA progression, especially in adults with severe HA experiencing joint pain, remain unclear. Blood markers, particularly collagen-related ones, have been explored to assess joint health in hemophilia. For example, markers like CTX-I and CTX-II reflect bone and cartilage turnover, respectively. Studies indicate elevated levels of certain markers post-bleeding episodes, suggesting joint health changes. However, longitudinal studies on collagen turnover and basement membrane or endothelial cell markers in relation to joint outcomes, particularly during painful episodes, are scarce. Given the role of the CX3CL1/CX3XR1 axis in arthritis, other studies investigate its involvement in HA. The importance of different inflammatory and bone damage biomarkers should be assessed, alongside articular cartilage and synovial membrane morphology, aiming to enhance understanding of hemophilic arthropathy progression.
Drug Index Terms
(Based on full text)
biological marker, blood clotting factor, cell marker, collagen
Non-drug Index Terms
(Based on full text)
adult, angiogenesis, arthralgia, articular cartilage, basement membrane, bleeding, bone injury, diagnosis, drug therapy, endothelium cell, etiology, hemarthrosis, hemophilia, hemophilic arthropathy, human, inflammation, longitudinal study, pathogenesis, review, second cervical vertebra, synovium, turnover rate
COVID-19 outcomes in persons with hemophilia: results from a US-based national COVID-19 surveillance registry
Sharathkumar A., Wendt L., Ortman C., Srinivasan R., Chute C.G., Chrischilles E., Takemoto C.M., Wilcox A.B., Lee A.M., Graves A., Anzalone A.J., Manna A., Saha A., Olex A., Zhou A., Williams A.E., Southerland A., Girvin A.T., Walden A., Sharathkumar A.A., Amor B., Bates B., Hendricks B., Patel B., Alexander C., Bramante C., Ward-Caviness C., Madlock-Brown C., Suver C., Chute C., Dillon C., Wu C., Schmitt C., Takemoto C., Housman D., Gabriel D., Eichmann D.A., Mazzotti D., Brown D., Boudreau E., Hill E., Zampino E., Marti E.C., Pfaff E.R., French E., Koraishy F.M., Mariona F., Prior F., Sokos G., Martin G., Lehmann H., Spratt H., Mehta H., Liu H., Sidky H., Hayanga J.W.A., Pincavitch J., Clark J., Harper J.R., Islam J., Ge J., Gagnier J., Saltz J.H., Saltz J., Loomba J., Buse J., Mathew J., Rutter J.L., McMurry J.A., Guinney J., Starren J., Crowley K., Bradwell K.R., Walters K.M., Wilkins K., Gersing K.R., Cato K.D., Murray K., Kostka K., Northington L., Pyles L.A., Misquitta L., Cottrell L., Portilla L., Deacy M., Bissell M.M., Clark M., Emmett M., Saltz M.M., Palchuk M.B., Haendel M.A., Adams M., Temple-O'Connor M., Kurilla M.G., Morris M., Qureshi N., Safdar N., Garbarini N., Sharafeldin N., Sadan O., Francis P.A., Burgoon P.W., Robinson P., Payne P.R.O., Fuentes R., Jawa R., Erwin-Cohen R., Patel R., Moffitt R.A., Zhu R.L., Kamaleswaran R., Hurley R., Miller R.T., Pyarajan S., Michael S.G., Bozzette S., Mallipattu S., Vedula S., Chapman S., O'Neil S.T., Setoguchi S., Hong S.S., Johnson S., Bennett T.D., Callahan T., Topaloglu U., Sheikh U., Gordon V., Subbian V., Kibbe W.A., Hernandez W., Beasley W., Cooper W., Hillegass W., Zhang X.T.
J. Thromb. Haemost. 2024 22:1 (61-75)
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Abstract
Background: Hypercoagulable state contributing to thrombotic complications worsens COVID-19 severity and outcomes, whereas anticoagulation improves outcomes by alleviating hypercoagulability. Objectives: To examine whether hemophilia, an inherent hypocoagulable condition, offers protection against COVID-19 severity and reduces venous thromboembolism (VTE) risk in persons with hemophilia (PwH). Methods: A 1:3 propensity score–matched retrospective cohort study used national COVID-19 registry data (January 2020 through January 2022) to compare outcomes between 300 male PwH and 900 matched controls without hemophilia. Results: Analyses of PwH demonstrated that known risk factors (older age, heart failure, hypertension, cancer/malignancy, dementia, and renal and liver disease) contributed to severe COVID-19 and/or 30-day all-cause mortality. Non–central nervous system bleeding was an additional risk factor for poor outcomes in PwH. Odds of developing VTE with COVID-19 in PwH were associated with pre-COVID VTE diagnosis (odds ratio [OR], 51.9; 95% CI, 12.8-266; p < .001), anticoagulation therapy (OR, 12.7; 95% CI, 3.01-48.6; p < .001), and pulmonary disease (OR, 16.1; 95% CI, 10.4-25.4; p < .001). Thirty-day all-cause mortality (OR, 1.27; 95% CI, 0.75-2.11; p = .3) and VTE events (OR, 1.32; 95% CI, 0.64-2.73; p = .4) were not significantly different between the matched cohorts; however, hospitalizations (OR, 1.58; 95% CI, 1.20-2.10; p = .001) and non–central nervous system bleeding events (OR, 4.78; 95% CI, 2.98-7.48; p < .001) were increased in PwH. In multivariate analyses, hemophilia did not reduce adverse outcomes (OR, 1.32; 95% CI, 0.74-2.31; p = .2) or VTE (OR, 1.14; 95% CI, 0.44-2.67; p = .8) but increased bleeding risk (OR, 4.70; 95% CI, 2.98-7.48; p < .001). Conclusion: After adjusting for patient characteristics/comorbidities, hemophilia increased bleeding risk with COVID-19 but did not protect against severe disease and VTE.
Non-drug Index Terms
(Based on full text)
adult, age, aged, all cause mortality, anticoagulant therapy, article, bleeding, cohort analysis, confidence interval, controlled study, coronavirus disease 2019, dementia, disease association, disease registry, disease severity, female, heart failure, hemophilia (etiology), hospitalization, human, hypertension, kidney disease, liver disease, lung disease, major clinical study, male, multivariate analysis, neoplasm, non central nervous system bleeding, odds ratio, pathophysiology, persons with hemophilia, phenotype, propensity score, retrospective study, risk factor, risk reduction, treatment outcome, United States, venous thromboembolism
Vir P., Gunasekera D., Dorjbal B., McDaniel D., Agrawal A., Merricks E.P., Ragni M.V., Leissinger C.A., Stering A.I., Lieuw K., Nichols T.C., Pratt K.P.
[Article in Press] J. Thromb. Haemost. 2024 :
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Abstract
Background: Almost half of severe hemophilia A (HA) cases are caused by an intron 22 inversion (Int22Inv) mutation, which truncates the 26-exon F8 messenger RNA (mRNA) after exon 22. Another F8 transcript, F8B, is initiated from within F8-intron-22. F8B mRNA consists of a short exon spliced to exons 23 to 26 and is expressed in multiple human cell types. It has been hypothesized that Int22Inv patients have self-tolerance to partial factor (F)VIII proteins expressed from these 2 transcripts. FVIII is expressed in endothelial cells, primarily in the liver and lungs. Several studies have reported FVIII expression in other cell types, although this has been controversial. Objectives: To determine if partial FVIII proteins are expressed from intron 22–inverted and/or F8B mRNA and if FVIII is expressed in nonendothelial cells. Methods: A panel of FVIII-specific antibodies was validated and employed to label FVIII in cells and tissues and for immunoprecipitation followed by western blots and mass spectrometry proteomics analysis. Results: Immunofluorescent staining localized FVIII to endothelial cells in liver sections from non-HA but not HA-Int22Inv dogs. Neither FVIII nor FVIIIB was detected in human peripheral blood mononuclear cells, B cell or T cell lines, or cell lines expanded from peripheral blood mononuclear cells, whereas FVIII antigen and activity were readily detected in primary nonhemophilic liver sinusoidal endothelial cells. Conclusion: If FVIII is expressed in nonendothelial cells or if partial FVIII proteins are expressed in HA-Int22Inv, the concentrations are below the detection limits of these sensitive assays. Our results argue against promotion of immune tolerance through expression of partial FVIII proteins in Int-22Inv patients.
Drug Index Terms
blood clotting factor 8, messenger RNA
Non-drug Index Terms
article, B lymphocyte, blood clotting, child, controlled study, dog, drug therapy, endothelium cell, etiology, exon, hemophilia A, hemostasis, human, human cell, immunological tolerance, immunoprecipitation, intron, limit of detection, liver sinusoidal endothelial cell, mass spectrometry, peripheral blood mononuclear cell, proteomics, vascular endothelial cell, Western blotting
Severe Hemophilic Arthropathy of the Knee: MRI Has Its Place
Kessi E.M.C.J., Maslouhi K., Guelzim Y., Belkouchi L., Allali N., Chat L., El Haddad S.
Glob. Pediatr. Health 2024 11:
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Abstract
Hemophilia is a congenital coagulopathy characterized by a deficiency of coagulation factors and the development of haematomas and haemarthrosis, either spontaneously or after minor trauma. Recurrent joint hemorrhage in hemophilia patients leads to progressive and degenerative arthropathy, which affects around 90% of patients with severe disease and contributes significantly to disease morbidity. Positive diagnosis is based on biology. Imaging, particularly MRI, plays an essential role in assessing the evolution and complications, especially osteoarticular complications. We report 2 cases of severe hemophilia A, who presented with almost identical clinical and radiological symptoms. The patients developed severe arthropathy with a course marked by recurrences of haemarthrosis.
Drug Index Terms
(Based on full text)
blood clotting factor 8 (endogenous compound), fibrinogen (endogenous compound)
Non-drug Index Terms
(Based on full text)
adolescent, article, bleeding, blood clotting disorder, case report, clinical article, disease severity, hemarthrosis, hematoma, hemophilia, hemophilia A, hemophilic arthropathy, human, joint cavity, knee, knee pain, male, minor injury, morbidity, nuclear magnetic resonance imaging, recurrent disease, synovitis, synovium, T1 weighted imaging, T2 weighted imaging, tibiofemoral joint
Women and girls’ participation in haemophilia clinical trials
Fedewa S.A., Cafuir L., Valentino L.A., Koo A., Antun A., Kempton C.L.
[Article in Press] [In Process] Haemophilia 2024 :
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Abstract
Key Points: women and girls were infrequently represented in haemophilia clinical trials intentional recruitment strategies are needed for haemophilia trials to be more inclusive of women and girls.
Non-drug Index Terms
adolescent, adult, diagnosis, female, hemophilia, human, letter, participation
Sexual functioning in men with haemophilia: Data from the haemophilia in the Netherlands-6 study
van Gastel T.C.M., Teela L., Mauser-Bunschoten E.P., Coppens M., Peters M., Fijnvandraat K.C.J., Haverman L., Gouw S.C.
Haemophilia 2024 30:5 (1243-1246)
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Non-drug Index Terms
(Based on full text)
anxiety, bleeding, data analysis software, depression, erectile dysfunction, exercise, fatigue, hemophilia, hemospermia, human, knowledge, letter, Netherlands, physical activity, quality of life, questionnaire, sexual behavior, sexual function, sexual orientation, sexuality, social support
Characterization of Anti-FVIII Antibodies in Acquired Hemophilia A Patients Using a bead-based multiplex immunoassay
Berkemeier A.C., Marquardt N., Oldenburg J., Pezeshkpoor B.
Transfus. Med. Hemotherapy 2024 51: (89)
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Abstract
Background: Acquired hemophilia A (AHA) is an autoimmune disorder characterized by bleeding due to neutralizing antibodies against coagulation factor VIII (FVIII). The Nijmegen Bethesda assay (NBA) is the gold standard for detection of neutralizing antibodies (inhibitors). Whereas both, inhibitors and non-neutralizing antibodies can be detected by immunoassays. Methods: The in-house multiplex Luminex™ bead-based domain-epitope binding assay (LumiTope) comprised full-length (FL) and B-domain deleted (BDD) FVIII, along with nine purified FVIII single or multi-domains as previously described1. These proteins were coupled to magnetic beads to detect domain specific Immunoglobulin (IgG (IgG1-4), IgA, IgM and IgE) anti-FVIII antibodies in a large cohort of AHA patients. Data were acquired as Mean Fluorescence Intensity (MFI). Results: The study included a total of 80 AHA patients. Demographic and baseline characteristics are detailed in Table 1. All patients were screened for anti-FVIII antibodies of IgG, IgM, IgA, and IgE isotypes, with no detection of anti-FVIII antibodies of the IgE subtype. Overall, the LumiTope assay demonstrated high sensitivity and specificity, with all ELISA-positive patients also testing positive in LumiTope. The BDD-FVIII bead exhibited higher MFI values compared to the FL-FVIII bead for anti-FVIII antibodies of the IgG isotype. MFI values for IgA and IgM antibodies were lower compared to IgG antibodies. AHA patients exhibited distinct differences in IgG subclasses and domain specificity of anti-FVIII antibodies compared to congenital hemophilia A (HA) patients. Analysis of IgG subtypes revealed that similar to HA patients IgG4 antibodies were predominant (96%). However, all other IgG subclasses were equally detected among AHA patients (IgG3 (60%), IgG1 (55%), and IgG2 (44%)). Interestingly, a comparison of the overall domain specificity of anti-FVIII antibodies in congenital and AHA patients showed that the majority of AHA patients had anti-FVIII antibodies directed towards the light-chain beads, specifically the C1C2 and C2 domain beads, whereas congenital H A patients primarily had antibodies directed towards the A2 and A2a2 bead. Conclusion: LumiTope assay provides a sensitive and specific method for detection but also domain specification of anti-FVIII-antibodies in AHA patients. Different domain specificities of the identified anti-FVIII antibodies may be associated with disease outcomes. (Figure Presented).
Drug Index Terms
(Based on full text)
blood clotting factor 8, butylamine, epitope, immunoglobulin E, immunoglobulin G, immunoglobulin G antibody, immunoglobulin G1, immunoglobulin G2, immunoglobulin G3, immunoglobulin G4, immunoglobulin M, immunoglobulin M antibody, neutralizing antibody
Non-drug Index Terms
(Based on full text)
adult, binding assay, bleeding, C2 domain, cohort analysis, conference abstract, controlled study, diagnosis, drug therapy, ELISA kit, enzyme linked immunosorbent assay, female, fluorescence intensity, hemophilia A, human, immunoassay, male, retrospective study, sensitivity and specificity
Pharmacokinetic-guided switching from standard half-life factor VIII to extended half-life pegylated factor VIII in the therapy of hemophilia A in clinical practice
Choví-Trull M., Megías-Vericat J.E., Bonanad Boix S., Haya Guaita S., Cid Haro A.R., Aguilar Rodriguez M., Poveda Andrés J.L.
[Article in Press] [In Process] Farm. Hosp. 2024 :
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Abstract
Objective: To analyze the differences in pharmacokinetic and clinical parameters (bleeding rates and joint health) before and after switching from standard half-life factor VIII (FVIII) to extended half-life pegylated FVIII in patients with severe/moderate hemophilia A on prophylaxis, one year before and after the switch in real-life. Method: This is a single-center, comparative, observational, sequential, retrospective, and multidisciplinary study. Population pharmacokinetic models from the WAPPS-Hemo® application were used to calculate pharmacokinetic parameters and individualize prophylaxis. The annual rate of total and joint bleeds, joint health (Hemophilia Joint Health Score), plasma half-life and area under the curve ratios, FVIII consumption, administration frequency, and cost were analyzed. Results: Thirty-eight adult patients with hemophilia A who switched from standard half-life FVIII to extended half-life pegylated FVIII were analyzed. Significant improvements (p < 0.05) were observed in all pharmacokinetic parameters, with plasma half-life and area under the curve improvement ratios of 1.5 and 1.9, respectively, as well as reductions in annual total and joint bleeding rates were registered. A higher number of patients with zero total (16.0 vs. 29.0) and joint bleeds (23.0 vs. 33.0) was also observed. The median reductions in administration frequency and dose/kg/week were 30.0% and 19.7%, respectively, avoiding 44.3 infusions/patient/year, resulting in savings of 20,843 €/patient/year. Furthermore, joint health improved (23.0 vs. 21.0; p = 0.017), and target joints resolved after the switch. Conclusions: The pharmacokinetically guided switch from standard half-life FVIII to pegylated FVIII demonstrated significant clinical benefits with reduced bleeding rates and improvements in joint health. Additionally, improvements in pharmacokinetic parameters were observed, allowing for reduced treatment burden by decreasing administration frequency, as well as lower consumption and costs.
Original (Non-English) Title
Intercambio guiado por farmacocinética de factores VIII de vida media estándar a factores VIII de vida media extendida pegilados en la terapia de la hemofilia A en práctica clínica
Drug Index Terms
blood clotting factor 8, macrogol derivative, recombinant blood clotting factor 8
Non-drug Index Terms
adult, area under the curve, area under the curve ratio, article, bleeding, clinical article, clinical practice, controlled study, drug therapy, half life time, hemarthrosis, hemophilia, hemophilia A, human, male, observational study, pharmacokinetic parameters, pharmacokinetics, plasma half life, retrospective study, therapy
Expert Opinion for Defining a Severe Bleeding Phenotype to Guide Prophylaxis in Patients with Nonsevere Hemophilia
Pfrepper C., Ettingshausen C.E., Klamroth R., Oldenburg J., Olivieri M.
[Article in Press] Hamostaseologie 2024 :
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Abstract
Prophylaxis is the standard of care for patients with severe hemophilia, patients with moderate hemophilia, or those with another congenital bleeding disorder that is associated with a severe bleeding phenotype and/or a high risk of spontaneous life-threatening bleeding. Patients with nonsevere hemophilia (factor VIII [FVIII] ≥ 1%) may also have a bleeding phenotype that requires prophylaxis. To date, however, there are no clear criteria as to when prophylaxis is indicated in these patients. Also, the term “severe bleeding phenotype (SBPT)” is neither included in the definitions of the International Society on Thrombosis and Haemostasis (ISTH) nor specified in the World Federation of Hemophilia (WFH) guidelines. Based on our personal experience and available evidence, we propose the criteria we use to define an SBPT and when we consider offering prophylaxis in patients with nonsevere hemophilia. Our proposals can be the basis for discussions in the community about the assessment of SBPT and the initiation of prophylaxis in patients with nonsevere hemophilia without inhibitors.
Drug Index Terms
blood clotting factor 8
Non-drug Index Terms
adolescent, adult, article, bleeding, bleeding disorder, child, clinical article, clinical practice guideline, controlled study, drug therapy, hemophilia, hemostasis, human, phenotype, practice guideline, prevention, prophylaxis
Exploring red blood cells as an antigen delivery system to modulate the immune response towards FVIII in hemophilia A
Miranda M., Brandsma E., Robben L., Van Dender H., van Alphen F.P.J., Fijnvandraat K., van den Biggelaar M., Lacroix-Desmazes S., van Bruggen R., Voorberg J.
[Article in Press] J Thromb Haemost 2024 :
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Abstract
BACKGROUND: The main complication in hemophilia A treatment is the development of inhibitory antibodies against factor VIII (FVIII). Immune tolerance induction, the gold standard for eradicating anti-FVIII antibodies, is efficient in only 60-80% of cases. This underscores the need for more efficient induction of tolerance in hemophilia A patients with FVIII inhibitors. OBJECTIVES: In this study we explored whether red blood cells (RBCs) can be utilized as antigen delivery system to modulate the immune response against FVIII. METHODS: Two promiscuously HLA-DR presented peptides derived from the A2 and C1 domains of FVIII were fused to the TAT-cell penetrating peptide and incubated with RBCs. RESULTS: Biotinylated TAT-A2 and TAT-C1 peptides were found to interact with RBCs as shown by flow cytometry and imaging flow cytometry. Moreover, macrophages efficiently phagocytosed TAT-FVIII peptide-treated RBCs. Using mass spectrometry based immunopeptidomics we established that TAT-FVIII peptides were presented on MHC class II of macrophages that phagocytosed TAT-peptide pulsed RBCs. Specifically, the TAT-A2 peptide exhibited efficient processing and presentation on HLA-DR molecules. Importantly, incubation of TAT-C1 peptide treated RBCs loaded macrophages with a FVIII-specific T cell hybridoma led to a significant increase in IL-2 production, suggesting functional presentation of TAT-C1 derived peptides by macrophages. CONCLUSIONS: Our findings indicate that RBCs can serve as effective vehicle for the delivery of FVIII derived peptides to antigen presenting cells. The successful display of T cell epitopes on APC using ex vivo loaded RBC may be potentially utilized to modulate pathogenic immune responses such as observed in a subset of patients with hemophilia A.
Drug Index Terms
blood clotting factor 8, cell penetrating peptide, epitope, interleukin 2, major histocompatibility antigen class 2
Non-drug Index Terms
antigen presenting cell, article, child, clinical article, controlled study, drug therapy, erythrocyte, ex vivo study, flow cytometry, hemophilia A, human, human cell, hybridoma, immune response, immunological tolerance, macrophage, mass spectrometry, T lymphocyte
Differences and similarities in patient-reported outcomes among men and women with haemophilia
Kempton C.L., Guasch S.A., Buckner T.W., Mattis S., Fedewa S.A.
Haemophilia 2024 30:6 (1383-1392)
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Abstract
Introduction: Both men and women can be diagnosed with haemophilia and the experience with haemophilia may be different between men and women. Aim: This study aimed to compare patient-reported outcomes in men versus women with haemophilia. Methods: This cross-sectional study is a post-hoc analysis of data collected as part of the Haemophilia-related Distress Questionnaire validation study. Adults aged ≥18 years with haemophilia A or B were recruited from one of two haemophilia treatment centres between July 2017 and December 2019. Outcomes included quality of life, measures of mental and physical health, and overall health. Unadjusted and multivariable linear regression models were used to examine potential mediators of sex-based differences in outcomes. Results: Of the 139 study participants included (21 women, 118 men), the mean age was 36.9 years and most (89.2%) had haemophilia A. Approximately 85.7% and 26.3% of women and men had mild haemophilia, respectively. PHQ-9 depression and PROMIS-29 Profile anxiety and fatigue scores were significantly higher in women than men in unadjusted and adjusted analyses. There were no statistically significant differences in other outcomes. Conclusions: Women with haemophilia are more likely to experience depression, anxiety, and fatigue than men with haemophilia. This study highlights the need for mental health services to be integrated into the care of women with haemophilia. Future research is needed to understand whether women with haemophilia are more or less likely to experience depression, anxiety, and fatigue than women without haemophilia as well as determine the impact of reduced mental health on clinical outcomes.
Non-drug Index Terms
(Based on full text)
adult, anxiety, article, bleeding prophylaxis, clinical outcome, controlled study, cross-sectional study, depression, disease severity, distress syndrome, European Quality of Life 5 Dimensions questionnaire, fatigue, female, hemophilia (prevention), hemophilia A (prevention), hemophilia B (prevention), hepatitis C, human, Human immunodeficiency virus infection, major clinical study, male, mental health, outcome assessment, pain intensity, Patient Health Questionnaire 9, patient reported outcomes measurement Information system 29, patient-reported outcome, promis 29, prophylaxis, quality of life, questionnaire, scoring system, self care, sleep disorder, social interaction, socioeconomics, validation study, visual analog scale
Determination of body composition by dual x-ray absorptiometry in persons with haemophilia
Ransmann P., Brühl M., Hmida J., Goldmann G., Oldenburg J., Strauss A.C., Hagedorn T., Schildberg F.A., Hilberg T., Strauss A.C.
Haemophilia 2024 30:6 (1332-1340)
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Abstract
Background: There is limited research on body composition in persons with haemophilia (PwH). The literature describes an increased body fat distribution and decreased lean mass in PwH compared to healthy controls using bioimpedance analysis. Using dual x-ray absorptiometry (DXA), which is known to be the most accurate method, this investigation aims to postulate reference data for body composition parameters within haemophilia severity phenotypes and age groups. Methods: Persons underwent whole body DXA screening using Horizon. Body fat percentage, estimated visceral adipose tissue (VAT), appendicular fat and lean mass, and lean and fat mass in relation to body height were assessed. Haemophilia severity and five age groups were distinguished. Results: Two hundred and one persons with mild (n = 44), moderate (n = 41), or severe (n = 116) haemophilia A/B (median age 40 [28–55; 1.IQ–3.IQ] years) were analysed. The median body fat percentage was 28.7% [25.5%–33.9%] and median estimated VAT was 657 g [403–954 g] with no significant difference between severity phenotypes (p =.474; p =.781). Persons with severe haemophilia had less lean mass compared to moderate and mild haemophilia (p =.013; p =.034). Total and appendicular fat is increased in older PwH (aged ≥40 years) compared to younger PwH (aged ≤29 years; p <.05). Lean mass did not differ between age groups. Conclusion: This study provides valuable reference data for body composition parameters in PwH. Persons with severe haemophilia show significantly less lean mass compared to persons with moderate or mild haemophilia. Body fat percentage and VAT did not differ between severity phenotypes, but increased with age.
Non-drug Index Terms
(Based on full text)
adult, aged, article, body composition, body fat, body fat distribution, body fat percentage, body height, body mass, clinical trial, cohort analysis, data analysis software, dual energy X ray absorptiometry, fat mass, hemophilia, hemophilia A, hemophilia B, human, intra-abdominal fat, lean body weight, male, middle aged, obesity, osteoporosis, phenotype, prospective study, Statistical Package for Social Sciences 29
Assessment of joint health in females with haemophilia: The carriers ultrasound project (CUP) study
Corrales-Medina F.F., Fraga K., D'Almeida Bastos M., Rafique A., Kempton C.L., Vijayvargia P., Davis J.A., Kronenfeld R.S.
Haemophilia 2024 30:6 (1422-1428)
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Abstract
Introduction: The needs of haemophilia carriers (HC) have been historically overlooked. It is now recognised that HC manifests bleeding symptoms, including haemarthrosis. The natural history of joint health in HC is not yet defined. Aim: A multi-institutional cross-sectional study aimed to evaluate the characteristics of joint disease in HC, aged 18–40 years, compared to age-matched controls. Methods: The carrier cohort included females with confirmed HC status. Controls had no personal or family history of bleeding disorders. All females with a history of joint trauma or surgery within 12 months or any history of joint replacement were excluded. Joint health was assessed by clinical history, Haemophilia Joint Health Score (HJHS) and point-of-care musculoskeletal ultrasonography (POC-MSKUS). Results: Thirty HC and 30 controls were enrolled. For HC, the median factor activity level was 52% (range 17%–100%). Carriers, regardless of baseline factor activity levels, reported higher prevalence of chronic joint pain (p <.001) and swelling (p =.002) than controls. Heavy menstrual bleeding, epistaxis, gingival bleeding and easy bruising were also more prevalent in HC (p <.001). Despite HC having a higher median HJHS score (5 vs. 0, p <.001), no differences were observed when using POC-MSKUS. HC with a body mass index ≥25 mg/m2 reported more haemarthrosis (p =.037). Conclusions: HC are at increased risk of joint-related symptoms and poorer joint health than age-matched controls. Dedicated follow-up to prevent and treat joint disease in HC is imperative. This study is also a call for additional investigation to clarify the association, or lack thereof, between factor activity and joint disease.
Drug Index Terms
(Based on full text)
blood clotting factor 8 (endogenous compound), blood clotting factor 9 (endogenous compound)
Non-drug Index Terms
(Based on full text)
adult, arthralgia, article, bleeding, body mass, chronic pain, clinical article, cohort analysis, controlled study, contusion, cross-sectional study, epistaxis, female, gingiva bleeding, hemarthrosis, hemophilia, hemophilia A, hemophilia B, human, joint swelling, menorrhagia, multicenter study, point of care musculoskeletal ultrasonography, point of care ultrasound, prevalence
Assessing the factors affecting the accessibility of primary dental care for people with haemophilia
Sipos K., Márton I., Móré M., Nagy A.C., Kiss C.
[Article in Press] [In Process] Haemophilia 2024 :
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Abstract
Introduction: Patients with haemophilia (PWH) often have difficulty accessing dental services. Aim: To determine the accessibility of dental care for PWH and to examine their perceptions of how coronavirus type-2 (CoV-2) disease (COVID-19) has affected their ability to access dental treatments following the pandemic. Methods: The questionnaire survey was conducted between July 2022 and December 2022 at haemophilia treatment centres in Hungary. Variables with statistical significance (Pearson's Chi-squared test; p <.05) were included in logistic regression analyses. Least absolute shrinkage and selection operator (LASSO) regression was used as a machine learning technique to identify the most predictive variables. Results: Twenty-one percent of the sixty-eight participants reported that they had been refused dental treatment, mainly in primary care (86%). Dental refusal was influenced by infectious disease (OR: 4.48, CI: 1.14–17.69) and previous dental bleeding complications (OR: 4.23, CI: 1.10–16.27). There was correlation between dental visits and having a permanent dentist or receiving oral hygiene advice (OR: 9.95, CI: 2.86–34.62 and OR: 3.84, CI: 1.09–13.58). Participation in an oral hygiene consultation increased patients’ satisfaction with their dental care (OR: 6.28, 95% CI:.71–55.88). Twenty-eight percent of patients had experienced difficulties since the start of the COVID-19, but 84% had visited their dentist at least once between 2021 and 2022 (p =.002). Nevertheless, 16% of respondents went for only the most necessary treatments due to pandemic. Conclusion: Refusal of dental care was high among participants, especially in primary care. The COVID-19 pandemic has exaggerated the difficulties of PWH in accessing dental treatment. Highlights: Patients with haemophilia (PWH) have difficulty accessing dental care, and the coronavirus type 2 (CoV-2) disease pandemic (COVID-19) has created a new barrier. The study revealed a high prevalence of dental care refusal (21%), particularly in primary care (86%). This 2022 survey found that 28% of patients experienced difficulties since the pandemic started and 16% only sought necessary treatments.
Non-drug Index Terms
adolescent, adult, article, bleeding, cohort analysis, consultation, coronavirus disease 2019, dental procedure, dentist, epidemiology, hemophilia, hemophilia A, hemophilia B, human, Hungary, least absolute shrinkage and selection operator, machine learning, major clinical study, male, mouth hygiene, pandemic, patient satisfaction, prevalence, primary medical care, questionnaire
Saliva of persons with hemophilia A triggers coagulation via extrinsic tenase complexes
Thaler J., Tripisciano C., Kraemmer D., Hau C., Samadi N., Ruf W., Pabinger I., Knoebl P., Nieuwland R., Ay C.
Blood 2024 144:25 (2666-2677)
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Abstract
Human saliva contains extracellular vesicles (EVs). These EVs expose extrinsic tenase complexes of tissue factor (TF) and activated factor VII (FVIIa), and trigger blood coagulation. Here, we show that EVs exposing extrinsic tenase complexes are also present in saliva of persons with severe hemophilia A, that is, persons with FVIII deficiency. Addition of these salivary EVs to autologous FVIII-deficient blood results in FXa generation, thereby compensating for the lack of FXa generation via intrinsic tenase (FVIIIa/FIXa) complexes. Consistently, in our retrospective analysis of persons with severe hemophilia A who do not receive prophylactic FVIII substitution, oropharyngeal mucosal bleedings are infrequent and self-limited. Conversely, in saliva of persons with severe FVII deficiency, in whom oropharyngeal bleedings are prevalent, functional extrinsic tenase complexes are absent, because EVs lack FVII. Saliva of persons with severe FVII deficiency is unable to restore blood coagulation, which is because of the absence of FVII in both their saliva and blood. Picomolar levels of recombinant FVIIa can restore the coagulant potential of saliva of persons with FVII deficiency. Taken together, our findings may explain the paucity of oropharyngeal bleedings in persons with hemophilia A as well as the occurrence of such bleedings in persons with severe FVII deficiency.
Drug Index Terms
(Based on full text)
blood clotting factor 10a (endogenous compound), blood clotting factor 7a (endogenous compound), buffer, calnexin, CD63 antigen (endogenous compound), phospholipid, recombinant tissue factor pathway inhibitor, thrombin (endogenous compound), thromboplastin (endogenous compound)
Non-drug Index Terms
(Based on full text)
article, blood autotransfusion, blood clotting, blood clotting time, flow cytometry, gastrointestinal hemorrhage, hematuria, hemophilia A, human, mucosal bleeding, muscle bleeding, oropharynx, retrospective study, saliva, saliva level, size exclusion chromatography, thromboelastograph, thromboelastography, tooth extraction
