2,548 results on '"Hemophilia A diagnosis"'
Search Results
2. Bleeding phenotype according to factor level in 825 children with nonsevere hemophilia: data from the PedNet cohort.
- Author
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de Kovel MS, Escuriola-Ettingshausen C, Königs C, Ranta S, and Fischer K
- Subjects
- Humans, Child, Child, Preschool, Adolescent, Male, Infant, Hemophilia B blood, Hemophilia B diagnosis, Hemophilia B genetics, Age of Onset, Female, Kaplan-Meier Estimate, Cohort Studies, Severity of Illness Index, Hemophilia A blood, Hemophilia A diagnosis, Hemophilia A complications, Factor VIII, Phenotype, Hemorrhage blood, Factor IX genetics
- Abstract
Background: Information on bleeding phenotype in nonsevere hemophilia may be used to determine target factor levels for prophylaxis or gene therapy in severe hemophilia., Objectives: To assess the association between endogenous factor level and bleeding phenotype in children with nonsevere (factor [F]VIII/FIX activity 1%-25%) hemophilia A (HA) and B without prophylaxis., Methods: Data on annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), and onset of bleeding were extracted from the international PedNet cohort including children born since 2000. Mean ABR and AJBR were modeled and compared according to FVIII/FIX endogenous activity (1%-2%, 3%-5%, 6%-10%, 11%-15%, 16%-20%, and 21%-25%) using negative binomial regression. Onset of bleeding was analyzed using Kaplan-Meier survival curves., Results: Eight hundred twenty-five children (40% with moderate hemophilia; 87% with HA) with median follow-up of 7.4 years/child were included. The median age at onset of bleeding and median bleeding rates changed with increasing endogenous activity. From endogenous FVIII 1% to 2% to 21% to 25%, the age at onset of bleeding changed from a median of 1.4 to 14.2 years, ABR from 1.6 to 0.1/y, and AJBR from 0.5 to 0.0/y. From endogenous FIX 1% to 2% to 16% to 25%, the onset of bleeding changed from a median of 1.7 to 6.1 years, ABR from 0.5 to 0.1/y, and AJBR from 0.1 to 0.0/y. The negative correlation between AJBR and factor level was most strongly pronounced up to a factor level of 6% in HA and hemophilia B., Conclusion: Endogenous factor activity of >5% was identified as a threshold to significantly lower joint bleeding rate, while FVIII levels >15% and FIX levels >10% were sufficient to achieve the goal of 0 bleeds in this pediatric cohort., Competing Interests: Declaration of competing interests This study is supported by the PedNet Haemophilia Research Foundation. Unrestricted sponsorship for the PedNet Haemophilia Research Foundation is currently received from Bayer AG, Takeda, Novo Nordisk, CSL Behring, Pfizer Inc, Swedish Orphan Biovitrum AB, Hoffmann-La Roche, and LFB Biotechnologies. M.S.d.K. has nothing to declare. C.E.-E. received grants, travel support, and/or honoraria from Bayer, BioMarin, Biotest, CSL Behring, Grifols, Kedrion, LFB, Octapharma, Novo Nordisk, Pfizer, Roche/Chugai, Sanofi, Sobi, and Takeda. C.K.’s institution has received grants for clinical trials and research from Bayer, Biotest, CSL Behring, Interseroh, Novo Nordisk, Pfizer, Roche/Chugai, Sobi/Sanofi, Takeda, the German Research Foundation (DFG), and the European Union. C.K. has received speaker’s fees and/or travel support from Bündnis zur Förderung der Sicherheit von Hämophilen (BFSH), Bayer, CSL Behring, MSD, Novo Nordisk, Roche/Chugai, Sobi/Sanofi, and Takeda. S.R.’s institution has received grants for research from the Childhood Cancer Foundation, PedNet, Stockholm County Council, and the Steering Committee of Roche. S.R. is investigator in clinical trials promoted by Novo Nordisk, Roche, and Sobi. K.F.’s institution has received speaker’s fees from CSL Behring, Novo Nordisk; consultancy fees from Biogen, CSL Behring, Freeline, Novo Nordisk, Roche, and Sobi; and research support from Bayer, Pfizer, and Novo Nordisk. K.F. is the epidemiologist for the European Haemophilia Safety Surveillance (EUHASS) and the PedNet Haemophilia Research Foundation., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
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- 2024
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3. International Society on Thrombosis and Haemostasis clinical practice guideline for treatment of congenital hemophilia A and B based on the Grading of Recommendations Assessment, Development, and Evaluation methodology.
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Rezende SM, Neumann I, Angchaisuksiri P, Awodu O, Boban A, Cuker A, Curtin JA, Fijnvandraat K, Gouw SC, Gualtierotti R, Makris M, Nahuelhual P, O'Connell N, Saxena R, Shima M, Wu R, and Rosendaal FR
- Subjects
- Humans, Coagulants therapeutic use, Consensus, Factor VIII therapeutic use, Factor VIII genetics, Hemorrhage blood, Hemostasis, Societies, Medical, Treatment Outcome, Hematology methods, Hematology standards, Evidence-Based Medicine standards, Hemophilia A blood, Hemophilia A genetics, Hemophilia A therapy, Hemophilia A diagnosis, Hemophilia B blood, Hemophilia B therapy, Hemophilia B diagnosis, Hemophilia B genetics
- Abstract
Background: Hemophilia is a rare congenital bleeding disorder that results from complete or partial deficiency of blood coagulation factor (F)VIII (hemophilia A) or FIX (hemophilia B) due to pathogenic variants in their coding genes. Hemophilia requires complex management. To date, there is no evidence-based clinical practice guideline on hemophilia treatment based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach., Objectives: This evidence-based clinical practice guideline from the International Society on Thrombosis and Haemostasis aims to provide an overview of evidence and support patients, caregivers, hematologists, pediatricians, other clinicians, researchers, and stakeholders in treatment decisions about congenital hemophilia A and B., Methods: The International Society on Thrombosis and Haemostasis formed a multidisciplinary guideline panel of physicians and patients with global representation, balanced to minimize potential bias from conflicts of interest. The panel prioritized a set of clinical questions and outcomes according to their importance for clinicians and patients. A methodological team supported the guideline development process, including searching for evidence and performing systematic reviews. The GRADE approach was used, including GRADE Evidence to Decision frameworks. The recommendations were subject to public comment., Results: The panel selected 13 questions, of which 11 addressed the treatment of hemophilia A and 2 the treatment of hemophilia B. Specifically, the panel addressed questions on prophylactic and episodic treatment with FVIII concentrates, bypassing agents, and nonfactor therapy (emicizumab) for hemophilia A (with and without inhibitors) as well as immune tolerance induction for hemophilia A. For hemophilia B, the panel addressed questions on prophylactic and episodic treatment of bleeding events with FIX concentrates. Agreement was reached for all 13 recommendations, of which 7 (54%) were based on evidence from randomized clinical trials, 3 (23%) on observational studies, and 3 (23%) on indirect comparisons., Conclusion: Strong recommendations were issued for prophylactic over episodic treatment for severe and moderately severe hemophilia A and B. Only conditional recommendations were issued for the remaining questions. Future research should focus on direct treatment comparisons and the treatment of hemophilia B with and without inhibitors. Future updates of this guideline will provide an updated evidence synthesis on the current questions and focus on new FVIII and FIX concentrates, novel nonfactor therapies, and gene therapy for severe and nonsevere hemophilia A and B., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)
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- 2024
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4. Prediction of inhibitor development in previously untreated and minimally treated children with severe and moderately severe hemophilia A using a machine-learning network.
- Author
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Jardim LL, Schieber TA, Santana MP, Cerqueira MH, Lorenzato CS, Franco VKB, Zuccherato LW, da Silva Santos BA, Chaves DG, Ravetti MG, and Rezende SM
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- Humans, Child, Child, Preschool, Male, Predictive Value of Tests, Risk Factors, Adolescent, Reproducibility of Results, Blood Coagulation Factor Inhibitors blood, Time Factors, Infant, Risk Assessment, Biomarkers blood, Treatment Outcome, Hemophilia A drug therapy, Hemophilia A blood, Hemophilia A diagnosis, Machine Learning, Factor VIII genetics, Severity of Illness Index
- Abstract
Background: Prediction of inhibitor development in patients with hemophilia A (HA) remains a challenge., Objectives: To construct a predictive model for inhibitor development in HA using a network of clinical variables and biomarkers based on the individual similarity network., Methods: Previously untreated and minimally treated children with severe/moderately severe HA, participants of the HEMFIL Cohort Study, were followed up until reaching 75 exposure days (EDs) without inhibitor (INH-) or upon inhibitor development (INH+). Clinical data and biological samples were collected before the start of factor (F)VIII replacement (T0). A predictive model (HemfilNET) was built to compare the networks and potential global topological differences between INH- and INH+ at T0, considering the network robustness. For validation, the "leave-one-out" cross-validation technique was employed. Accuracy, precision, recall, and F1-score were used as evaluation metrics for the machine-learning model., Results: We included 95 children with HA (CHA), of whom 31 (33%) developed inhibitors. The algorithm, featuring 37 variables, identified distinct patterns of networks at T0 for INH+ and INH-. The accuracy of the model was 74.2% for CHA INH+ and 98.4% for INH-. By focusing the analysis on CHA with high-risk F8 mutations for inhibitor development, the accuracy in identifying CHA INH+ increased to 82.1%., Conclusion: Our machine-learning algorithm demonstrated an overall accuracy of 90.5% for predicting inhibitor development in CHA, which further improved when restricting the analysis to CHA with a high-risk F8 genotype. However, our model requires validation in other cohorts. Yet, missing data for some variables hindered more precise predictions., Competing Interests: Declaration of competing interests The authors state that they have no conflict of interest., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
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- 2024
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5. The Role of Clot Waveform Analysis and Related Parameters in the Diagnosis and Treatment of Hemophilia A.
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Song G, Wang Y, Zhang L, and Xia M
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- Humans, Partial Thromboplastin Time, Adult, Male, Severity of Illness Index, Adolescent, Young Adult, Child, Middle Aged, ROC Curve, Blood Coagulation Tests, Child, Preschool, Predictive Value of Tests, Hemophilia A blood, Hemophilia A diagnosis, Hemophilia A drug therapy, Factor VIII therapeutic use, Blood Coagulation drug effects
- Abstract
Background: Hemophilia A (HA) is an inherited bleeding disorder caused by a deficiency or defect in factor VIII (FVIII)., Methods: We investigated the role of clot waveform analysis (CWA) of activated partial thromboplastin time in the diagnosis and therapeutic monitoring of HA. The changes in CWA parameters the maximum clotting velocity (|Min1|), maximum clotting acceleration (|Min2|), and maximum clotting deceleration (|Max2|) were detected among mild, moderate, and severe HA groups., Results: As the severity of HA subtypes increased, the levels of |Min1|, |Min2|, and |Max2| progressively decreased ( p < 0.05). Receiver operating characteristic curve analysis showed that |Max2| and |Min2| were more effective than |Min1| in distinguishing different types of HA patients, with higher diagnostic efficacy. The standard curves based on Actin FSL reagent for normal and low levels of FVIII:C-|Max2| were established, with R2 values of 0.98 and 0.99, respectively. These curves can be utilized for monitoring during replacement therapies involving full-length recombinant FVIII and B-domain-deleted FVIII. Thirty cases of HA patients utilized the FVIII-|Max2| standard curve to obtain individual pharmacokinetics characteristic parameters. The clearance, half-life (t
1/2 ), time to FVIII:C of 1% above baseline (tt1%), and predicted dosage showed no statistically significant differences compared with one-stage assay ( p > 0.05)., Conclusion: CWA is an economical and practical tool, and its related parameters are associated with the severity of HA. It has promising clinical prospects in predicting FVIII:C levels and individualized treatment when HA patients undergo replacement therapy., Competing Interests: None declared., (Thieme. All rights reserved.)- Published
- 2024
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6. ISTH clinical practice guideline for treatment of congenital hemophilia A and B based on the Grading of Recommendations Assessment, Development, and Evaluation methodology: considerations for practice management and implementation.
- Author
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Ní Áinle F, DiMichele D, Falck-Ytter Y, Smit C, De Paula EV, Seth T, Chuansumrit A, and Middeldorp S
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- Humans, Evidence-Based Medicine standards, Consensus, Hemophilia A therapy, Hemophilia A diagnosis, Hemophilia B therapy, Hemophilia B diagnosis
- Abstract
Competing Interests: Declaration of competing interests The authors declare the following conflicts of interest (past 36 months): F.N.A.: member of the International Society on Thrombosis and Haemostasis (ISTH) Council and Vice-Chair of the ISTH Guideline and Guidance Committee; research funding (investigator-initiated studies, paid to university) from Bayer, Daiichi-Sankyo, and Sanofi; and consultancy fees (paid to university) from Boston Scientific. D.D.M.: member of the ISTH Council and consultant to the National Bleeding Disorders Foundation, the American Society of Hematology, and Believe Ltd on matters related to future research and workforce development in the areas of hematology and inherited bleeding disorders. A.C.: serves on the advisory board of Novo Nordisk and has received honoraria from Novo Nordisk, Grifols, Takeda, and Roche. E.V.D.P.: medical consultant for the area of the Brazilian Ministry of Health responsible for the national program of hereditary bleeding disorders. S.M.: member of the ISTH Council and reports participation in advisory or educational activities with AbbVie, Bayer, Astra Zeneca, Alveron (Advisory Board), Hemab, Norgine, Sanofi, Synapse, and Viatris; all honoraria are being paid to her institution. Y.F.-Y, T.S., and C.S. report no conflict of interest.
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- 2024
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7. Pros and cons of the ISTH treatment guidelines for hemophilia.
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Mannucci PM
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- Humans, Hemorrhage therapy, Societies, Medical, Treatment Outcome, Factor VIII therapeutic use, Factor VIII administration & dosage, Hemophilia A therapy, Hemophilia A diagnosis, Hemophilia A blood, Practice Guidelines as Topic
- Abstract
Competing Interests: Declaration of competing interests P.M.M. has received Roche, Takeda, and Werfen honoraria for lectures at educational symposia.
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- 2024
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8. [Acquired hemophilia A and emicizumab for the treatment of bleeding: two case report and a literature review].
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Launois A, Martin-Toutain I, Devaux F, Lambert J, Longval T, Merabet F, Jaidi R, Le Dore S, Ferre E, Rousselot P, De Raucourt E, and Flaujac C
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- Humans, Male, Aged, Treatment Outcome, Factor VIII immunology, Factor VIII therapeutic use, Factor VIII antagonists & inhibitors, Middle Aged, Antibodies, Bispecific therapeutic use, Hemophilia A drug therapy, Hemophilia A complications, Hemophilia A diagnosis, Hemophilia A blood, Hemophilia A immunology, Antibodies, Monoclonal, Humanized therapeutic use, Hemorrhage
- Abstract
Emicizumab is a bispecific antibody that mimics the function of factor VIII (FVIII) and is indicated for prophylactic use in patients with congenital hemophilia A with or without inhibitors. Acquired hemophilia A (AHA) is a rare and severe disorder causes by autoantibodies that inhibit FVIII. In AHA, acute bleeding are managed with bypassing agents but several reports described the off-label use of emicizumab. The aim of this article is to describe two cases of AHA treated with emicizumab and a review of the scientific littérature. Reports indicate that the use of emicizumab is efficacious to treat acute bleeding with less thrombotic events thant with bypassing agents and with a reduced hospitalisation duration. Nevertheless biological monitoring is more complicated with assay interferences and a persistent circulation more than 6 months after the last injection was observed for our two patients.
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- 2024
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9. Acute Acquired Hemophilia A Following Snake Bite: A Case Report and Clinical Insights.
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Walker N, Beedupalli K, Ramadas P, and Sharma S
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- Humans, Male, Middle Aged, Acute Disease, Snake Bites complications, Snake Bites diagnosis, Hemophilia A complications, Hemophilia A diagnosis
- Abstract
BACKGROUND Coagulopathies can manifest on a spectrum, from minor mucosal bleeding to life-threatening hemorrhage. Minor cases can be discovered in the setting of known risk factors, such as malignancy, old age, immunosuppression. However, acquired hemophilia A diagnosed after a snake bite is of lesser-known incidence and can present in a more acute, potentially life- or limb-threatening fashion. To properly diagnose this coagulopathy, one must be familiar with the related signs, symptoms, and laboratory findings so that swift diagnosis can follow. Diagnosis is key for early proper management, as displayed in the following case. CASE REPORT Our case report details a male patient presenting with diffuse bruising after a snake bite. Initially, on presentation to outside facilities, the diagnosis of acquired hemophilia A was not found. However, upon worsening of bruising in the setting of previous treatments initiated for the patient, he presented to our facility, where he subsequently received a diagnosis with acquired hemophilia A. He developed compartment syndrome due to excessive bleeding, requiring surgical intervention. With proper diagnosis, his bleeding diathesis was corrected with multiple rounds of repletion of factors and immunosuppression. His follow-up laboratory test results and examinations have shown continued resolution of his symptoms. CONCLUSIONS As acquired hemophilia A is less often linked with snake bites, this case highlights the importance of considering this disease process as a differential in patients with bleeding diathesis after a snake bite. The coagulation dysfunction can be severe, and, as such, early identification of this diagnosis leads to more targeted and effective therapy.
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- 2024
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10. Detection of hemophilia A genetic variants using third-generation long-read sequencing.
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Ling X, Pan L, Li L, Huang Y, Wang C, Huang C, Long Y, Zhai N, Xiao Q, Luo J, Tang R, Meng L, and Huang Y
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- Humans, Genetic Variation, Mutation, Polymerase Chain Reaction methods, Sequence Analysis, DNA, Hemophilia A genetics, Hemophilia A diagnosis, Factor VIII genetics
- Abstract
Background: Hemophilia A (HA) is an X-linked recessive genetic disorder caused by pathogenic variations of the factor VIII -encoding gene, F8 gene. Due to the large size and diverse types of variations in the F8 gene, causative mutations in F8 cannot be simultaneously detected in one step by traditional molecular analysis, and genetic molecular diagnosis and prenatal screening of HA still face significant difficulties and challenges in clinical practice. Therefore, we aimed to develop and validate an efficient, accurate, and time-saving method for the genetic detection of HA., Methods: A comprehensive analysis of hemophilia A (CAHEA) method based on long-range PCR and long-read sequencing (LRS) was used to detect F8 gene mutations in 14 clinical HA samples. The LRS results were compared with those of the conventional methods to evaluate the accuracy and sensitivity of the proposed approach., Results: The CAHEA method successfully identified 14 F8 variants in all probands, including 3 small insertion deletions, 4 single nucleotide variants, and 7 intron 22 inversions in a "one-step" manner, of which 2 small deletions have not been reported previously. Moreover, this method provided an opportunity to analyze the mechanism of rearrangement and the pathogenicity of F8 variants. The LRS results were validated and found to be in 100% agreement with those obtained using the conventional method., Conclusion: Our proposed LRS-based F8 gene detection method is an accurate and reproducible genetic screening and diagnostic method with significant clinical value. It provides efficient, comprehensive, and accurate genetic screening and diagnostic services for individuals at high risk of HA as well as for premarital and prenatal populations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
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- 2024
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11. Bacillus cereus Endophthalmitis in a Child with Hemophilia: A Case Report.
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Park H, Lee CS, Kang HG, and Kwak JJ
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- Humans, Male, Gram-Positive Bacterial Infections diagnosis, Gram-Positive Bacterial Infections microbiology, Anti-Bacterial Agents therapeutic use, Vitreous Body microbiology, Child, Endophthalmitis microbiology, Endophthalmitis diagnosis, Eye Infections, Bacterial diagnosis, Eye Infections, Bacterial microbiology, Bacillus cereus isolation & purification, Hemophilia A complications, Hemophilia A diagnosis
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- 2024
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12. Subarachnoid Hemorrhage as a Presentation of Hemophilia: A Case Report.
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Saiduzzaman M, Hasan MT, and Mia E
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- Humans, Male, Adolescent, Hemophilia A complications, Hemophilia A diagnosis, Subarachnoid Hemorrhage etiology, Subarachnoid Hemorrhage complications
- Abstract
A young boy presented with features of non-traumatic Subarachnoid hemorrhage (SAH) with hematemesis and melaena. He has had past history of prolonged bleeding following cut injury even requiring blood transfusion after circumcision. On examination, he was found confused, severely anemic, with presence of neck rigidity and painful swelling of right knee joint. But no positive family history was found. Non-contrast CT scan showed SAH. Cerebral angiography showed no aneurysm but knee joint had features of hemarthrosis. He was resuscitated and hemophilia was diagnosed on the basis of clinical suspicion of clotting factor assay. Specific treatment started in collaboration with Department of Hematology. This is a rare presentation of hemophilia as well as very uncommon cause of non-traumatic non-aneurysmal SAH.
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- 2024
13. Application of machine learning approaches for predicting hemophilia A severity.
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Rawal A, Kidchob C, Ou J, and Sauna ZE
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- Humans, Female, Predictive Value of Tests, Reproducibility of Results, Phenotype, Genetic Predisposition to Disease, Male, Databases, Genetic, Genotype, Hemophilia A diagnosis, Hemophilia A genetics, Hemophilia A blood, Machine Learning, Severity of Illness Index, Factor VIII genetics
- Abstract
Background: Hemophilia A (HA) is an X-linked congenital bleeding disorder, which leads to deficiency of clotting factor (F) VIII. It mostly affects males, and females are considered carriers. However, it is now recognized that variants of F8 in females can result in HA. Nonetheless, most females go undiagnosed and untreated for HA, and their bleeding complications are attributed to other causes. Predicting the severity of HA for female patients can provide valuable insights for treating the conditions associated with the disease, such as heavy bleeding., Objectives: To predict the severity of HA based on F8 genotype using a machine learning (ML) approach., Methods: Using multiple datasets of variants in the F8 and disease severity from various repositories, we derived the sequence for the FVIII protein. Using the derived sequences, we used ML models to predict the severity of HA in female patients., Results: Utilizing different classification models, we highlight the validity of the datasets and our approach with predictive F1 scores of 0.88, 0.99, 0.93, 0.99, and 0.90 for all the validation sets., Conclusion: Although with some limitations, ML-based approaches demonstrated the successful prediction of disease severity in female HA patients based on variants in the F8. This study confirms previous research findings that ML can help predict the severity of hemophilia. These results can be valuable for future studies in achieving better treatment and clinical outcomes for female patients with HA, which is an urgent unmet need., (Copyright © 2024 International Society on Thrombosis and Haemostasis. All rights reserved.)
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- 2024
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14. [Treatment of haemophilia in Austria].
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Male C, Ay C, Crevenna R, Eichinger S, Feistritzer C, Füller R, Haushofer A, Kurringer A, Neumeister P, Puchner S, Rettl J, Schindl T, Schuster G, Schwarz R, Sohm M, Streif W, Thom K, Wagner B, Wissmann E, Zwiauer K, and Pabinger I
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- Humans, Austria, Child, Adult, Practice Guidelines as Topic, Hemophilia A therapy, Hemophilia A diagnosis
- Abstract
This guideline is intended to provide practical guidance for the diagnosis and treatment of haemophilia in Austria. Few randomized controlled interventional trials are available addressing the treatment of haemophilia, therefore recommendations are usually based on low level of evidence and represent expert consensus.This guideline is based on the WFH guideline, published in 2020, and adapted according to the national circumstances and experience.It includes recommendations and suggestions for diagnosis and follow-up visits and pharmacological therapies for treatment and prophylaxis. Further topics comprise special aspects in children and adults with severe haemophilia, outcome measurement, and management of trauma, special bleedings and interventions, including dental procedures, inhibitors, management of haemophilia carriers, and psychosocial aspects., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)
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- 2024
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15. The influence of dead space in blood sampling needle on FVIII level and pharmacokinetic profiles in children with hemophilia.
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Zhen Y, Ai D, Huang K, Li G, Chen Z, and Wu R
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- Child, Humans, Blood Coagulation, Half-Life, Needles, Factor VIII pharmacokinetics, Hemophilia A blood, Hemophilia A diagnosis, Partial Thromboplastin Time standards, Blood Specimen Collection standards
- Abstract
Objective: To investigate the influence of the dead space in disposable blood sampling needle on activated partial thromboplastin time (APTT), FVIII level and pharmacokinetic (PK) profiles in children with hemophilia., Methods: Children (<18 years) with severe hemophilia A were enrolled. After three days' washout-period, blood samples were collected at pre-dose, 1 h, 3 h, 9 h, 24 h and 48 h post-infusion. At each timepoint, two 2 mL vacuum tubes with 3.2% trisodium citrate were used. The first tube was signed as 'non-standard' (NS) and the second tube was signed as 'standard' (S). FVIII activities were evaluated by one-stage assay. WAPPS-Hemo was used to generate PK profiles like half-life time (t
1/2 ), clearance (CL), trough level and time to 1, 2 and 5IU/dL after a dose of 50 ± 10IU/dL. The FVIII activities at 9 h and 24 h post-infusion were put into WAPPS and thus brought four combinations by true or biased FVIII level that used., Result: Compared with standard-collected blood samples, prolonged APTT results ( P -values < 0.01) and decreased FVIII activity ( P -values < 0.05) were revealed in those non-standard blood samples. The corresponding bias was in positive relation to both APTT-S (r = 0.44, P < 0.0001) and FVIII-S level(r = 0.68, P < 0.001). The FVIII bias percentage got larger as FVIII-S level reduced (r = -0.24, P < 0.01). During the four combinations of FVIII activity at 9 h and 24 h, statistically longer t1/2 , lower CL and longer time to 1, 2 or 5IU/dL were observed in 9H-S&24H-S group and 9H-NS&24H-S group., Conclusion: While using vacuum tubes for clotting indicators and PK profiles, the dead space of blood sampling needle should be eliminated in advance.- Published
- 2024
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16. Crohn's disease in hemophilic arthropathy patient: a case report.
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Zhang Z, Chen L, Zhou H, Chen G, and Tong P
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- Humans, Male, Adult, Joint Diseases etiology, Joint Diseases diagnosis, Hemarthrosis etiology, Hemarthrosis diagnosis, Crohn Disease complications, Crohn Disease diagnosis, Hemophilia A complications, Hemophilia A diagnosis
- Abstract
Crohn's disease (CD) is an inflammatory bowel disease affecting the digestive tract, the incidence of which is on the rise worldwide. The most common clinical manifestation of hemophilia is arthropathy secondary to recurrent joint effusions and chronic synovitis. This article reports on a rare 25-year-old male patient with both hemophilic arthropathy and Crohn's disease who was at risk for pathogenic gastrointestinal bleeding. After undergoing endoscopic pathologic testing and genetic testing, a multidisciplinary expert work-up of a treatment and nutritional plan was performed. The patient improved clinically and adhered to conservative treatment. This case report is the first report of this rare co-morbidity, demonstrating the highly pathogenic mutation locus and summarizing the clinical experience of early diagnosis and treatment., (© 2024. The Author(s).)
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- 2024
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17. Comprehensive domain-specific analysis and immunoglobulin G profiling of anti-factor VIII antibodies using a bead-based multiplex immunoassay.
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Pezeshkpoor B, Berkemeier AC, Herbst K, Albert T, Müller J, and Oldenburg J
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- Humans, Immunoassay methods, Predictive Value of Tests, Reproducibility of Results, Male, Protein Domains, Antibodies, Neutralizing blood, Antibodies, Neutralizing immunology, Adolescent, Microspheres, Factor VIII immunology, Hemophilia A immunology, Hemophilia A blood, Hemophilia A diagnosis, Immunoglobulin G blood, Immunoglobulin G immunology, Enzyme-Linked Immunosorbent Assay methods
- Abstract
Background: Antibodies against factor (F)VIII are a major complication in the treatment of patients with severe hemophilia A. The Nijmegen-Bethesda assay (NBA) is the gold standard for detection of neutralizing antibodies (inhibitors), whereas both inhibitors and nonneutralizing antibodies can be detected by immunoassays such as enzyme-linked immunosorbent assay (ELISA) and multiplex bead-based assays., Objectives: Evaluation of an in-house Luminex bead-based assay (LumiTope) compared with a commercially available ELISA and NBA., Methods: The LumiTope method comprised full-length and B-domain-deleted FVIII as well as 9 purified FVIII single or multidomains. The respective proteins were coupled to magnetic beads to detect domain-specific immunoglobulin (IgG; IgG
1-4 ) anti-FVIII antibodies in a large cohort of patients with hemophilia A with and without inhibitors., Results: Overall, LumiTope assay had a high sensitivity (94.9%) and specificity (91.2%), particularly in patients with low-titer inhibitors compared with ELISA (sensitivity of 72.2% vs 27.7%). IgG4 was the most abundant IgG subclass in NBA-positive patients. NBA-positive and -negative patients showed different domain profiles. Patients with genetic variants in the heavy chain predominantly exhibited antibodies specific to this chain, while those with a light-chain variant showed a more diverse distribution of antibody specificities. Patients with an intron 22 inversion resembled those with a light-chain defect, with a majority of antibodies targeting the light chain., Conclusion: LumiTope assay provides a sensitive and specific method for not only detection but also domain specification of anti-FVIII-antibodies. Implementation of bead-based assays could improve antibody detection, profiling, and comparability of results and complement NBA., Competing Interests: Declaration of competing interests B.P. reports having received grants for research from Biotest and Octapharma as well as personal fees for lectures and advisory board meetings from Novo Nordisk and Octapharma. A.-C.B. and K.H. report no conflict of interest. T.A. reports having received grants for a patient support association from Bayer, Biotest, Chugai, CSL Behring, Grifols, Novo Nordisk, Octapharma, Roche, Swedish Orphan Biovitrum, and Takeda, as well as personal fees for advisory board meetings, consulting and/or travel support from Bayer, BioMarin, Biotest, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Swedish Orphan Biovitrum, and Takeda. J.M. received honoraria from Siemens Healthineers and Octapharma. J.O. reports having received grants for studies and research from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, Sobi, and Takeda and travel support as well as personal fees for lectures and advisory board meetings from Bayer, Biogen Idec, BioMarin, Biotest, CSL Behring, Chugai, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sparks, Swedish Orphan Biovitrum, and Takeda., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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18. Renal inflammatory myofibroblastic tumor coexisting with hemophilia A carrier: a case report and literature review.
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Zhang Z, Wang H, Jiang Y, and Huang Z
- Subjects
- Humans, Female, Middle Aged, Neoplasms, Muscle Tissue complications, Neoplasms, Muscle Tissue diagnosis, Neoplasms, Muscle Tissue surgery, Arthritis, Rheumatoid complications, Ultrasonography methods, Hemophilia A complications, Hemophilia A diagnosis, Hematuria etiology, Hematuria diagnosis, Factor VIII administration & dosage, Factor VIII therapeutic use, Kidney Neoplasms complications, Kidney Neoplasms surgery, Kidney Neoplasms diagnosis, Tomography, X-Ray Computed
- Abstract
Renal inflammatory myofibroblastic tumor (IMT) is an exceptionally uncommon occurrence. This report presented the first documented case of renal IMT coexisting with hemophilia A carrier status. A 52-year-old asymptomatic female was incidentally discovered to have a kidney mass during a routine computed tomography (CT) scan spanning a 5-month period. Ultrasonography and contrast-enhanced CT scan raised suspicion of a potential renal malignant tumor. Over 2 decades ago, the patient experienced significant bleeding during childbirth, and she possessed a 5-year history of rheumatoid arthritis. Following a radical surgical procedure, intravenous supplementation of factor VIII was administered during the perioperative period. Subsequent to strenuous defecation, the patient encountered hematuria. Continued coagulation factor supplementation led to alleviation of hematuria symptoms. The underlying causes and pathogenesis responsible for IMT remain unclear. IMT is often associated with rheumatoid arthritis, possibly suggesting a connection to its etiology. Surgical excision stands as the primary approach to treatment, with recurrence being an exceedingly rare event. In instances where hemophilia is a complicating factor, vigilant monitoring of coagulation function and appropriate coagulation factor supplementation is imperative., (© 2023. The Author(s), under exclusive licence to Japanese Society of Nephrology.)
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- 2024
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19. Whole F8 gene sequencing identified pathogenic structural variants in the remaining unsolved patients with severe hemophilia A.
- Author
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Jourdy Y, Chatron N, Frétigny M, Zawadzki C, Lienhart A, Stieltjes N, Rohrlich PS, Thauvin-Robinet C, Volot F, Hamida YF, Hariti G, Leuci A, Dargaud Y, Sanlaville D, and Vinciguerra C
- Subjects
- Humans, Male, Genetic Predisposition to Disease, Severity of Illness Index, Pedigree, Chromosomes, Human, Pair 6 genetics, DNA Mutational Analysis, Chromosomes, Human, Pair 9 genetics, Sequence Analysis, DNA, Mutation, Female, Hemophilia A genetics, Hemophilia A diagnosis, Factor VIII genetics, Introns, Chromosome Inversion, Phenotype
- Abstract
Background: No F8 genetic abnormality is detected in approximately 1% to 2% of patients with severe hemophilia A (HA) using conventional genetic approaches. In these patients, deep intronic variation or F8 disrupting genomic rearrangement could be causal., Objectives: The study aimed to identify the causal variation in families with a history of severe HA for whom genetic investigations failed., Methods: We performed whole F8 gene sequencing in 8 propositi. Genomic rearrangements were confirmed by Sanger sequencing of breakpoint junctions and/or quantitative polymerase chain reaction., Results: A structural variant disrupting F8 was found in each propositus, so that all the 815 families with a history of severe HA registered in our laboratory received a conclusive genetic diagnosis. These structural variants consisted of 3 balanced inversions, 3 large insertions of gained regions, and 1 retrotransposition of a mobile element. The 3 inversions were 105 Mb, 1.97 Mb, and 0.362 Mb in size. Among the insertions of gained regions, one corresponded to the insertion of a 34 kb gained region from chromosome 6q27 in F8 intron 6, another was the insertion of a 447 kb duplicated region from chromosome 9p22.1 in F8 intron 14, and the last one was the insertion of an Xq28 349 kb gained in F8 intron 5., Conclusion: All the genetically unsolved cases of severe HA in this cohort were due to structural variants disrupting F8. This study highlights the effectiveness of whole F8 sequencing to improve the molecular diagnosis of HA when the conventional approach fails., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
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- 2024
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20. Comprehensive analysis and clinical case studies on pseudoeosinophilia: insights and implications - unraveling the complexity: analytical approaches and clinical significance.
- Author
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Hu Y and Chen Y
- Subjects
- Humans, Male, Female, Middle Aged, Clinical Relevance, Hemophilia A blood, Hemophilia A diagnosis
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- 2024
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21. Women and girls with inherited bleeding disorders: Focus on haemophilia carriers and heavy menstrual bleeding.
- Author
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Hermans C, Johnsen JM, and Curry N
- Subjects
- Male, Female, Humans, Hemorrhage genetics, Hemophilia A complications, Hemophilia A diagnosis, Hemophilia A genetics, Menorrhagia etiology, Menorrhagia genetics
- Abstract
Raising awareness and improving recognition, accurate classification, and enhanced access to new treatments represent current key challenges for carriers of haemophilia. Women and girls carrying genes for haemophilia often experience significant bleeding and/or low factor levels. The bleeding associated with female haemophilia is frequently overlooked, has a weak correlation with factor levels, and manifests differently than in males, with heavy menstrual bleeding being a predominant symptom. Recent changes in terminology now allow the diagnosis of haemophilia in females with low factor levels and differentiate between symptomatic and asymptomatic carriers of the gene. Observations from real-world experiences and limited clinical trial data have highlighted the positive impact of various new haemophilia treatments for women and girls with clotting factor deficiencies. There is an urgent need for initiatives that increase their access to these treatments and encourage well-designed clinical trials focusing on female-specific outcomes. In women with inherited bleeding disorders, early recognition and optimal management of heavy menstrual bleeding are crucial. However, treatment options and guidance from high-quality clinical trials are currently insufficient. Menstrual health assessment should be a regular part of monitoring women and girls with inherited bleeding disorders throughout their lives, emphasizing the importance of gathering data to improve future management., (© 2024 John Wiley & Sons Ltd.)
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- 2024
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22. Lower-dose emicizumab prophylaxis: can less be more?
- Author
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Srivastava A and Iorio A
- Subjects
- Humans, Factor VIII, Hemorrhage chemically induced, Hemorrhage prevention & control, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Bispecific adverse effects, Hemophilia A diagnosis, Hemophilia A drug therapy
- Abstract
Competing Interests: Declaration of competing interests A.S. has received research grants from Roche, Novo Nordisk, Sanofi, and Pfizer, speaker assignments from Sanofi, Novo Nordisk, Roche, Takeda, Pfizer, Sanofi, BioMarin, and Spark, and is on the advisory boards of Sanofi, Novo Nordisk, Roche, Takeda, Pfizer, BioMarin, Spark. A.I.’s institution, McMaster University, has received funds via research service agreements and research grants from Bayer, CSL, Novo Nordisk, Pfizer, Roche, Sanofi, Sobi, and Takeda.
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- 2024
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23. Haemophilic arthropathy: Diagnosis, management, and aging patient considerations.
- Author
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Bakeer N, Saied W, Gavrilovski A, and Bailey C
- Subjects
- Humans, Quality of Life, Hemarthrosis diagnosis, Hemarthrosis etiology, Hemarthrosis therapy, Aging, Arthrodesis, Hemophilia A complications, Hemophilia A therapy, Hemophilia A diagnosis, Synovitis diagnosis, Synovitis etiology, Synovitis therapy, Arthritis
- Abstract
Gene therapy and universal use of safer, more effective, and personalised prophylactic regimens (factor, and nonfactor) are expected to prevent joint bleeding and promote joint health in persons with haemophilia (PwH). Growing evidence suggests that subclinical bleeding, with active and inactive synovial proliferation, continues and haemophilic arthropathy remains a major morbidity in PwH despite early institution of joint prophylaxis. Joint health assessment is evolving with physical examination scores complementing imaging scores. Point-of-care ultrasound is emerging as a safe, cost-effective, and readily available tool for acute determination of musculoskeletal abnormalities, serial evaluation of joints for sonographic markers of haemophilic arthropathy, and in providing objective insight into the efficacy of new therapies. In acute haemarthrosis, arthrocentesis expedites recovery and prevent the vicious cycle of bleed-synovitis-rebleed. When synovial proliferation develops, a multidisciplinary team approach is critical with haematology, orthopaedics, and physiotherapy involvement. Synovectomy is considered for patients with chronic synovitis that fail conservative management. Non-surgical and minimally invasive procedures should always be offered and considered first. Careful patient selection, screening and early intervention increase the success of these interventions in reducing bleeding, pain, and improving joint function and quality of life. Chemical synovectomy is practical in developing countries, but radioactive synovectomy appears to be more effective. When surgical synovectomy is considered, arthroscopic/minimally invasive approach should be attempted first. In advanced haemophilic arthropathy, joint replacement and arthrodesis can be considered. While excited about the future of haemophilia management, navigating musculoskeletal challenges in the aging haemophilia population is equally important., (© 2024 John Wiley & Sons Ltd.)
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- 2024
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24. The role of rheumatologist in the assessment of hemophilic arthropathy using head-us in patients with hemophilia.
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Yılmaz E, Kaya Z, Satış H, Yazol M, Kirkiz S, and Koçak Ü
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- Humans, Rheumatologists, Hemophilia A complications, Hemophilia A diagnosis, Arthritis, Vascular Diseases, Joint Diseases diagnostic imaging, Joint Diseases etiology
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- 2024
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25. FRONTIER1: a partially randomized phase 2 study assessing the safety, pharmacokinetics, and pharmacodynamics of Mim8, a factor VIIIa mimetic.
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Lentz SR, Chowdary P, Gil L, Lopez-Jaime FJ, Mahlangu J, Matytsina I, Nielsen AL, and Windyga J
- Subjects
- Humans, Factor VIIIa adverse effects, Factor VIIIa pharmacokinetics, Factor VIIIa pharmacology, Hemorrhage drug therapy, Thrombin, Hemophilia A diagnosis, Hemophilia A drug therapy, Hemostatics adverse effects, Hemostatics pharmacokinetics, Hemostatics pharmacology
- Abstract
Background: Mim8 (denecimig) is a factor VIII (FVIII) mimetic bispecific antibody in development for the treatment of hemophilia. Data from the phase 1 part of FRONTIER1 (EudraCT: 2019-000465-20, NCT04204408, and NN7769-4513) suggested that Mim8 was well tolerated in healthy participants and exhibited pharmacokinetic (PK) properties consistent with dose proportionality., Objectives: The partially randomized, phase 2, multiple ascending dose (MAD) part of FRONTIER1 aimed to evaluate the safety, PK, pharmacodynamics (PD), and exploratory efficacy of Mim8 in participants with hemophilia A with or without FVIII inhibitors., Methods: The MAD part of FRONTIER1 consisted of 42 participants, assigned to 5 cohorts, with participants in cohorts 3 and 4 randomized 1:1 to dosing weekly or every 4 weeks, respectively. Four of the 42 participants (9.5%) had FVIII inhibitors prior to study enrolment. The primary endpoint was treatment-emergent adverse events (TEAEs). PK and PD were evaluated by Mim8 plasma concentration and thrombin generation, respectively. Exploratory efficacy was assessed via the number of treated bleeds. Safety and PD parameters were also evaluated from an exploratory cohort treated with emicizumab., Results: Mim8 was well tolerated, with 1 serious TEAE (anxiety-related chest pain) deemed unrelated to Mim8. There was no dose dependency on the number, causality, type, or severity of TEAEs. PK/PD properties supported weekly to monthly dosing approaches, and few participants experienced treated bleeds beyond the lowest dose cohort (1 in cohorts 2 and 3, and 3 in cohort 5)., Conclusion: These data support the continued clinical development of Mim8, and FRONTIER1 has proceeded onto an extension phase., Competing Interests: Declaration of competing interests S.R.L. has consulted for Argenx, Novo Nordisk, and Takeda. P.C. has served on advisory boards for ApcinteX, Bayer, Boehringer Ingelheim, CSL Behring, Chugai, Freeline, Novo Nordisk, Pfizer, Roche, Sanofi, Spark, Sobi, and Takeda, and has received research funding from Bayer, CSL Behring, Freeline, Novo Nordisk, Pfizer, Sobi, and Takeda. F.L.J. has served as a speaker or on advisory boards for Amgen, Bayer, CSL Behring, Novartis, Novo Nordisk, Pfizer, Roche, Rovi, Sobi, and Takeda, and has received research funding from Sobi. J.M. has received research grants from BioMarin, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Spark, and UniQure; served as a consultant for BioMarin, Novo Nordisk, Roche, Sanofi, Spark, and Takeda; and served on a speaker’s bureau for the International Society on Thrombosis and Haemostasis, Novo Nordisk, Pfizer, Roche, Sanofi, Takeda, and World Federation of Hemophilia. I.M. and A.L.N. are employed at Novo Nordisk and own stocks in the company. J.W. has received research funding and honorarium from AlfaSigma, Alnylam, Amgen, AstraZeneca, Bayer AG, CSL Behring, Novartis, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Siemens, Sobi, Swixx BioPharma, and Takeda. L.G. has no competing interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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26. The underevaluated impacts of the therapeutic revolution of hemophilia on women and girls.
- Author
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Hermans C, Krumb E, Rotellini D, and Pierce GF
- Subjects
- Humans, Male, Female, Chronic Disease, Hemophilia A diagnosis, Hemophilia A drug therapy, Hemostatics therapeutic use
- Abstract
The advent of new treatment options over the last decades has markedly improved the lives of male persons with hemophilia (PwH). However, this therapeutic revolution has not benefited women and girls with hemophilia (WGH) and symptomatic carriers of the disease to the same extent as their male counterparts. This inequity is primarily due to the exclusion of WGH from clinical trials and a failure to fully recognize their specific treatment needs. Additionally, the indirect impact of innovative therapies, when used for male PwH, on the lives of mothers, other relatives, and partners of these individuals has been largely overlooked until now. In addition to improving access of WGH and carriers to new hemostatic treatments and comprehensive hemophilia care, it is imperative to strive for alleviating the mental burden imposed on them by this chronic disease. The recently proposed concept of a "hemophilia-free mind," primarily focused on male PwH, should therefore also be applied to WGH, symptomatic carriers, and the predominantly female support network of PwH., Competing Interests: Declaration of competing interest This manuscript reflects the positions of the authors. The authors have no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
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- 2024
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27. A patient with concomitant epidermolysis bullosa acquisita, acquired hemophilia and disseminated warts.
- Author
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Didona D, Maglie R, Eming R, Hertl M, and Solimani F
- Subjects
- Humans, Skin, Epidermolysis Bullosa Acquisita complications, Epidermolysis Bullosa Acquisita diagnosis, Hemophilia A complications, Hemophilia A diagnosis, Warts complications, Warts diagnosis, Epidermolysis Bullosa
- Published
- 2024
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28. Diagnosis and treatment challenges in lower resource countries: State-of-the-art.
- Author
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Mahlangu J, Diop S, and Lavin M
- Subjects
- Humans, Blood Coagulation Factors therapeutic use, Hemophilia A diagnosis, Hemophilia A epidemiology, Hemophilia A therapy, von Willebrand Diseases diagnosis, von Willebrand Diseases epidemiology, von Willebrand Diseases therapy
- Abstract
The 2022 World Federation of Haemophilia Annual Global Survey (AGS) reports that 454,690 patients with inherited bleeding disorders (IBD) have been identified globally. While this represents noteworthy progress, haemophilia epidemiology data indicate that 75% of people with inherited bleeding disorders living in low-income and low-to-middle-income countries have yet to be diagnosed. The AGS also revealed that 11 billion clotting factor units are available to treat haemophilia A and B globally. Due to a lack of finance, these treatments are unavailable to haemophilia in low-income countries with a consequence lack of access equity for haemophilia treatment in these communities. This sobering reality is not limited to haemophilia but applies to von Willebrand Disease (VWD). While VWD is the most prevalent IBD, only 103,844 people living with this condition have been diagnosed globally. Of the diagnosed patients, only a fraction live in low- or middle-income countries. Moreover, the majority of VWD patients are still treated sub-optimally without replacement therapies or prophylaxis, both of which are now accepted as global standards of care. In this state-of-the-art review, the authors reflect on three issues. First, the minimum elements required to diagnose haemophilia in a resource-constrained setting are identified. Second, this review points to the critical stakeholders and outlines their roles in removing access to haemophilia treatment barriers. Finally, the authors examine von Willebrand disease's ongoing diagnostic and treatment challenges and compare these to haemophilia. With the rapidly evolving novel therapies, the therapeutic landscape of all IBD will likely change for the better., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)
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- 2024
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29. Knowledge and attitudes toward gene therapy of a cohort of Italian patients with hemophilia.
- Author
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Cutica I, Mortarino M, Garagiola I, Pravettoni G, and Peyvandi F
- Subjects
- Humans, Fear, Genetic Therapy adverse effects, Italy, Hemophilia A diagnosis, Hemophilia A therapy, Hemophilia A complications, Hemophilia B diagnosis, Hemophilia B genetics, Hemophilia B therapy
- Abstract
Background: Gene therapy (GT) has recently become a new therapeutic option for hemophilia A and B. However, patient levels of knowledge and attitudes toward it are poorly understood. A general lack of knowledge and education has been highlighted in previous studies. To date, no studies focused on patient attitudes toward GT, priorities, concerns, and information needs, nor how these factors might influence their willingness to accept it., Objectives: To evaluate knowledge and attitudes toward GT of an Italian cohort of patients with hemophilia., Methods: A questionnaire was administered to patients with hemophilia A and B to evaluate: (1) clinical data; (2) GT knowledge; (3) willingness to accept GT, perceived benefits and concerns, and information needs., Results: Eighty-five patients participated in the study; 64 with severe hemophilia A and 4 with severe hemophilia B. Participants appeared to know only general information on GT, but little about its detailed functioning. The avoidance of frequent infusions and the reduction of bleeding episodes seem to be the most relevant expected benefits. The possibility of failing or losing effectiveness of GT over time was the main concern. Regarding willingness to undergo GT, 54.4% of respondents gave a negative response, mainly due to fear that treatment will lose effectiveness over time, fear of side effects, and lack of GT knowledge. Greater knowledge increased the acceptability of this disruptive therapy among patients with severe hemophilia., Conclusion: Overall, Italian patients with hemophilia showed poor knowledge of GT. However, it seems that greater knowledge was associated with a greater willingness to have GT., Competing Interests: Declaration of competing interests F.P.: speaker fees for educational programs/symposia organized by Spark and Takeda. Advisory boards/consultant for Sanofi, Sobi, Roche, Biomarin, CSL Behring. I.C.: speaker fees for educational symposia organized by Spark. M.M., I.G., and G.P. have no conflicts of interest., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
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- 2024
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30. Acquired Hemophilia: A Rare Complication of Pediatric Idiopathic Multicentric Castleman Disease.
- Author
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Appell LE, Mack JM, Farrar JE, Roper SN, Savage MR, Pandey S, and Crary SE
- Subjects
- Humans, Child, Factor VIII, Hemorrhage etiology, Autoantibodies, Hemophilia A complications, Hemophilia A diagnosis, Castleman Disease complications, Castleman Disease diagnosis
- Abstract
Acquired hemophilia is caused by acquired autoantibodies to 1 of the factors of the coagulation cascade, usually factor VIII or IX, and is an exceedingly rare phenomenon in children. The finding of an acquired factor VIII inhibitor in a pediatric patient with idiopathic multicentric Castleman disease has never been reported. Patients with acquired hemophilia can have life-threatening bleeds that are refractory to blood product support, requiring bypassing agents to manage bleeding symptoms. We present the novel finding of acquired hemophilia resulting from an autoantibody to factor VIII in a pediatric patient with idiopathic multicentric Castleman disease and discuss the optimal management of bleeding in a patient with acquired hemophilia., (Copyright © 2024 by the American Academy of Pediatrics.)
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- 2024
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31. Low-dose emicizumab prophylaxis in patients with severe hemophilia A: a retrospective study bringing new hope for our patients.
- Author
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Patil R, Shanmukhaiah C, Gogtay NJ, Pandey P, Patil K, Jijina F, and Madkaikar M
- Subjects
- Humans, Factor VIII adverse effects, Retrospective Studies, Hemorrhage chemically induced, Hemorrhage prevention & control, Hemorrhage drug therapy, Hemophilia A diagnosis, Hemophilia A drug therapy, Antibodies, Bispecific adverse effects, Antibodies, Monoclonal, Humanized
- Abstract
Background: Low-dose emicizumab can potentially offer a cost-effective treatment option in persons with hemophilia A, especially in developing countries., Objectives: To compare the efficacy and safety of low-dose emicizumab with those on low-dose factor (F)VIII prophylaxis via chart review., Methods: After ethics approval, chart data of 2 groups of patients were reviewed: group 1 (low-dose emicizumab, n = 10; 3 mg/kg monthly without a loading dose) and group 2 (low-dose FVIII prophylaxis, n = 10; 10-20 IU/kg of FVIII concentrates twice a week). Outcomes were target joints, annual bleeding rate, annual joint bleeding rate, Hemophilia Joint Health Score, nonactivated thromboelastometry-rotational thromboelastometry clotting time, plasma emicizumab levels, and direct costs of treatment., Results: All outcome measures were significantly better in the low-dose emicizumab group than in the low-dose FVIII prophylaxis group. For nonactivated thromboelastometry-rotational thromboelastometry, median values after 6 months in the low-dose emicizumab group were comparable with values seen in patients with mild hemophilia, while the values in the low-dose FVIII prophylaxis group were similar to those of patients with moderate hemophilia. The direct cost of low-dose emicizumab was found to be approximately US $6000 and that for low-dose recombinant FVIII prophylaxis used in our study was US $6282 (the cost may range from US $3432 to $7920 depending on the type of factor) when compared to approximately US $15 000 for standard-dose emicizumab., Conclusion: Low-dose emicizumab offers a cost-effective treatment option and can improve access in developing countries. These findings need to be confirmed in a larger and better-controlled study., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
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- 2024
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32. A rare twist: COVID-19 infection masquerading as IgA vasculitis in a hemophilia a patient.
- Author
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Alnaqbi KA, Abunamous N, and Saleem T
- Subjects
- Male, Adult, Humans, Young Adult, Skin pathology, Gastrointestinal Tract, IgA Vasculitis complications, IgA Vasculitis diagnosis, IgA Vasculitis pathology, Hemophilia A complications, Hemophilia A diagnosis, Hemophilia A pathology, COVID-19 complications, COVID-19 diagnosis
- Abstract
Hemophilia A and B are one of the most common hereditary bleeding disorders. Patients are predisposed to bleeding spontaneously or after minor trauma in different areas such as the skin, gastrointestinal, or joints. COVID-19 infection has been associated with various clinical manifestations and complications including rarely triggering IgA vasculitis. We report a 23-year-old man who was previously diagnosed with severe hereditary hemophilia A. He presented to our hospital with classic symptoms of IgA vasculitis, complaining of petechiae and purpura in his limbs, fatigue, body aches, poor oral intake, abdominal pain, and watery non-bloody diarrhea. He did not present with respiratory symptoms or fever typical of COVID-19 infection. Abnormal blood tests were mildly elevated C-reactive protein, elevated d-dimers, and low Factor VIII activity. Extensive immunological tests were negative. CT abdomen with contrast was unremarkable. A skin biopsy strongly indicated IgA vasculitis. COVID-19 test came back positive. The patient was managed symptomatically and with glucocorticosteroids which significantly improved his symptoms. The available literature on clinical features, laboratory tests, and management of COVID-19-associated IgA vasculitis is discussed. However, there is no case reported on the associations between hemophilia, COVID-19 infection, and IgA vasculitis. This is the first case of atypical COVID-19 infection masquerading as de novo IgA vasculitis in an adult patient with underlying hemophilia. Our case contributes to the growing body of literature about hemophilia being a possible predisposing factor that a COVID-19 virus relies on to amplify immune dysregulation resulting in IgA vasculitis., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)
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- 2024
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33. Rifampicin-Induced Toxic Hepatitis in a Patient with Hemophilia After Chemical Synovectomy
- Author
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Uğur MC, Aydoğdu S, Kaya Biçer E, Balkan C, and Kavaklı K
- Subjects
- Humans, Synovectomy, Rifampin adverse effects, Recurrence, Hemophilia A diagnosis
- Abstract
Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors.
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- 2024
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34. Advancements in haemophilia A and health equity: is it time to redefine severity?
- Author
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Weyand AC, Malec L, and Pipe SW
- Subjects
- Humans, Severity of Illness Index, Hemophilia A diagnosis, Hemophilia A therapy, Health Equity
- Abstract
Competing Interests: ACW has research funding from Pfizer, Takeda, Novo Nordisk, and Sanofi; has received consulting fees from Spark, Genentech, Sanofi, Takeda, Bayer, and Novo Nordisk; has received honoraria from Sanofi and Genentech; and has received travel support from Sanofi, Genentech, Spark, and Takeda. LM has received consulting fees from Takeda, CSL Behring, Sanofi, Sobi, Novo Nordisk, and Bayer; and received honoraria from Sanofi, CSL Behring, and the National Hemophilia Foundation. SWP has grants and contracts from Siemens and Yewsavin; has received consulting fees from Apcintex, ASC Therapeutics, Bayer, BioMarin, CSL Behring, HEMA Biologics, Freeline, LFB, Novo Nordisk, Pfizer, Regeneron/Intellia, Roche/Genentech, Sanofi, Takeda, Spark Therapeutics, and uniQure; and serves on the scientific advisory board for GeneVentiv and Equilibra Bioscience.
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- 2024
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35. Stromal cell-derived factor 1 alpha (SDF-1alfa) and cartilage oligomeric matrix protein (COMP): Two potential signature biomarkers of radiological detectable hemophilic arthropathy.
- Author
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Leuci A, Robert M, Josset L, Marano M, Connes P, Désage S, Meunier S, Lienhart A, and Dargaud Y
- Subjects
- Humans, Chemokine CXCL12, Cartilage Oligomeric Matrix Protein, Retrospective Studies, Hemarthrosis diagnostic imaging, Hemarthrosis etiology, Radiography, Biomarkers, Hemophilia A complications, Hemophilia A diagnosis, Hemophilia A pathology, Arthritis complications
- Abstract
Introduction: Hemophilia is a rare constitutional bleeding disorder due to a deficiency in Factor VIII or Factor IX. Recurrent hemarthroses, one of the major complications of the disease, lead to hemophilic arthropathy, a disabling condition that requires early diagnosis. Traditionally, clinical examination and plain film radiography have been used to diagnose hemophilic arthropathy. Magnetic resonance imaging (MRI) and ultrasound can be more useful for diagnosing soft-tissue changes. However, but each of these methods has limitations and diagnosis of arthropathy can be delayed., Aim: The aim of this project was to assess plasmatic biomolecules indicative of osteo-cartilaginous damage in patients with hemophilia with or without known arthropathy, in order to improve the diagnosis of this major complication of the disease., Methods: In this monocentric retrospective study, 40 patients with hemophilia A or B, for whom a plasma sample was available, provided informed consent for further analyses (multiplex immunoassays and ELISA) and collection of relevant clinical information in their medical files. Correlations were sought for between biomarkers of interest and the severity of joint lesions assessed according to Pettersson's radiologic score., Results: Two biomarkers were identified, respectively SDF-1α and COMP. Their plasmatic levels were significantly increased in patients with arthropathy compared to controls and patients without arthropathy. These values correlated significantly with the Pettersson score in patients under regular prophylaxis., Conclusion: Two plasma biomarkers have been identified that could help assess the presence and severity of hemophilic arthropathy., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)
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- 2024
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36. [Living with… hemophilia].
- Author
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Borel-Derlon A
- Subjects
- Humans, Quality of Life, Hemophilia A diagnosis, Hemophilia A therapy, Medicine
- Abstract
Competing Interests: A. Borel-Derlon déclare appartenir au board d’experts de LFB pour la recherche clinique sur la maladie de Willebrand.
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- 2024
37. Agreement between one stage and chromogenic assays in samples from patients receiving recombinant porcine FVIII (Obizur, Susoctocog-alfa).
- Author
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Guy S, Bowyer AE, Shepherd MF, Maclean RM, and Kitchen S
- Subjects
- Humans, Swine, Animals, Factor VIII, Actins, Plasma, Blood Coagulation Tests methods, Hemophilia A diagnosis, Hemophilia A drug therapy, Hemostatics
- Abstract
Introduction: Recombinant porcine FVIII (rpFVIII) (Obizur, Susoctcog-alfa, Takeda, Japan) is licensed for the treatment of bleeding in acquired Haemophilia A (AHA). The summary of product characteristics state that monitoring should be by one stage assay (OSA) rather than chromogenic assay (CSA). CSA have been shown to underestimate activity when rpFVIII is added to plasma in vitro., Methods: Samples from three AHA patients (n = 21) (pre- and post rpFVIII) were assessed using FVIII:C assays; OSA methods: Actin, Actin FS, Actin FSL and Pathromtin SL performed on CS5100i (Sysmex, Kobe, Japan); APTT-SP, SynthASil and SynthAFax performed on ACL TOP (Werfen, Barcelona, Spain). CSA methods on CS5100i: Siemens Chromogenic Assay, Biophen FVIII:C, Technochrom FVIII:C; on ACL TOP: Rox Factor VIII, Coamatic Factor VIII and CRYOcheck Factor VIII., Results: OSA and CSA varied according to reagent used median OSA 61 IU/dL (range 41.5-81 IU/dL (ANOVA p < 0.0001)) median CSA 46.5 IU/dL (range of method specific medians 36.5-84 IU/dL (ANOVA p < 0.0001)). Amongst OSA, Actin FS was associated with the highest FVIII:C, APTT-SP was associated with the lowest. Variation in CSA results by different methods was also seen with highest FVIII:C levels obtained using the Technochrom FVIII:C and the lowest levels obtained with Siemens Assay., Conclusion: The relationship between OSA and CSA was not consistent between method or patient. Previously there has been reports of underestimation by CSA in in vitro spiked samples. Investigation into concentration of phospholipids in the APTT reagents may explain some of these variations., (© 2023 John Wiley & Sons Ltd.)
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- 2024
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38. Relapse of Acquired Hemophilia A after COVID-19 Infection.
- Author
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Marumo A, Sugihara H, Omori I, and Morishita E
- Subjects
- Aged, 80 and over, Humans, Male, Chronic Disease, Factor VIII, Recurrence, RNA, Viral, SARS-CoV-2, von Willebrand Factor, COVID-19 complications, Hemophilia A complications, Hemophilia A drug therapy, Hemophilia A diagnosis
- Abstract
Acquired hemophilia A (AHA) is a rare disease in which an autoantibody causes bleeding by interacting with and inhibiting the coagulation activity of endogenous factor VIII (FVIII). Most cases of AHA are idiopathic; known causes include autoimmune diseases, malignant tumors, pregnancy, drugs, and viral infections. An 86-year-old man was diagnosed with AHA based on the following results: an activated partial thromboplastin time (aPTT) extension of 130.7 seconds, presence of an inhibitor pattern in a mixing study, an endogenous factor VIII (FVIII) level of <1%, and an FVIII inhibitor titer of >5.1 Bethesda units (BU). The activity of von Willebrand factor (vWF) was diminished (<10%), which was considered a complication of acquired von Willebrand syndrome (AVWS). The patient was started on prednisolone, and the inhibitor level eventually became negative. vWF values also became normal. However, 1 year later, he was hospitalized for treatment of coronavirus disease 2019 (COVID-19). Blood testing showed an aPTT extension of 110.5 seconds, FVIII level of 4%, and FVIII inhibitor titer of 0.8 BU; thus, a relapse of AHA was diagnosed. After administration of corticosteroid and remdesivir, he recovered from COVID-19 and AHA. The inhibitor level became negative on the 9th day of admission. Several studies have implicated COVID-19 infection and vaccination in AHA. We recommend that aPTT be measured when patients with AHA are infected with SARS-CoV2, to confirm AHA relapse.
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- 2024
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39. Evaluation of collagen turnover biomarkers as an objective measure for efficacy of treatment with rurioctocog alfa pegol in patients with hemophilia A: a secondary analysis of a randomized controlled trial.
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Manon-Jensen T, Tangada S, Bager C, Chowdary P, Klamroth R, von Drygalski A, Windyga J, Escobar M, Frederiksen P, Engl W, Ewenstein B, and Karsdal M
- Subjects
- Humans, Factor VIII therapeutic use, Collagen, Biomarkers, Hemophilia A diagnosis, Hemophilia A drug therapy, Vascular Diseases complications
- Abstract
Background: Patients with hemophilia who have recurrent hemarthroses develop hemophilic arthropathy (HA). Regular prophylaxis with factor (F) VIII (FVIII) can reduce HA, but there is a need for objective outcome measures to evaluate treatment efficacy., Objectives: Evaluate and assess collagen turnover biomarkers in patients with hemophilia A to determine the efficacy of rurioctocog alfa pegol treatment and understand their potential as tools for guiding treatment decisions and monitoring outcomes., Methods: Joint remodeling was assessed by analyzing serum levels of collagen remodeling products at baseline and months 3, 6, 9, and 12 in a 98 patient subset receiving pharmacokinetics-guided prophylaxis with rurioctocog alfa pegol, targeting FVIII trough levels of 1 to 3 International Units (IU)/dL or 8 to 12 IU/dL (PROPEL study, NCT0285960)., Results: Basement membrane metabolism-related type 4 collagen remodeling products (C4M and PRO-C4) decreased after 3 months at all time points by up to 25% at 1 to 3 IU/dL (P = .049, P < .0001) and 8 to 12 IU/dL FVIII trough levels (P = .0002, P < .0001). Interstitial tissue metabolism-related type 3 (C3M) and 5 (PRO-C5) collagen remodeling products decreased after 3 months, by up to 19% at 1 to 3 IU/dL FVIII trough level (P = .0001, P = .009) and 23% at 8 to 12 IU/dL FVIII trough level (P = .0002, P = .001). An increase of up to 12% was seen for cartilage metabolism-related type 2 collagen product (PRO-C2, not C2M) after 6 months at both trough levels (P = .01, P = .005). When stratified by prior treatment, changes in C3M (P = .03) and C4M (P = .02) levels were observed between trough levels for prior on-demand treatment but not for prophylaxis prior to study entry., Conclusion: Joint improvement measured by collagen remodeling biomarkers specific to the basement membrane, interstitial matrix, and cartilage was seen with pharmacokinetics-guided prophylaxis. These collagen remodeling biomarkers warrant further exploration as biomarkers to guide treatment toward improvement in HA., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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40. Absence of femur induced by haemophilic pseudotumour.
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Wei Z and Weng X
- Subjects
- Humans, Femur diagnostic imaging, Femur pathology, Lower Extremity, Hemophilia A complications, Hemophilia A diagnosis, Hemophilia A pathology
- Published
- 2024
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41. Characteristics and outcome of a territory-wide cohort study of patients with acquired hemophilia A in Hong Kong.
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Sin CF, Li THS, Wong KP, Wong KW, Sin YT, Lam WK, Mak HC, Lau WP, Yeung KP, Leung FSK, and Li CH
- Subjects
- Humans, Aged, Aged, 80 and over, Factor VIII, Cohort Studies, Hong Kong epidemiology, Pathologic Complete Response, Hemophilia A epidemiology, Hemophilia A diagnosis, Sepsis complications
- Abstract
Introduction: Acquired hemophilia A (AHA) is a rare bleeding disorder with destruction of factor VIII by autoantibodies. Comprehensive data for Chinese patients are lacking. Predictors of hospital stay have not been investigated., Methods: A territory-wide review of patients diagnosed with AHA from January 1, 2012, to December 31, 2021 was performed by retrieving patients' information from an electronic database system in Hong Kong., Results: Overall, 165 patients were included in this 10-year study, and the estimated incidence was 2.4 per million/year, which was higher than those reported from Caucasian cohorts. The median age of diagnosis was 80 years old. Patients had a long hospital stay (median: 25 days) and high mortality (55.2 %). The majority of deaths were caused by immunosuppression-related sepsis (49.5 %). Age was an independent predictor of overall survival (Hazard ratio: 1.065, 95 % CI: 1.037-1.093, p < 0.001), complete remission (CR) status (odd ratios (OR): 0.948, 95 % CI: 0.921-0.976, p < 0.001) and time to achieve CR (OR: 1.043, 95 % CI: 1.019-1.067, p < 0.001). Higher hemoglobin level on presentation was associated with shorter time to achieve CR (OR: 0.888, 95 % CI: 0.795-0.993, p = 0.037). Factor VIII level < 1 % normal, high inhibitor titer and intensive immunosuppressive regimen predicted long hospital stay., Conclusion: We presented comprehensive data of Chinese patients with AHA which comprised predominantly frail elderly who required long hospital stay and had high sepsis-related mortality. This posed challenges in managing AHA in such patients. Individualized immunosuppressive therapy is needed to balance the benefits and risk of septic complications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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42. COVID-19 outcomes in persons with hemophilia: results from a US-based national COVID-19 surveillance registry.
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Sharathkumar A, Wendt L, Ortman C, Srinivasan R, Chute CG, Chrischilles E, and Takemoto CM
- Subjects
- Humans, Male, Anticoagulants therapeutic use, Retrospective Studies, Hemorrhage chemically induced, Registries, Venous Thromboembolism etiology, Hemophilia A complications, Hemophilia A diagnosis, Hemophilia A drug therapy, COVID-19 complications
- 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., Competing Interests: Declaration of competing interests A.S. has received honoraria and served as institutional principal investigator for clinical studies from CSL Behring, Genentech, Pfizer, Bristol-Meier Squibb, Takeda, and National Institutes of Health. C.T. has received honoraria and served as institutional principal investigator for clinical studies from Novartis, Global Blood Therapeutics, Forma Therapeutics, Genentech, and Daiichi-Sankyo. C.C. has received NIH/NCATS funding for the N3C Collaborative. L.W., C.O., E.C., R.S., and the N3C investigators declare no conflicts of interest., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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43. Patients with moderate hemophilia A and B with a severe bleeding phenotype have an increased burden of disease.
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Verhagen MJA, van Balen EC, Blijlevens NMA, Coppens M, van Heerde WL, Leebeek FWG, Rijpma SR, van Vulpen LFD, Gouw SC, and Schols SEM
- Subjects
- Adult, Humans, Thrombin therapeutic use, Quality of Life, Hemorrhage drug therapy, Hemarthrosis prevention & control, Phenotype, Cost of Illness, Factor VIII therapeutic use, Hemophilia A complications, Hemophilia A diagnosis, Hemophilia A epidemiology
- Abstract
Background: Patients with moderate hemophilia express varying bleeding phenotypes., Objectives: To assess the burden of disease in patients with moderate hemophilia and a mild or severe phenotype incorporating the thrombin generation profile., Methods: This sub-study of the 6th Hemophilia in the Netherlands study, analyzed data of adults with moderate hemophilia A or B. Patient characteristics and information on bleeding tendency, joint status, and quality of life were obtained from electronic patient files and self-reported questionnaires. A severe bleeding phenotype was defined as an annual bleeding rate ≥5, an annual joint bleeding rate ≥3, and/or the use of secondary/tertiary prophylaxis, and a mild phenotype vice versa. TG was measured with the Nijmegen Hemostasis Assay., Results: This study included 116 patients: 21% had a severe phenotype of whom 46% used prophylaxis. Patients with a severe phenotype treated on demand reported a higher median annual bleeding rate (7), annual joint bleeding rate (3), and more frequently an impaired joint (77%) than patients with a severe phenotype on prophylaxis (2; 0; 70%) or patients with a mild phenotype (0; 0; 47%). Furthermore, patients with a severe phenotype treated on demand experienced a more decreased quality of life. Despite similar factor activity levels, patients with a severe phenotype had a lower thrombin peak height and thrombin potential (0.7%; 0.06%) than patients with a mild phenotype (21.3%; 46.8%)., Conclusion: Patients with moderate hemophilia and a severe phenotype treated on demand displayed a high burden of disease as well as a low thrombin generation profile advocating them toward more intensive prophylactic treatment., Competing Interests: Declaration of competing interests N.M.A.B, S.R.R, E.C.v.B., and M.J.A.V. have no conflicts of interest to declare. M.C. has received financial support for research from Bayer, CSL Behring, Daiichi Sankyo, Portola/Alexion, Roche, Sanquin Blood Supply, and UniQure; and consultancy or lecturing fees from Bayer, CSL Behring, Medcon International, Medtalks, Novo Nordisk, Pfizer, and Sobi. W.L.v.H. has received unrestricted grants from Bayer, Shire, Novo Nordisk, and CSL Behring; and is the founder and CSO of Enzyre BV, a Radboudumc spinoff company. F.W.G.L. has received unrestricted grants or research funding from CLS Behring, Sobi, Takeda, and Uniqure; consultancy fees from BioMarin, CLS Behring, Takeda, and Uniqure (of which all fees go to the University); and was a Data Safety Monitoring Board Member for Roche. L.F.D.v.V. has received a research grant from Griffols (fee paid to the institution). S.C.G. has received an unrestricted research grant from SOBI. S.E.M.S. has received an unrestricted research grant from Bayer., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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44. Management of pregnant women who have bleeding disorders.
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James AH, Pacheco LD, and Konkle BA
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- Child, Infant, Newborn, Female, Pregnancy, Male, Humans, Pregnant Women, Placenta, Hemorrhage therapy, Blood Coagulation Factors therapeutic use, Hemophilia A diagnosis, Hemophilia A therapy, von Willebrand Diseases diagnosis, von Willebrand Diseases therapy
- Abstract
Bleeding disorders, including von Willebrand disease (VWD), hemophilia, other coagulation factor deficiencies, platelet disorders, defects of fibrinolysis, and connective tissue disorders, have both maternal and fetal implications. Successful management of bleeding disorders in pregnant women requires not only an understanding of bleeding disorders but also an understanding of when and how bleeding occurs in pregnancy. Bleeding does not occur during a normal pregnancy with a healthy placenta. Bleeding occurs during pregnancy when there is an interruption of the normal utero-placental interface, during miscarriage, during an ectopic pregnancy, or at the time of placental separation at the conclusion of pregnancy. Although mild platelet defects may be more prevalent, the most commonly diagnosed bleeding disorder among women is VWD. Other bleeding disorders are less common, but hemophilia carriers are unique in that they are at risk of bleeding themselves and of giving birth to an affected male infant. General guidance for maternal management of a woman who is moderately or severely affected includes obtaining coagulation factor levels at a minimum in the third trimester; planning for delivery at a center with hemostasis expertise; and anticipating the need for hemostatic agents. General guidance for fetal management includes pre-pregnancy counseling; the option of preimplantation genetic testing for hemophilia; delivery at a tertiary care center with pediatric hematology and newborn intensive care; consideration of cesarean delivery of a potentially severely affected infant; and avoidance of invasive procedures such as scalp electrodes and operative vaginal delivery in any potentially affected infant., (Copyright © 2023 by The American Society of Hematology.)
- Published
- 2023
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45. Diagnosis and laboratory monitoring of hemophilia A.
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Platton S, Sivapalaratnam S, and Raheja P
- Subjects
- Humans, Factor VIII, Blood Coagulation Tests methods, Blood Coagulation, Blood Coagulation Factors, Anticoagulants, Hemophilia A diagnosis, Hemophilia A therapy, Hemostatics
- Abstract
Acquired hemophilia A (AHA) is a rare disorder in which autoantibodies against factor VIII (FVIII) lead to a bleeding phenotype that varies from life-threatening to no bleeding at all. Prolonged activated partial thromboplastin times (APTT) in patients with a bleeding phenotype should be investigated to rule out AHA and should never be ignored in a preprocedure patient. Most inhibitors in AHA are heat and time dependent, so mixing studies performed only on an immediate mix are not useful: both lupus anticoagulants and treatment with direct oral anticoagulants can coexist with AHA and confound the diagnosis. Assays for intrinsic coagulation factors and von Willebrand factor should always be performed, regardless of the results of mixing studies. A Bethesda or modified Bethesda assay should be performed to quantify any inhibitor, and if susoctocog alfa (rpFVIII) is available, then an assay for cross-reacting antibodies should also be performed. At diagnosis and until complete remission, if the FVIII in the patient sample is >5 IU/dL, heat inactivation should be performed before the inhibitor assays are performed. While there are no conventional tests available to measure the effects of FVIII bypassing therapies, newer therapies may require monitoring, or their effects may need to be considered when choosing appropriate assays. Measurement of rpFVIII requires a 1-stage clotting assay, and measurement of patient FVIII while on emicizumab requires a chromogenic assay that does not contain human FX. Close communication is required between the treating clinicians and the laboratory to ensure that the correct tests are performed while patients are receiving treatments., (Copyright © 2023 by The American Society of Hematology.)
- Published
- 2023
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46. Comprehensive Analysis of Hemophilia A (CAHEA): Towards Full Characterization of the F8 Gene Variants by Long-Read Sequencing.
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Liu Y, Li D, Yu D, Liang Q, Chen G, Li F, Gao L, Li Z, Xie T, Wu L, Mao A, Wu L, and Liang D
- Subjects
- Humans, Factor VIII genetics, Genetic Testing, Introns, Multiplex Polymerase Chain Reaction, Mutation, Hemophilia A diagnosis, Hemophilia A genetics
- Abstract
Background: Hemophilia A (HA) is the most frequently occurring X-linked bleeding disorder caused by heterogeneous variants in the F8 gene, one of the largest genes known. Conventional molecular analysis of F8 requires a combination of assays, usually including long-range polymerase chain reaction (LR-PCR) or inverse-PCR for inversions, Sanger sequencing or next-generation sequencing for single-nucleotide variants (SNVs) and indels, and multiplex ligation-dependent probe amplification for large deletions or duplications., Materials and Methods: This study aimed to develop a LR-PCR and long-read sequencing-based assay termed comprehensive analysis of hemophilia A (CAHEA) for full characterization of F8 variants. The performance of CAHEA was evaluated in 272 samples from 131 HA pedigrees with a wide spectrum of F8 variants by comparing to conventional molecular assays., Results: CAHEA identified F8 variants in all the 131 pedigrees, including 35 intron 22-related gene rearrangements, 3 intron 1 inversion (Inv1), 85 SNVs and indels, 1 large insertion, and 7 large deletions. The accuracy of CAHEA was also confirmed in another set of 14 HA pedigrees. Compared with the conventional methods combined altogether, CAHEA assay demonstrated 100% sensitivity and specificity for identifying various types of F8 variants and had the advantages of directly determining the break regions/points of large inversions, insertions, and deletions, which enabled analyzing the mechanisms of recombination at the junction sites and pathogenicity of the variants., Conclusion: CAHEA represents a comprehensive assay toward full characterization of F8 variants including intron 22 and intron 1 inversions, SNVs/indels, and large insertions and deletions, greatly improving the genetic screening and diagnosis for HA., Competing Interests: A.M., T.X., and L.W. are employees of Berry Genomics Corporation. The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)
- Published
- 2023
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47. Health-related quality of life following valoctocogene roxaparvovec gene therapy for severe hemophilia A in the phase 3 trial GENEr8-1.
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O'Mahony B, Dunn AL, Leavitt AD, Peyvandi F, Ozelo MC, Mahlangu J, Peerlinck K, Wang JD, Lowe GC, Tan CW, Giermasz A, Tran H, Khoo TL, Cockrell E, Pepperell D, Chambost H, López Fernández MF, Kazmi R, Majerus E, Skinner MW, Klamroth R, Quinn J, Yu H, Wong WY, Robinson TM, and Pipe SW
- Subjects
- Adult, Male, Humans, Quality of Life, Hemorrhage, Surveys and Questionnaires, Hemophilia A diagnosis, Hemophilia A drug therapy, Hemophilia A genetics
- Abstract
Background: Severe hemophilia A (HA) negatively impacts health-related quality of life (HRQOL)., Objectives: We aimed to analyze HRQOL in adult men with severe HA without inhibitors after valoctocogene roxaparvovec gene transfer in the phase 3 trial GENEr8-1., Methods: Participant-reported outcomes were the hemophilia-specific quality of life questionnaire for adults (Haemo-QOL-A), the EQ-5D-5L instrument, the Hemophilia Activities List (HAL), and the Work Productivity and Activity Impairment Questionnaire: Hemophilia Specific (WPAI+CIQ:HS). Participants completed the questionnaires at baseline and through 104 weeks postinfusion with 6 × 10
13 vg/kg of valoctocogene roxaparvovec. Scores were analyzed per participant characteristics and outcomes., Results: For 132 HIV-negative participants, mean change from baseline in Haemo-QOL-A Total Score met the anchor-based clinically important difference (CID: 5.5) by week 12; the mean (SD) increase was 7.0 (12.6) at week 104. At week 104, improvement in Consequences of Bleeding, Treatment Concern, Worry, and Role Functioning domain scores exceeded the CID (6). EQ-5D-5L Utility Index scores improved above the CID at week 52, but not at week 104. EQ-5D-5L visual analog scale and HAL scores increased from baseline to week 104. Participants reported less activity and work impairment at week 104 than baseline. Participants with problem joints had lower mean baseline Haemo-QOL-A Total and domain scores than those without them, but improved over 104 weeks, except for 11 participants with ≥3 problem joints. Participants with 0 bleeds during the baseline prophylaxis period reported Haemo-QOL-A score improvements above the CID, including in the Consequences of Bleeding domain., Conclusion: Valoctocogene roxaparvovec provided clinically meaningful HRQOL improvement for men with severe HA., Competing Interests: Declaration of competing interests B.O.M. reports consulting fees from BioMarin Pharmaceutical Inc and Freeline. A.L.D. reports research funding from Sanofi, Takeda, Freeline, BioMarin Pharmaceutical Inc, and the American Thrombosis and Hemostasis Network; consulting fees from BioMarin Pharmaceutical Inc, Genentech/Roche, Kedrion, CSL Behring, and uniQure; and service on the board of the World Federation of Hemophilia USA. A.D.L. reports consulting or advisory panel fees from BioMarin Pharmaceutical Inc, Dova, CSL Behring, Merck, Catalyst, and HEME Biologics; and participation as a clinical trial investigator in trials sponsored by BioMarin Pharmaceutical Inc, Sangamo, and Pfizer. F.P. reports honoraria as a speaker for educational symposia by Grifols, Sanofi, and Takeda and as an advisory member for Sanofi and Roche. M.C.O. reports consulting fees from Bayer, BioMarin Pharmaceutical Inc, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda; research grants from Pfizer, Roche, and Takeda; service as a clinical trial investigator for BioMarin Pharmaceutical Inc, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda; speaker honoraria from Bayer, BioMarin Pharmaceutical Inc, Novo Nordisk, Roche, and Takeda; travel support from Novo Nordisk, Roche, and Takeda; and participation in grant reviewing for Grifols. J.M. reports consulting fees from Baxalta, CSL Behring, Catalyst Biosciences, Freeline, LFB, Novo Nordisk, and Spark; research grants from and service as a clinical trial investigator for BioMarin Pharmaceutical Inc, CSL Behring, Novo Nordisk, Pfizer, Sobi, Roche, Novartis, Sanofi, and Unique; and speaker fees from Novo Nordisk, Pfizer, Sanofi, Sobi, Shire, Roche, Takeda, the International Society on Thrombosis and Haemostasis, and the World Federation of Hemophilia. K.P. reports consulting fees and research grants from Sobi, Octapharma, Novo Nordisk, and Pfizer; and served as a clinical trial investigator for uniQure, BioMarin Pharmaceutical Inc, and Roche. J-D.W. reports consulting fees from Bayer, Novo Nordisk, Pfizer, Chugai, Sanofi, Takeda, and Sobi; speaker fees from Bayer, CSL Behring, Novo Nordisk, Pfizer, Chugai, Sanofi, and Takeda; and service as a clinical trial investigator for Bayer, BioMarin Pharmaceutical Inc, Novo Nordisk, Pfizer, Roche/Chugai, and Sanofi. G.L. has received honoraria for participating in educational events from Novartis, LEO, Sobi, Alexion, Takeda, Novo Nordisk, and Sanofi; and consulting fees from UCB. A.G. reports honoraria for service on advisory boards from BioMarin Pharmaceutical Inc, Genentech, Pfizer, Bayer, ATHN, Novo Nordisk, uniQure, and Sanofi Genzyme; and travel grants from BioMarin Pharmaceutical Inc. E.C. reports consulting fees from Genentech, BioMarin Pharmaceutical Inc, Novo Nordisk, Takeda, Sanofi, HEMA Biologics, and CSL Behring; and speaker fees from Genentech. D.P. reports a travel grant from Pfizer. H.C. reports consulting fees from Bayer, BioMarin Pharmaceutical Inc, Roche, and Sobi; served as a clinical trial investigator for BioMarin Pharmaceutical Inc, Bioverativ, CSL Behring, LFB, Octapharma, Roche, Pfizer, Sobi, and Takeda; reports speaker fees from BioMarin Pharmaceutical Inc, Pfizer, Roche, and Sobi; and reports travel grants from BioMarin Pharmaceutical Inc, CSL Behring, Octapharma, Roche, and Sobi. M.F.L.F. reports participation in advisory boards and receiving speaking fees from Shire/Takeda, Amgen, CSL Behring, Novo Nordisk, Bayer, LFB, Pfizer, and Sobi. E.M. reports consulting fees and travel support from BioMarin Pharmaceutical Inc and served as a clinical trial investigator for BioMarin Pharmaceutical Inc. M.W.S. reports consulting fees from Bayer, BioMarin Pharmaceutical Inc, Pfizer (DMC), Roche/Genentech, Sanofi, Spark (DMC), and Takeda; and research grants from BioMarin Pharmaceutical Inc, Freeline, Roche, Takeda, and uniQure. R.Klamroth reports consulting fees from Bayer, Biotest, BioMarin Pharmaceutical Inc, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, and Sobi; research grants from Bayer and LEO; speaker fees from Bayer, Biotest, BioMarin Pharmaceutical Inc, CSL Behring, Daiichi Sankyo, LEO, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, and Sobi; travel support from Bayer, Biotest, BioMarin Pharmaceutical Inc, CSL Behring, Daiichi Sankyo, LEO, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, and Sobi; and service as a clinical trial investigator for Bayer, BioMarin Pharmaceutical Inc, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, Sobi, and uniQure. S.W.P. reports consulting fees from Apcintex, ASC Therapeutics, Bayer, BioMarin Pharmaceutical Inc, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, Roche/Genentech, Sanofi, Spark Therapeutics, Takeda, and uniQure; and service as a clinical trial investigator for BioMarin Pharmaceutical Inc, Freeline, Genentech/Roche, Sanofi, and uniQure. J.Q. is a former employee of BioMarin Pharmaceutical and may hold stock. H.Y., T.M.R., and W.Y.W. are employees and stockholders of BioMarin Pharmaceutical Inc. C.W.T., H.T., R.Kazmi, and T-L.K. have no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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48. Functional determination of emicizumab in presence of factor VIII activity.
- Author
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Hamedani NS, Donners AAMT, van Luin M, Gasper S, Rühl H, Klein C, Albert T, El Amrani M, Pötzsch B, Oldenburg J, and Müller J
- Subjects
- Humans, Animals, Cattle, Factor VIII therapeutic use, Partial Thromboplastin Time, Hemophilia A diagnosis, Hemophilia A drug therapy, Antibodies, Bispecific pharmacology, Antibodies, Bispecific therapeutic use, Hemostatics therapeutic use
- Abstract
Background: Accurate measurement of emicizumab in the presence of factor (F) VIII is required in patients with severe hemophilia A treated with emicizumab, as well as additional need for FVIII substitution or emicizumab prophylaxis in patients with acquired or moderate to mild hemophilia A. However, the presence of FVIII potentially biases the results., Objectives: To assess the impact of plasma FVIII activity on determined emicizumab levels and evaluate different strategies for correction for or preanalytical inhibition of FVIII., Methods: Evaluated strategies comprised of the following: (1) calculation of actual emicizumab plasma levels based on measured FVIII activities and FVIII-affected emicizumab values, (2) preanalytical heat treatment (56 °C for 40 minutes), and (3) neutralization of FVIII activity using FVIII inhibitors. Emicizumab levels and FVIII activities were measured using a modified FVIII one-stage clotting assay and a chromogenic FVIII assay based on bovine factors, respectively., Results: Spiking experiments revealed a consistent linear association between FVIII activities and determined (FVIII-affected) emicizumab results at different emicizumab input levels (∼0.12 μg/mL per IU/dL of FVIII). This principally allowed for mathematical correction of measured emicizumab levels in the presence of FVIII. While a 40% to 50% activity loss of intrinsic plasma emicizumab through heat treatment was observed in patient samples, emicizumab spiked into FVIII-deficient plasma was not or only marginally affected. Application of inhibitor-based FVIII neutralization led to good agreement of results when compared with direct quantification of emicizumab by liquid chromatography-tandem mass spectrometry., Conclusion: Inhibitor-based FVIII neutralization appears to be a feasible strategy for accurate measurement of plasma emicizumab levels in the presence of FVIII activity., Competing Interests: Declaration of competing interests J.M. has received honoraria from Octapharma and Siemens Healthineers. J.O. has received research funding from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, Swedish Orphan Biovitrum, and Takeda; consultancy, speakers bureau, honoraria, scientific advisory board, and travel expenses from Bayer, Biogen Idec, BioMarin, Biotest, Chugai Pharmaceutical Co, Ltd, CSL Behring, Freeline, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi, Spark Therapeutics, Swedish Orphan Biovitrum, and Takeda. N.S.H., A.D., M.v.L., S.G., H.R., C.K., T.A., M.A., and B.P. report no conflicts of interest., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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49. Pharmacokinetic-guided versus standard prophylaxis in hemophilia: a systematic review and meta-analysis.
- Author
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Kraemmer D, Königsbrügge O, Moik F, Wildner B, Ay C, and Pabinger I
- Subjects
- Humans, Hemorrhage prevention & control, Hemophilia A diagnosis, Hemophilia A drug therapy
- Abstract
Background: With population pharmacokinetic (PK) modeling more readily available and PK-guided prophylaxis endorsed by current hemophilia guidelines, we conducted a systematic review to summarize current evidence in the literature., Objectives: To assess the efficacy of PK-guided compared with non-PK-guided prophylaxis., Methods: We did not restrict inclusion to specific study design labels and included all studies consisting of at least one distinct cohort arm receiving PK-guided prophylaxis. We searched the following databases from inception to date of search: MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and the EU Clinical Trial Register. Following title, abstract, and full-text screening conducted independently by 2 review authors, we summarized studies qualitatively and synthesized included randomized clinical trials (RCTs) quantitatively by fitting random-effects models., Results: Search of databases on February 3, 2023, yielded 25 studies fitting our inclusion criteria. Of those, only 2 RCTs and 17 nonrandomized studies included a standard prophylaxis comparator group. Furthermore, risk of bias in the latter was substantial, primarily due to before-after study designs and retrospective comparator groups. Thus, nonrandomized studies were only presented qualitatively. A random-effects meta-analysis of the 2 identified RCT remained inconclusive with regards to bleeding outcomes (ratio of means, 1.15; 95% CI, 0.85-1.56) and factor consumption (ratio of means, 0.82; 95% CI, 0.58-1.18)., Conclusion: Evidence in the literature suggesting a clinical benefit of PK-guided over standard fixed-dose prophylaxis was weak and mainly found in nonrandomized studies limited by lack of concurrent controls, heterogeneity in outcome reporting, small sample sizes, and high risk of bias., Competing Interests: Declaration of competing interests B.W. and F.M. have no conflicts of interest to declare. C.A. received personal fees for lectures and/or participation in advisory boards from Bayer, CSL Behring, Sobi, Roche, Takeda, LFB, and Novo Nordisk. D.K. has received honoraria for advisory boards from CSL Behring. I.P. is a consultant for CSL Behring and has received honoraria for lectures and advisory board sessions from Bayer, CSL Behring, Pfizer, Roche, Sobi, and Takeda and a research grant to the Institution from CSL Behring and Sobi. O.K. has received honoraria for advisory boards from CSL Behring., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
50. Periprocedural management of type 2N von Willebrand disease with efanesoctocog alfa.
- Author
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Ryu JH, Bauer KA, and Schulman S
- Subjects
- Female, Humans, Aged, von Willebrand Factor therapeutic use, von Willebrand Factor metabolism, Factor VIII therapeutic use, Factor VIII metabolism, Hemostasis, von Willebrand Disease, Type 2 diagnosis, von Willebrand Disease, Type 2 drug therapy, Hemostatics, Hemophilia A diagnosis, Hemophilia A drug therapy, von Willebrand Diseases drug therapy
- Abstract
Type 2 Normandy von Willebrand disease (type 2N VWD) is a rare qualitative defect in von Willebrand factor (VWF) that results in impaired factor VIII (FVIII) binding and consequently reduced FVIII levels. Current perioperative strategies require VWF concentrates to attain durable hemostatic FVIII levels. This case highlights the successful perioperative management of a 78-year-old female with type 2N VWD and coronary artery disease utilizing efanesoctocog alfa, a novel long-acting recombinant FVIII product approved for hemophilia A. By decoupling the FVIII-VWF interaction, efanesoctocog alfa achieves prolonged FVIII circulation independent of VWF. A single administration targeting 90% FVIII levels yielded sustained FVIII elevation without achieving supraphysiologic VWF levels, thus mitigating potential cardiovascular risks. This is the first report of efanesoctocog alfa use in type 2N VWD. Further clinical studies are necessary to corroborate its efficacy and safety for this indication., Competing Interests: Declaration of competing interests J.H.R. has no relationships to disclose. K.A.B. has consulted for Abbott and Sanofi. S.S. has received research materials from Novo Nordisk and Genentech, research funding from Quercis, and serves on an advisory board for Penumbra., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
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