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Objectives: We aimed to characterise baseline disease and treatment burden in a large population with haemophilia A/B, both with (HAwI/HBwI) and without (HA/HB) inhibitors., Methods: The prospective, non-interventional explorer6 study included patients ≥12 years old with severe HA, severe/moderate HB or HAwI/HBwI of any severity, treated according to local standard of care (excluding previous/current exposure to concizumab or emicizumab). Baseline characteristics and historical clinical data were collected and patient-reported outcomes, including treatment burden, were assessed., Results: The explorer6 study enrolled 231 patients with haemophilia (84 HAwI/HBwI) from 33 countries. At baseline, patients with HA/HB treated with prophylaxis had the lowest median annualised bleeding rates (ABRs; 2.0), irrespective of haemophilia type; of these patients, 27.5% (HA) and 31.4% (HB) had target joints. Patients with HAwI/HBwI treated episodically reported the highest treatment burden. Of these patients, 28.5% (HAwI) and 25.1% (HBwI) performed sports activities in the month before screening., Conclusion: Despite receiving routine clinical care, historical and baseline information from patients enrolled in explorer6 showed that patients with HA/HB treated episodically and patients with HAwI/HBwI had higher ABRs, higher treatment burden and participated in sports less than those with HA/HB treated with prophylaxis. Emerging treatments could be beneficial in addressing these unmet medical needs., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Abstract: Despite numerous efforts to raise awareness, many hemophilia carriers and female persons with hemophilia (PWHs) remain undiagnosed. Between May 2021 and April 2023, we identified potential and obligate carriers of hemophilia A (HA) and hemophilia B (HB) by updating pedigrees of all PWHs followed at the Cliniques universitaires Saint-Luc, Brussels. Retrospective data on previously screened females were collected, including bleeding history, coagulation factor levels, and testing for the proband's pathogenic variant. In addition, a proactive approach involved sending 125 invitation letters to unscreened or incompletely screened individuals, through related PWHs. In pedigrees of 287 male PWHs (226 HA and 61 HB) and 7 female index patients from 236 families (184 HA and 52 HB), a total of 900 female individuals were identified. Of those, 454 were obligate and/or genetically proven carriers, and 118 were noncarriers. Genetic testing was conducted in 133 obligate, 237 potential, and 4 sporadic carriers, with 190 obligate and 328 potential carriers remaining untested. Among carriers with known factor levels (261/454), 42 HA (23.0%) and 23 HB carriers (29.5%) had a factor level <40 IU/dL. Carriers with a factor deficiency were screened on average 6 years earlier than other females (P = .034). This study, to our knowledge, represents the first systematic effort to identify potential carriers among families of all PWHs within a single center, emphasizing the challenges in comprehensive screening for female individuals genetically linked to one or more PWHs. Such initiatives are vital for achieving equitable access to hemophilia care for all potentially affected individuals, irrespective of gender. This trial was registered at www.ClinicalTrials.gov as #NCT05217992., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

This case report of a 73-year-old male with bleedings provides insights into the clinical characteristics, diagnosis och treatment of acquired hemophilia A. It's a dangerous non-hereditary bleeding disorder caused by autoantibodies against coagulation factor VIII, often linked with other autoimmune diseases or malignancies, but it is also often idiopathic. The diagnosis remains a challenge due to its rarity and non-specific symtoms, but should be considered in unexplained bleeding cases with prolonged activated partial thromboplastin time (APTT). Quick  diagnosis and treatment can significantly reduce the risk of serious complications and mortality. The long-term prognosis usually depends on the presence of any underlying disease.

A 3-month-old domestic shorthair tomcat born on a farm was unsuccessfully treated with meloxicam for alternating lameness, fever and inappetence. On presentation, there was lameness (grade 2/4) of the right forelimb with mild swelling of the soft tissue. Rectal temperature was 39.9°C, a moderate anemia developed. Inadequate bleeding occurred during arthrocentesis performed on suspicion of polyarthritis. Coagulation tests revealed an isolated prolonged activated partial thromboplastin time (aPTT). Activity of factor VIII was 5% (reference range: 70-125%), of factor IX 55% (80-130%), and of factor XII 73% (50-140%).In a genetic study, exons and adjacent intron sequences of the feline F8-gene were sequenced and compared with the reference (ENSFCAT000078256.1). While no non-synonymous variants were found in coding sequences, intron 19 revealed the variant c.6073+2 T>C. This variant likely results in splice site alteration, atypical splicing, and thus an altered mRNA for FVIII.The patient was treated symptomatically (metamizole, buprenorphine, tranexamic acid) and clinical signs improved. Chemical castration with a GnRH implant was performed at 8 and 18 months of age, whereby minor bleeding at the implantation site occurred after the second implantation. After 3.5 years, the cat lives nearly without clinical signs of bleeding.aPTT prolongation with normal PT indicated a factor deficiency. Determination of factor activity led to the diagnosis of hemophilia A. Genetic testing detected a splice variant in the F8-gene., Competing Interests: Die Autoren versichern, dass keine persönlichen Interessen, sei es beruflicher oder anderer Art, an einem Produkt oder Unternehmen bestehen, die Einfluss auf die im vorliegenden Fallbericht behandelten Inhalte ausüben könnten., (Thieme. All rights reserved.)

Objective: To evaluate the level of care available for haemophilia patients., Methods: The descriptive, retrospective analytical study was conducted from December 15, 2020, to March 1, 2021, after approval from the Mustansiriyah University, Baghdad, Iraq, and comprised data from 3 haemophilia treating centres in Iraq participating in the World Bleeding Disorders Registry. The data collected related to patients with haemophilia A and B enrolled in the registry since March 2018, and included age at diagnosis, type of haemophilia, disease severity, age at first bleed and at first joint bleed, type of replacement therapy and outcome. Data was analysed using statistical package of social sciences (SPSS) version 20., Results: Of the 638 patients with mean age 16.2±4.3 (range: 9-29 years), 581(91%) had haemophilia A, 57(8.9%) had haemophilia B, 385(60.5%) had severe haemophilia, 126(19.8%) moderate and 125(19.7%) mild. Further, 259(41%) patients had been diagnosed for <1 year. There were 1354 bleeding events, and haemarthrosis accounted for 959(70.8%) of them. The mean annualised bleeding rate for severe patients was 2 ± 0.6(range 0-4), while the mean annualised joint bleeding rate was 4 ± 1.3(range :2-8). There were 256(32.3%) patients who were tested for inhibitors, and 62(24.3%) were positive. Among 426(73.3%) haemophilia A patients with a treatment history, 248(58%) were on prophylactic therapy, and the corresponding value among 37(65%) haemophilia B patients was 17(46%)., Conclusions: Access to treatment was found to be limited, and patients were found to be suffering from high bleeding rates and joint damage.

Competing Interests: Declaration of competing interests There are no competing interests to disclose.

Introduction: The improved quality of care and increased drug availability have shifted the goal of treating people with hemophilia from life-threatening bleeding prevention to joint health preservation and quality of life amelioration. Many tools are now available to the clinician in order to optimize the management of hemophilic arthropathy., Areas Covered: This paper reviews the pivotal role of ultrasound evaluation in early detection of joint bleeding and differential diagnosis of joint pain, with a focus on the feasibility of a long-term monitoring of joint health through the use of artificial intelligence and telemedicine. The literature search methodology included using keywords to search in PubMed and Google Scholar, and articles used were screened by the coauthors of this review., Expert Opinion: Joint ultrasound is a practical point-of-care tool with many advantages, including immediate correlation between imaging and clinical presentation, and dynamic evaluation of multiple joints. The potential of telemedicine care, coupled with a point-of-care detection device assisted by artificial intelligence, holds promises for even earlier diagnosis and treatment of joint bleeding. A multidisciplinary approach including early intervention by physical medicine and rehabilitation (PMR) physicians and physiotherapists is crucial to ensure the best possible quality of life for the patient.

Background: Acquired hemophilia A (AHA) is an autoimmune bleeding disorder caused by neutralizing antibodies against coagulation factor VIII. Immunosuppressive therapy (IST) is standard of care to eradicate autoantibody production and protect from further bleeding but carries a risk of severe infection and mortality in frail patients with AHA. Recently, emicizumab has been studied for its potential to reduce the need for early and aggressive IST., Objectives: To compare outcomes of 2 studies that used either IST (GTH-AH 01/2010; N = 101) or prophylaxis with emicizumab (GTH-AHA-EMI; N = 47) early after diagnosis of AHA., Methods: Baseline characteristics were balanced by propensity score matching. Primary endpoint was the rate of clinically relevant new bleeds during the first 12 weeks; secondary endpoints were adverse events and overall survival., Results: The negative binominal model-based bleeding rate was 68% lower with emicizumab as compared with IST (incident rate ratio, 0.325; 95% CI, 0.182-0.581). No difference was apparent in the overall frequency of infections (emicizumab 21%, IST 29%) during the first 12 weeks, but infections were less often fatal in emicizumab-treated patients (0%) compared with IST-treated patients (11%). Thromboembolic events occurred less often with emicizumab (2%) than with IST (7%). Overall survival after 24 weeks was better with emicizumab (90% vs 76%; hazard ratio, 0.44; 95%, CI, 0.24-0.81)., Conclusion: Using emicizumab instead of IST in the early phase after initial diagnosis of AHA reduced bleeding and fatal infections and improved overall survival., Competing Interests: Declaration of competing interests C.H. reports honoraria for lectures or consultancy from Bayer, BMS, SOBI, Daiichi Sankyo, Roche/Chugai, Pfizer, Sanofi, and Takeda. R.K. reports institutional grants for research and studies from Bayer, CSL Behring, Novo Nordisk, Octapharma, and SOBI, and honoraria for lectures or consultancy from Bayer, Biotest, BioMarin, CSL Behring, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, SOBI, and Takeda. U.J.S. reports institutional grants for research and studies from Octapharma and honoraria for lectures or consultancy from Bayer, SOBI, CSL Behring, and Pfizer. R.G. reports institutional grants for research and studies from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, and Daiichi Sankyo, and honoraria for lectures or consultancy from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, Daiichi Sankyo, and Sanofi. P.K. reports institutional grants for research and studies from Ablynx/Sanofi, Novo Nordisk, Roche, and Takeda, and honoraria for lectures or consultancy from Ablynx/Sanofi, Alexion, Biotest, CSL Behring, Novo Nordisk, Roche, Takeda, and Technoclone. J.O. reports institutional grants for research and studies from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, SOBI, and Takeda, and honoraria for lectures or consultancy from Bayer, Biogen Idec, BioMarin, Biotest, CSL Behring, Chugai, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sparks, SOBI, and Takeda. W.M. reports institutional grants for research and studies from Bayer, Biotest, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, and Takeda/Shire, and honoraria for lectures or consultancy from Bayer, BioMarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Regeneron, Roche, Sanofi, Takeda/Shire, and uniQure. C.P. reports institutional grants for research and studies from Chugai/Roche, Takeda, Zacros, and LeoPharma, and honoraria for lectures or consultancy from Bayer, BioMarin, Chugai/Roche, CSL Behring, Novo Nordisk, Pfizer, BMS, SOBI, and Takeda. K.T.G. reports honoraria for lectures or consultancy from Takeda, Roche, Grifols, and SOBI. I.P. reports institutional grants for research and studies from Takeda and honoraria for lectures or consultancy from BMS and Novo Nordisk. K.H. reports institutional grants for research and studies from Bayer, CSL Behring, Novo Nordisk, Pfizer, and SOBI, and honoraria for lectures or consultancy from Bayer, Biotest, Chugai, CSL Behring, LFB, Novo Nordisk, Pfizer, Roche, SOBI, and Takeda. H.E. reports institutional grants for research and studies from Bayer Vital and CSL Behring and honoraria for lectures or consultancy from Bayer Vital, BioMarin, CSL Behring, Novo Nordisk, Pfizer, Roche, and SOBI. C.W. has nothing to disclose. D.S. has nothing to disclose. S.W. reports institutional grants for research and studies from Biotest and Octapharma, and honoraria for lectures or consultancy from Biotest and Stago. A.T. reports institutional grants for research and studies from Bayer, Biotest, Chugai, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda, and honoraria for lectures or consultancy from Bayer, BioMarin, Biotest, Chugai, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background:  Desmopressin (DDAVP) is used in patients with moderate/mild hemophilia A (PWMHs) to increase their factor VIII (FVIII) level and, if possible, normalize it. However, its effectiveness varies between individuals. The GIDEMHA study aims to investigate the influence of F8 gene variants., Material and Methods:  The study collected the trajectory of FVIII levels from therapeutic intravenous DDAVP tests in four French hemophilia treatment centers. A pharmacological analysis was performed associated with efficacy scores according to F8 variants: absolute and relative responses, as well as new scores: absolute duration (based on duration with FVIII ≥ 0.50 IU.mL -1 ) and relative duration (based on half-life)., Results:  From enrolled 439 PWMHs, 327 had a hot-spot F8 variant (with ≥5 PWMHs). For these, the median (min-max) basal and peak FVIII were 0.20 (0.02-0.040) and 0.74 (0.14-2.18) IU.mL -1 respectively, with FVIII recovery being 3.80 IU.ml -1 (1.15-14.75). The median FVIII half-life was 3.9 hours (0.7-15.9 hours). FVIII was normalized (≥0.50 IU.mL -1 ) in 224/327 PWMHs (69%) and the median time with normalized FVIII was 3.9 hours (0.0-54.1 hours). Following the response profiles to DDAVP defined by the four efficacy scores, four groups of F8 variants were isolated, and then compared using survival curves with normalized FVIII ( p  < 0.0001): "long-lastingly effective" [p.(Glu739Lys), p.(Ser2030Asn), p.(Arg2178His), p.(Gln2208Glu), and T-stretch deletion in intron 13]; "moderately effective" [p.(Ser112Phe), p.(Ala219Thr), p.(Thr2105Ile), p.Phe2146Ser), and p.(Asp2150Asn)]; "moderately ineffective" [p.Ala81Asp), p.(Gln324Pro), p.(Tyr492His), p.(Arg612Cys), p.(Met701Val), p.(Val2035Asn), and p.(Arg2178Cys)]; and "frequently ineffective" [c.-219C > T, p.(Cys2040Tyr), p.(Tyr2169His), p.(Pro2319Leu), and p.(Arg2326Gln)]., Conclusion:  In view of our data, we propose indications for DDAVP use in PWMH based on F8 variants for minor and major invasive procedures., Competing Interests: B.G. has received grants or consultant fees from CSL-Behring, LFB, NovoNordisk, Octapharma, Roche/Chugaï, and Sobi. Y.R. has received funding or consultant fees from BioMarin, CSL-Behring, LFB, NovoNordisk, Octapharma, Roche, Shire, Sobi, and Takeda. X.D. has received honoraria for participation in symposia by CSL Behring, Shire, Octapharma, and Sobi. M.T. has received funding or consultant fees from Bayer Healthcare, CSL-Behring, NovoNordisk, Octapharma, Parexel, Roche, Sanofi, Shire, Sobi, and Takeda. P.J.L. has received grants from Pfizer, Sanofi, Sobi, and Roche. M.P., S.B., P.Be., and P.Bo. declare no disclosure., (Thieme. All rights reserved.)

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.)

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.)

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.)

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.

Competing Interests: Declaration of competing interests P.M.M. has received Roche, Takeda, and Werfen honoraria for lectures at educational symposia.

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.

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.

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.)

Most invasive dental procedures elicit some degree of bleeding which ultimately leads to clotting and eventual hemostasis. However, patients with inherited coagulation disorders may exhibit prolonged or, in some cases, excessive bleeding requiring multiple perioperative interventions. Von Willebrand disease is the most common inherited coagulopathy and often manifests via easy bruising, epistaxis, or prolonged bleeding. Hemophilia A (factor VII) and B (factor IX) are factor deficiencies that are clinically indistinguishable and managed according to severity and the required dental treatment. Other coagulopathies are rare (ie, inheritance is autosomal recessive) and may only become evident in homozygotes or compound heterozygotes. Current lab values and medical consultation with the patient's hematologist are imperative prior to rendering invasive dental treatment. There are a myriad of sedation and general anesthesia considerations, including risks for epistaxis with nasal instrumentation and bruising with improper patient positioning. Preoperative treatment with desmopressin or factor replacement may be required and generally should facilitate normal hemostasis. Additional therapies should be considered to help ensure adequate postoperative hemostasis, including pressure dressings, resorbable clotting materials, laser therapy, and oral rinses.

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.

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.)

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.)

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).)

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%). IgG 4 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.)

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.)

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.)

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.)

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.

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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).)

Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors.

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.

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.)

Competing Interests: A. Borel-Derlon déclare appartenir au board d’experts de LFB pour la recherche clinique sur la maladie de Willebrand.

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.)

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.

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.)

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.)