{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:50:00Z","timestamp":1793321400299,"version":"4.5.0"},"reference-count":52,"publisher":"Georg Thieme Verlag KG","issue":"02","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hamostaseologie"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Emicizumab is the first approved nonreplacement therapy for bleeding prophylaxis in hemophilia A (HA) patients. In 2018, it was licensed for HA patients with inhibitors, subsequently followed by an \u201cEuropean Medicines Agency (EMA)\u201d approval for patients with severe HA in the absence of inhibitors in 2019. This is immediately raising the question whether emicizumab is suitable as a first-line treatment for all pediatric patients with severe HA. In this review, we want to discuss what we have, what we know, and what we would like to know. Severe HA is characterized by severe spontaneous and traumatic bleedings, particularly into muscles and joints leading to chronic joint damage. Standard of care is the regular, prophylactic replacement of factor VIII to prevent bleedings. Due to approval of emicizumab\u2014the first nonreplacement therapy for bleeding prophylaxis\u2014in HA patients with inhibitors, and severe HA patients without inhibitors, it is of pivotal interest whether emicizumab could be the first-line treatment in all pediatric patients with severe HA. Clinical trials and real-world observational studies could demonstrate a good efficacy and safety for bleeding prevention during emicizumab treatment in HA patients with and without inhibitors. This clearly indicates that emicizumab could improve HA treatment. However, some crucial and critical questions are remaining with regard to the use of emicizumab. Some of this missing information is already under investigation in the context of clinical trials. Until getting finalized data to shed insights into the points that are currently being discussed, there is a variety of expert and expert group recommendations, which are tackling questions concerning the treatment of HA patients. This review will address major information that is already available, but will also focus on important points that remain to be elucidated in the context of HA treatment.<\/jats:p>","DOI":"10.1055\/a-1727-1384","type":"journal-article","created":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T23:06:59Z","timestamp":1651273619000},"page":"104-115","source":"Crossref","is-referenced-by-count":13,"title":["Emicizumab for All Pediatric Patients with Severe Hemophilia A"],"prefix":"10.1055","volume":"42","author":[{"given":"Ivonne","family":"Wieland","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2022,4,29]]},"reference":[{"issue":"06","key":"ref1","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1111\/hae.14412","article-title":"Prophylaxis in children with haemophilia in an evolving treatment landscape","volume":"27","author":"M E Mancuso","year":"2021","journal-title":"Haemophilia"},{"issue":"05","key":"ref2","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1111\/jth.13298","article-title":"When and how to start prophylaxis in boys with severe hemophilia without inhibitors: communication from the SSC of the ISTH","volume":"14","author":"K Fischer","year":"2016","journal-title":"J Thromb Haemost"},{"issue":"02","key":"ref4","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1111\/j.1365-2516.2009.02122.x","article-title":"New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development","volume":"16","author":"K Kurnik","year":"2010","journal-title":"Haemophilia"},{"issue":"02","key":"ref5","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1111\/bjh.14844","article-title":"Intracranial haemorrhage in children and adolescents with severe haemophilia A or B - the impact of prophylactic treatment","volume":"179","author":"N G Andersson","year":"2017","journal-title":"Br J Haematol"},{"issue":"04","key":"ref6","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1111\/hae.13461","article-title":"Intracranial haemorrhage in children with inherited bleeding disorders in the UK 2003-2015: a national cohort study","volume":"24","author":"E A Chalmers","year":"2018","journal-title":"Haemophilia"},{"issue":"05","key":"ref7","first-page":"378","article-title":"Intracranial haemorrhage in children and adults with haemophilia A and B: a literature review of the last 20 years","volume":"17","author":"E Zanon","year":"2019","journal-title":"Blood Transfus"},{"issue":"02","key":"ref8","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/j.1365-2141.2010.08469.x","article-title":"Associations between intracranial haemorrhage and prescribed prophylaxis in a large cohort of haemophilia patients in the United States","volume":"152","author":"C Witmer","year":"2011","journal-title":"Br J Haematol"},{"issue":"11","key":"ref9","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1182\/bloodadvances.2019001311","article-title":"Young adult outcomes of childhood prophylaxis for severe hemophilia A: results of the Joint Outcome Continuation Study","volume":"4","author":"B B Warren","year":"2020","journal-title":"Blood Adv"},{"issue":"13","key":"ref10","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1182\/blood-2015-01-528414","article-title":"Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens","volume":"125","author":"J Oldenburg","year":"2015","journal-title":"Blood"},{"issue":"S 06","key":"ref11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/hae.14046","article-title":"WFH guidelines for the management of hemophilia, 3rd edition","volume":"26","author":"A Srivastava","year":"2020","journal-title":"Haemophilia"},{"issue":"01","key":"ref13","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1111\/j.1365-2516.2008.01880.x","article-title":"The North American Immune Tolerance Registry: contributions to the thirty-year experience with immune tolerance therapy","volume":"15","author":"D Dimichele","year":"2009","journal-title":"Haemophilia"},{"issue":"11","key":"ref14","doi-asserted-by":"crossref","first-page":"4648","DOI":"10.1182\/blood-2006-11-056291","article-title":"Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL Cohort study","volume":"109","author":"S C Gouw","year":"2007","journal-title":"Blood"},{"issue":"03","key":"ref15","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1182\/blood.2019000658","article-title":"Timing of inhibitor development in more than 1000 previously untreated patients with severe hemophilia A","volume":"134","author":"H M van den Berg","year":"2019","journal-title":"Blood"},{"issue":"21","key":"ref16","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1056\/NEJMoa1516437","article-title":"A randomized trial of factor VIII and neutralizing antibodies in hemophilia A","volume":"374","author":"F Peyvandi","year":"2016","journal-title":"N Engl J Med"},{"issue":"06","key":"ref17","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1111\/j.1538-7836.2004.00759.x","article-title":"Recombinant factor VIIa: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors","volume":"2","author":"T Abshire","year":"2004","journal-title":"J Thromb Haemost"},{"issue":"03","key":"ref18","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1111\/j.1365-2516.2007.01451.x","article-title":"Sequential therapy with activated prothrombin complex concentrates and recombinant FVIIa in patients with severe haemophilia and inhibitors: update of our previous experience","volume":"13","author":"J Schneiderman","year":"2007","journal-title":"Haemophilia"},{"issue":"02","key":"ref19","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1182\/blood-2006-04-017988","article-title":"A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study","volume":"109","author":"J Astermark","year":"2007","journal-title":"Blood"},{"issue":"09","key":"ref20","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.1111\/j.1538-7836.2007.02663.x","article-title":"Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors","volume":"5","author":"B A Konkle","year":"2007","journal-title":"J Thromb Haemost"},{"issue":"18","key":"ref21","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1056\/NEJMoa1104435","article-title":"Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors","volume":"365","author":"C Leissinger","year":"2011","journal-title":"N Engl J Med"},{"issue":"S 06","key":"ref22","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/hae.12466","article-title":"ITI choice for the optimal management of inhibitor patients - from a clinical and pharmacoeconomic perspective","volume":"20","author":"J Oldenburg","year":"2014","journal-title":"Haemophilia"},{"issue":"06","key":"ref23","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1111\/hae.12986","article-title":"Long-term outcome of haemophilia A patients after successful immune tolerance induction therapy using a single plasma-derived FVIII\/VWF product: the long-term ITI study","volume":"22","author":"V Jim\u00e9nez-Yuste","year":"2016","journal-title":"Haemophilia"},{"issue":"06","key":"ref24","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1182\/blood-2011-08-369132","article-title":"The principal results of the International Immune Tolerance Study: a randomized dose comparison","volume":"119","author":"C R Hay","year":"2012","journal-title":"Blood"},{"issue":"11","key":"ref25","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1111\/jth.13143","article-title":"Inhibitor recurrence after immune tolerance induction: a multicenter retrospective cohort study","volume":"13","author":"A Antun","year":"2015","journal-title":"J Thromb Haemost"},{"issue":"06","key":"ref26","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1182\/blood.2019004334","article-title":"A hemophilia A mouse model for the in vivo assessment of emicizumab function","volume":"136","author":"S Ferri\u00e8re","year":"2020","journal-title":"Blood"},{"issue":"24","key":"ref27","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.1182\/blood.2019001869","article-title":"A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors","volume":"134","author":"G Young","year":"2019","journal-title":"Blood"},{"issue":"03","key":"ref28","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1111\/bjh.15942","article-title":"How I treat children with haemophilia and inhibitors","volume":"186","author":"G Young","year":"2019","journal-title":"Br J Haematol"},{"issue":"09","key":"ref29","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1056\/NEJMoa1803550","article-title":"Emicizumab prophylaxis in patients who have hemophilia a without inhibitors","volume":"379","author":"J Mahlangu","year":"2018","journal-title":"N Engl J Med"},{"issue":"09","key":"ref30","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1056\/NEJMoa1703068","article-title":"Emicizumab prophylaxis in hemophilia A with inhibitors","volume":"377","author":"J Oldenburg","year":"2017","journal-title":"N Engl J Med"},{"issue":"16","key":"ref31","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1182\/blood.2020009217","article-title":"Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies","volume":"137","author":"M U Callaghan","year":"2021","journal-title":"Blood"},{"issue":"01","key":"ref32","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/hae.14205","article-title":"Long-term safety and efficacy of emicizumab for up to 5.8 years and patients' perceptions of symptoms and daily life: a phase 1\/2 study in patients with severe haemophilia A","volume":"27","author":"M Shima","year":"2021","journal-title":"Haemophilia"},{"issue":"09","key":"ref33","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1055\/s-0039-1692427","article-title":"Laboratory monitoring in emicizumab-treated persons with hemophilia A","volume":"119","author":"J M\u00fcller","year":"2019","journal-title":"Thromb Haemost"},{"issue":"06","key":"ref34","doi-asserted-by":"crossref","first-page":"e295","DOI":"10.1016\/S2352-3026(19)30054-7","article-title":"Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study","volume":"6","author":"S W Pipe","year":"2019","journal-title":"Lancet Haematol"},{"issue":"09","key":"ref35","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1111\/jth.14957","article-title":"Neutralizing antidrug antibody to emicizumab in a patient with severe hemophilia A with inhibitors: new case with detailed laboratory evaluation","volume":"18","author":"C Harkins Druzgal","year":"2020","journal-title":"J Thromb Haemost"},{"issue":"03","key":"ref36","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1111\/jth.15226","article-title":"Characterization of the neutralizing anti-emicizumab antibody in a patient with hemophilia A and inhibitor","volume":"19","author":"C Valsecchi","year":"2021","journal-title":"J Thromb Haemost"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"469","DOI":"10.2147\/DDDT.S167731","article-title":"Clinical evidence and safety profile of emicizumab for the management of children with hemophilia A","volume":"14","author":"S Le Quellec","year":"2020","journal-title":"Drug Des Devel Ther"},{"issue":"05","key":"ref38","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1055\/a-1127-6476","article-title":"Practical guidance of the GTH Haemophilia Board on the use of emicizumab in patients with haemophilia A","volume":"40","author":"K Holstein","year":"2020","journal-title":"Hamostaseologie"},{"issue":"02","key":"ref39","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1111\/bjh.16964","article-title":"Emicizumab treatment and monitoring in a paediatric cohort: real-world data","volume":"191","author":"A A Barg","year":"2020","journal-title":"Br J Haematol"},{"issue":"06","key":"ref40","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1111\/hae.13848","article-title":"A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors","volume":"25","author":"M Shima","year":"2019","journal-title":"Haemophilia"},{"issue":"04","key":"ref41","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1111\/hae.14005","article-title":"Real-world use of emicizumab in patients with haemophilia A: bleeding outcomes and surgical procedures","volume":"26","author":"I McCary","year":"2020","journal-title":"Haemophilia"},{"issue":"03","key":"ref42","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1111\/hae.14318","article-title":"Emicizumab prophylaxis: prospective longitudinal real-world follow-up and monitoring","volume":"27","author":"A A Barg","year":"2021","journal-title":"Haemophilia"},{"issue":"S 01","key":"ref43","first-page":"2020","article-title":"emicizumab treatment in pediatric patients with hemophilia A without inhibitors: a single-institution study","volume":"4","author":"M NC Mori","year":"2020","journal-title":"Res Pract Thromb Haemost"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1182\/blood-2020-138918","article-title":"Real-world clinical outcomes in previously untreated and minimally treated patients with congenital factor VIII deficiency: the San Diego experience","volume":"136","author":"K A Bush","year":"2020","journal-title":"Blood"},{"issue":"S 01","key":"ref45","first-page":"2020","article-title":"Real life use of emicizumab in pediatric patients without inhibitors","volume":"4","author":"S I Heine","year":"2020","journal-title":"Res Pract Thromb Haemost"},{"issue":"03","key":"ref46","doi-asserted-by":"crossref","first-page":"e84","DOI":"10.3324\/haematol.2014.115709","article-title":"Bleeding before prophylaxis in severe hemophilia: paradigm shift over two decades","volume":"100","author":"A Nijdam","year":"2015","journal-title":"Haematologica"},{"issue":"05","key":"ref47","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1182\/blood.V72.5.1651.1651","article-title":"Development of the human coagulation system in the healthy premature infant","volume":"72","author":"M Andrew","year":"1988","journal-title":"Blood"},{"issue":"07","key":"ref48","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1111\/jth.15342","article-title":"Management of children with hemophilia A: how emicizumab has changed the landscape","volume":"19","author":"G Young","year":"2021","journal-title":"J Thromb Haemost"},{"issue":"20","key":"ref49","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.1182\/bloodadvances.2018015842","article-title":"Implementing emicizumab in hemophilia inhibitor management: emicizumab should be prescribed after tolerance","volume":"2","author":"G Young","year":"2018","journal-title":"Blood Adv"},{"issue":"20","key":"ref50","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1182\/bloodadvances.2018015859","article-title":"Emicizumab should be prescribed independent of immune tolerance induction","volume":"2","author":"S Le Quellec","year":"2018","journal-title":"Blood Adv"},{"issue":"04","key":"ref51","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1111\/hae.13762","article-title":"The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab","volume":"25","author":"M Carcao","year":"2019","journal-title":"Haemophilia"},{"issue":"03","key":"ref52","doi-asserted-by":"crossref","first-page":"e305","DOI":"10.1111\/hae.14010","article-title":"Optimizing the management of patients with haemophilia A and inhibitors in the era of emicizumab: recommendations from a German expert panel","volume":"27","author":"C Escuriola-Ettingshausen","year":"2021","journal-title":"Haemophilia"},{"issue":"05","key":"ref53","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1111\/hae.13819","article-title":"Immune tolerance induction in paediatric patients with haemophilia A and inhibitors receiving emicizumab prophylaxis","volume":"25","author":"G Batsuli","year":"2019","journal-title":"Haemophilia"},{"issue":"02","key":"ref54","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1002\/rth2.12475","article-title":"Emicizumab in tolerized patients with hemophilia A with inhibitors: a single-institution pediatric cohort assessing inhibitor status","volume":"5","author":"G Batsuli","year":"2021","journal-title":"Res Pract Thromb Haemost"}],"container-title":["H\u00e4mostaseologie"],"original-title":[],"language":"de","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-1727-1384.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T21:51:05Z","timestamp":1675461065000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-1727-1384"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4]]},"references-count":52,"journal-issue":{"issue":"02","published-online":{"date-parts":[[2022,4,29]]},"published-print":{"date-parts":[[2022,4]]}},"URL":"https:\/\/doi.org\/10.1055\/a-1727-1384","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0720-9355","2567-5761"],"issn-type":[{"value":"0720-9355","type":"print"},{"value":"2567-5761","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4]]}}}