When and how to start prophylaxis in boys with severe hemophilia without inhibitors: communication from the SSC of the ISTH

Abstract

Regular replacement therapy (prophylaxis) with clotting factor concentrates for hemophilia was first introduced in Sweden in the 1960s 1.Nilsson I.M. Hedner U. Ahlberg A. Haemophilia prophylaxis in Sweden.Acta Paediatr Scand. 1976; 65: 129-35Crossref PubMed Scopus (133) Google Scholar. When available, it has been very effective in improving long‐term outcomes and preventing hemophilic arthropathy, allowing persons with hemophilia to lead a near normal life. From the first single‐center cohort studies spanning several decades, it became clear that starting prophylaxis early is a key driver of success. Primary prophylaxis is defined as: ‘Regular continuous replacement therapy started in the absence of documented joint disease, determined by physical examination and/or imaging studies, and before the second clinically evident joint bleed and 3 years’ 2.Blanchette V.S. Key N.S. Ljung L.R. Manco‐Johnson M.J. van den Berg H.M. Srivastava A. Definitions in hemophilia: communication from the SSC of the ISTH.J Thromb Haemost. 2014; 12: 1935-9Abstract Full Text Full Text PDF PubMed Scopus (410) Google Scholar. This definition of primary prophylaxis deliberately did not include the exact time of initiation, dosing and frequency of administration due to lack of evidence regarding optimal strategies. When starting prophylaxis in young children, the benefits of preventing bleeds need to be balanced against the burden of frequent injections and the need for central venous access devices (CVADs). The aim of these recommendations is to provide evidence‐based guidance on when and how to start prophylaxis in boys with severe hemophilia without inhibitors. Its contents can be used for shared decision‐making between healthcare providers and parents. Published information was gathered from a MEDLINE search (haemophilia/hemophilia AND prophylaxis AND starting/start*/initiation/onset), including related article searches and cross‐referencing of references retrieved and references known to the authors. When studying the effects of prophylaxis, a follow‐up of years, often decades, is needed to observe the clinically significant effects of any regimen. During the past few decades, early initiation and an increase in prophylactic dose resulted in fewer bleeds and improved joint status 3.Nilsson I.M. Berntorp E. Lofqvist T. Pettersson H. Twenty‐five years’ experience of prophylactic treatment in severe haemophilia A and B.J Intern Med. 1992; 232: 25-32Crossref PubMed Scopus (823) Google Scholar, 4.van den Berg H.M. Fischer K. Mauser‐Bunschoten E.P. Beek F.J.A. Roosendaal G. van der Bom J.G. Nieuwenhuis H.K. Long term outcome of individualised prophylactic treatment of children with severe haemophilia.Br J Haematol. 2001; 107: 561-5Crossref Scopus (170) Google Scholar. This trend was also observed in the PedNet cohort of 919 boys with severe hemophilia A, where prophylaxis is currently initiated at a median age of 1.3 years (interquartile range [IQR], 0.9–1.9) after a median of one joint bleed, with 70% of patients fulfilling the criteria of primary prophylaxis 5.Nijdam A. Altisent C. Carcao M.D. Cid A.R. Claeyssens‐Donadel S. Kurnik K. Ljung R. Nolan B. Petrini P. Platokouki H. Rafowicz A. Thomas A.E. Fischer K. Bleeding before prophylaxis in severe hemophilia: paradigm shift over two decades.Haematologica. 2015; 100: e84-6Crossref PubMed Scopus (18) Google Scholar. Based on their experience, Nilsson et al. recommended that prophylaxis should be started before clinical and/or radiological evidence of joint damage in order to prevent arthropathy 3.Nilsson I.M. Berntorp E. Lofqvist T. Pettersson H. Twenty‐five years’ experience of prophylactic treatment in severe haemophilia A and B.J Intern Med. 1992; 232: 25-32Crossref PubMed Scopus (823) Google Scholar. These observations were first confirmed in a single‐center study 6.Liesner R.J. Khair K. Hann I.M. The impact of prophyactic treatment on children with severe haemophilia.Br J Haematol. 1996; 92: 973-8Crossref PubMed Scopus (167) Google Scholar. Table 1 summarizes five studies reporting on the effects of the age at starting prophylaxis on the index joints (ankles, knees and elbows) using physical examination (Gilbert score)7.Gilbert M.S. Musculoskeletal complications of haemophilia: the joint.Haemophilia. 2000; 6: 34-7Crossref PubMed Scopus (32) Google Scholar and/or the Pettersson score based on plain X‐rays 8.Pettersson H. Aledort L.M. Bergman G. Gilbert M.S. Savidge G.F. Mannucci P.M. Radiographic scores and implications.Semin Hematol. 1993; 30: 7-11PubMed Google Scholar. Three studies reported a better outcome in boys who started prophylaxis before the age of 3 years 9.Kreuz W. Escuriola‐Ettingshausen C. Funk M. Schmidt H. Kornhuber B. When should prophylactic treatment in patients with haemophilia A and B start?–The German experience.Haemophilia. 1998; 4: 413-7Crossref PubMed Scopus (136) Google Scholar, 10.Astermark J. Petrini P. Tengborn L. Schulman S. Ljung R.C.R. Berntorp E. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized.Br J Haematol. 1999; 105: 1109-13Crossref PubMed Scopus (244) Google Scholar, 11.Gringeri A. Lundin B. von Mackensen S. Mantovani L. Mannucci P.M. ESPRIT Study GroupA randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study).J Thromb Haemost. 2011; 9: 700-10Crossref PubMed Scopus (370) Google Scholar; the other two reported a better outcome in boys who started prophylaxis before the second or third joint bleed 12.Fischer K. van der Bom J.G. Mauser‐Bunschoten E.P. Roosendaal G. Prejs R. De Kleijn P. Grobbee D.E. van den Berg H.M. Effects of postponing prophylactic treatment on long‐term outcome in patients with severe haemophilia.Blood. 2002; 99: 2337-41Crossref PubMed Scopus (217) Google Scholar, 13.Yee T.T. Beeton K. Griffioen A. Harrington C. Miners A. Lee C.A. Brown S.A. Experience of prophylaxis treatment in children with severe haemophilia.Haemophilia. 2002; 8: 76-82Crossref PubMed Scopus (64) Google Scholar. Only two studies followed cases until adulthood and reported a significantly better outcome for prophylaxis started earlier 12.Fischer K. van der Bom J.G. Mauser‐Bunschoten E.P. Roosendaal G. Prejs R. De Kleijn P. Grobbee D.E. van den Berg H.M. Effects of postponing prophylactic treatment on long‐term outcome in patients with severe haemophilia.Blood. 2002; 99: 2337-41Crossref PubMed Scopus (217) Google Scholar or before age 3 years 10.Astermark J. Petrini P. Tengborn L. Schulman S. Ljung R.C.R. Berntorp E. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized.Br J Haematol. 1999; 105: 1109-13Crossref PubMed Scopus (244) Google Scholar, respectively. When interpreting these results, it is important to consider that benefits of starting prophylaxis early may have been overestimated, as physical examination and X‐rays are unable to pick up early joint changes. Moreover, the onset of joint bleeding varies widely (median age, 1.7 years; IQR 1.0–2.8) 14.Nijdam A. Kurnik K. Liesner R. Ljung R. Nolan B. Petrini P. Fischer K. How to achieve full prophylaxis in young boys with severe haemophilia A: different regimens and their effect on early bleeding and venous access.Haemophilia. 2015; 21: 444-50Crossref PubMed Scopus (24) Google Scholar and is a predictor of bleeding phenotype and long‐term outcome 15.van Dijk K. van der Bom J.G. Lenting P.J. de Groot P.G. Mauser‐Bunschoten E.P. Roosendaal G. Grobbee D.E. van den Berg H.M. Factor VIII half‐life and clinical phenotype of severe hemophilia A.Haematologica. 2005; 90: 494-8PubMed Google Scholar, 16.Hang M.X. Blanchette V.S. Pullenayegum E. McLimont M. Feldman B.M. Age at first joint bleed and bleeding severity in boys with severe hemophilia A: Canadian Hemophilia Primary Prophylaxis Study.J Thromb Haemost. 2011; 9: 1067-9Crossref PubMed Scopus (23) Google Scholar.Table 1Summary of studies reporting the effects of age at start of prophylaxis on outcomeStudyDesign (follow‐up)Numbers of patientsOutcome parameterAge (years) at evaluationResultsKreuz 1998 9.Kreuz W. Escuriola‐Ettingshausen C. Funk M. Schmidt H. Kornhuber B. When should prophylactic treatment in patients with haemophilia A and B start?–The German experience.Haemophilia. 1998; 4: 413-7Crossref PubMed Scopus (136) Google ScholarSingle‐center cohort(FU 4 years)19 severe and 2 moderate(hem A, 18;hem B, 3)Clinical andX‐ray1The Gilbert score 7 was used for clinical evaluation and X‐rays were scored according to Pettersson 8. RCT, randomized controlled study; hem, hemophilia.12.2All 8 patients (100%) who started prophylaxis < age 3 years had normal joints at evaluation, vs. < 25% of those who started prophylaxis later (P‐value unknown)Astermark 1999 10.Astermark J. Petrini P. Tengborn L. Schulman S. Ljung R.C.R. Berntorp E. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized.Br J Haematol. 1999; 105: 1109-13Crossref PubMed Scopus (244) Google ScholarNationwide cohort(FU 18 years)121 severe(hem A, 108;hem B, 13)ClinicalUp to 18Joint changes occurred from age 6 onwards;85% of 75 patients who started prophylaxis < age 3 years had normal joints vs. 50% of patients who started later (P < 0.001).Outcome was dependent on age at start of prophylaxis only, not on dose and interval of prophylaxis at initiation (multivariable analysis)Fischer 2002 12.Fischer K. van der Bom J.G. Mauser‐Bunschoten E.P. Roosendaal G. Prejs R. De Kleijn P. Grobbee D.E. van den Berg H.M. Effects of postponing prophylactic treatment on long‐term outcome in patients with severe haemophilia.Blood. 2002; 99: 2337-41Crossref PubMed Scopus (217) Google ScholarSingle‐center cohort(FU 16 years)76 severe(hem A, 66; hem B, 10)X‐ray19At age 19, Pettersson score increased by 8% for each years’ delay in starting prophylaxis following the first joint bleed, independent of prophylactic dose, age at first joint bleed and age at evaluation (P = 0.03).In a subgroup analysis in 43 patients,13 patients who started prophylaxis before the third joint bleed had a better outcome (70% normal joints vs. 24% in those who started later, P > 0.05)Yee 2002 13.Yee T.T. Beeton K. Griffioen A. Harrington C. Miners A. Lee C.A. Brown S.A. Experience of prophylaxis treatment in children with severe haemophilia.Haemophilia. 2002; 8: 76-82Crossref PubMed Scopus (64) Google ScholarSingle‐center cohort(FU 4 years)41 severe(hem A, 34;hem B, 7)Clinical5 and 9.5, respectivelyNine patients who started before the second joint bleed had a better outcome (90% with normal joint scores at age 5 years vs. 70% in patients who started later, evaluated at age 9.5 years, P > 0.05)Gringeri 2011 11.Gringeri A. Lundin B. von Mackensen S. Mantovani L. Mannucci P.M. ESPRIT Study GroupA randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study).J Thromb Haemost. 2011; 9: 700-10Crossref PubMed Scopus (370) Google ScholarMulticenter RCT(FU 10 years)21 severe(hem A, 21)X‐ray12.3Better outcome in 8 patients who started prophylaxis < age 3 years (100% normal joints vs. 84.6%, P > 0.05)1 The Gilbert score 7.Gilbert M.S. Musculoskeletal complications of haemophilia: the joint.Haemophilia. 2000; 6: 34-7Crossref PubMed Scopus (32) Google Scholar was used for clinical evaluation and X‐rays were scored according to Pettersson 8.Pettersson H. Aledort L.M. Bergman G. Gilbert M.S. Savidge G.F. Mannucci P.M. Radiographic scores and implications.Semin Hematol. 1993; 30: 7-11PubMed Google Scholar. RCT, randomized controlled study; hem, hemophilia. Open table in a new tab The optimum strategy for starting prophylaxis will avoid under‐treatment in those who bleed very early, as well as avoid over‐treatment in those with a milder bleeding phenotype. Therefore, we recommend starting prophylaxis no later than immediately or shortly after the first recognized joint bleed or clinically significant muscle bleed. After an intracranial bleed, prophylaxis should be started immediately 2.Blanchette V.S. Key N.S. Ljung L.R. Manco‐Johnson M.J. van den Berg H.M. Srivastava A. Definitions in hemophilia: communication from the SSC of the ISTH.J Thromb Haemost. 2014; 12: 1935-9Abstract Full Text Full Text PDF PubMed Scopus (410) Google Scholar. As bleeding risk increases with age, both spontaneous and traumatic bleeding should be considered indications to start prophylaxis. This strategy depends on adequate detection of bleeding events, which requires frequent assessment and adequate instructions for parents and caregivers. The use of extended half‐life (EHL) FVIII/IX concentrates should not affect the decision on when to start prophylaxis. The goal of prophylaxis is to prevent bleeding and maintain normal joint and muscle function. With conventional factor concentrates (adult FVIII half‐life ± 12 h, FIX half‐life ± 24 h), optimum bleeding control requires infusions at least 3× per week for hemophilia A (and 2× per week for hemophilia B). The optimum frequency of infusions at initiation of prophylaxis is unknown. In children younger than 6 years, FVIII/IX half‐life is shorter (6–8 h for FVIII and ± 16 h for FIX 17.Bjorkman S. Folkesson A. Jonsson S. Pharmacokinetics and dose requirements of factor VIII over the age range 3‐74 years: a population analysis based on 50 patients with long‐term prophylactic treatment for haemophilia A.Eur J Clin Pharmacol. 2009; 65: 989-98Crossref PubMed Scopus (128) Google Scholar, 18.Collins P.W. Fischer K. Morfini M. Blanchette V.S. Björkman S. Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia.Haemophilia. 2011; 17: 2-10Crossref PubMed Scopus (168) Google Scholar, 19.Bjorkman S. Shapiro A.D. Berntorp E. Pharmacokinetics of recombinant factor IX in relation to age of the patient: implications for dosing in prophylaxis.Haemophilia. 2001; 7: 133-9Crossref PubMed Scopus (100) Google Scholar) but reported bleeding rates are lower 20.Fischer K. van Hout B.A. van der Bom J.G. Grobbee D.E. van den Berg H.M. Association between joint bleeds and Pettersson scores in severe haemophilia.Acta Radiol. 2002; 43: 528-32Crossref PubMed Scopus (76) Google Scholar, 21.Manco‐Johnson M.J. Abshire T.C. Shapiro A.D. Riske B. Hacker M.R. Kilcoyne R. Ingram J.D. Manco‐Johnson M.L. Funk S. Jacobson L. Valentino L.A. Hoots W.K. Buchanan G.R. Dimichele D. Recht M. Brown D. Leissinger C. Bleak S. Cohen A. Mathew P. et al.Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia.N Engl J Med. 2007; 357: 535-44Crossref PubMed Scopus (1461) Google Scholar, suggesting that lower frequency regimens may be sufficient in young children. However, this is contradicted by reports of soft tissue changes on magnetic resonance imaging (MRI) in up to 31% of joints without reported bleeding in patients treated on demand or with prophylaxis once per week 21.Manco‐Johnson M.J. Abshire T.C. Shapiro A.D. Riske B. Hacker M.R. Kilcoyne R. Ingram J.D. Manco‐Johnson M.L. Funk S. Jacobson L. Valentino L.A. Hoots W.K. Buchanan G.R. Dimichele D. Recht M. Brown D. Leissinger C. Bleak S. Cohen A. Mathew P. et al.Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia.N Engl J Med. 2007; 357: 535-44Crossref PubMed Scopus (1461) Google Scholar, 22.Kraft J. Blanchette V. Babyn P. Feldman B. Cloutier S. Israels S. Pai M. Rivard G.‐.E. Gomer S. McLimont M. Moineddin R. Doria A.S. Magnetic resonance imaging and joint outcomes in boys with severe hemophilia A treated with tailored primary prophylaxis in Canada.J Thromb Haemost. 2012; 10: 2494-502Crossref PubMed Scopus (63) Google Scholar. The difficult balance between achieving protection from bleeding and acquiring venous access in young boys is reflected in the different regimens used. Overall, FVIII prophylaxis is started with a ‘full’ regimen of infusions ≥ 3× per week, or with infusions 1–2× per week using different step‐up criteria to increase the frequency of infusions (Fig. 1). Starting prophylaxis with infusions ≥ 3× per week provides immediate protection, but requires the insertion of a CVAD in the majority of patients (88% in PedNet 14.Nijdam A. Kurnik K. Liesner R. Ljung R. Nolan B. Petrini P. Fischer K. How to achieve full prophylaxis in young boys with severe haemophilia A: different regimens and their effect on early bleeding and venous access.Haemophilia. 2015; 21: 444-50Crossref PubMed Scopus (24) Google Scholar). Prophylaxis started with once weekly infusions has been description of ‘training the vein’ and limits the use of CVADs, while allowing gradual acceptance of prophylaxis in children and their parents 23.Petrini P. How to start prophylaxis.Haemophilia. 2003; 9: 83-5Crossref PubMed Scopus (16) Google Scholar. Consequently, two approaches can be taken to intensify prophylaxis (Fig. 1). The first strategy, intensifying ‘as soon as possible’, entails moving to 3× per week within 3–6 months, as is practised in Sweden 10.Astermark J. Petrini P. Tengborn L. Schulman S. Ljung R.C.R. Berntorp E. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized.Br J Haematol. 1999; 105: 1109-13Crossref PubMed Scopus (244) Google Scholar. In PedNet centers, this strategy required CVADs in 34% and 3× per week prophylaxis was achieved at 1.8 years (IQR, 1.2–3.1) 14.Nijdam A. Kurnik K. Liesner R. Ljung R. Nolan B. Petrini P. Fischer K. How to achieve full prophylaxis in young boys with severe haemophilia A: different regimens and their effect on early bleeding and venous access.Haemophilia. 2015; 21: 444-50Crossref PubMed Scopus (24) Google Scholar. The second strategy, intensifying ‘according to bleeding’, adds one weekly infusion immediately after each joint or muscle bleed. This strategy is included in some guidelines 24.(NVHB) Nederlandse Vereniging voor HemofiliebehandelarenLeebeek FWG Mauser‐Bunschoten EP Richtlijn Diagnostiek en behandeling van hemofilie en aanverwante hemostasestoornissen. van Zuiden Communications BV, Utrecht2009Google Scholar, 25.Meunier S. Trossart M. Berger G. Borel‐Derlon A. Dirat G. Assolant A.D. Guérois C. Lutz P. Rafowicz A. Rothschild C. Chambost H. Groupe Prophylaxie CoMETH[French guidelines. Long term prophylaxis for severe haemophilia A and B children to proevent haemophiliac arthropathy].Arch Pediatr. 2009; 16: 1571-8Crossref PubMed Google Scholar and was widely used in PedNet, requiring CVADs in 22% and achieving 3× per week prophylaxis at 3.9 years (IQR, 2.3–6.0) 14.Nijdam A. Kurnik K. Liesner R. Ljung R. Nolan B. Petrini P. Fischer K. How to achieve full prophylaxis in young boys with severe haemophilia A: different regimens and their effect on early bleeding and venous access.Haemophilia. 2015; 21: 444-50Crossref PubMed Scopus (24) Google Scholar. A variant of the latter strategy was used in Canada and allowed up to two bleeds per joint in 3 months before intensifying prophylaxis 26.Feldman B.M. Pai M. Rivard G.E. Israels S. Poon M.‐.C. Demers C. Robinson S. Luke K.‐.H. Wu J.K.M. Gill K. Lillicrap D. Babyn P. McLimont M. Blanchette V.S. Tailored prophylaxis in severe hemophilia A: interim results from the first 5 years of the Canadian Hemophilia Primary Prophylaxis Study.J Thromb Haemost. 2006; 4: 1228-36Crossref PubMed Scopus (204) Google Scholar; this resulted in osteochondral changes on MRI in 50% of patients at age 8.8 years 22.Kraft J. Blanchette V. Babyn P. Feldman B. Cloutier S. Israels S. Pai M. Rivard G.‐.E. Gomer S. McLimont M. Moineddin R. Doria A.S. Magnetic resonance imaging and joint outcomes in boys with severe hemophilia A treated with tailored primary prophylaxis in Canada.J Thromb Haemost. 2012; 10: 2494-502Crossref PubMed Scopus (63) Google Scholar and a more rapid escalation is now recommended. Some centers prefer a strategy of early low‐dose, low‐frequency prophylaxis to avoid inhibitor development, although definitive data regarding efficacy are lacking 27.Kurnik K. Bidlingmaier C. Engl W. Chehadeh H. Reipert B. Auerswald G. New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development.Haemophilia. 2010; 16: 256-62Crossref PubMed Scopus (150) Google Scholar. The use of EHL concentrates may improve FVIII/IX trough levels, even in low‐frequency regimens. When using these concentrates, it is recommended that FVIII/IX levels and bleeding patterns be closely monitored to maintain optimum protection. Due to the available vial sizes, the initial dose of prophylaxis is 250–500 IU per infusion. As children starting prophylaxis are usually aged 1–3 years, their average weight is 10–14 kg. Although many start with an initial dose of 500 IU (± 35–50 IU kg−1) 14.Nijdam A. Kurnik K. Liesner R. Ljung R. Nolan B. Petrini P. Fischer K. How to achieve full prophylaxis in young boys with severe haemophilia A: different regimens and their effect on early bleeding and venous access.Haemophilia. 2015; 21: 444-50Crossref PubMed Scopus (24) Google Scholar, 25.Meunier S. Trossart M. Berger G. Borel‐Derlon A. Dirat G. Assolant A.D. Guérois C. Lutz P. Rafowicz A. Rothschild C. Chambost H. Groupe Prophylaxie CoMETH[French guidelines. Long term prophylaxis for severe haemophilia A and B children to proevent haemophiliac arthropathy].Arch Pediatr. 2009; 16: 1571-8Crossref PubMed Google Scholar, the use of 250 IU (± 20–25 IU kg−1) as an initial dose has been increasing 14.Nijdam A. Kurnik K. Liesner R. Ljung R. Nolan B. Petrini P. Fischer K. How to achieve full prophylaxis in young boys with severe haemophilia A: different regimens and their effect on early bleeding and venous access.Haemophilia. 2015; 21: 444-50Crossref PubMed Scopus (24) Google Scholar. Compared with 250 IU, giving 500 IU adds only one half‐life (6–8 h) protection, and high doses for initial treatment may be associated with inhibitor development 28.Iorio A. Halimeh S. Holzhauer S. Goldenberg N. Marchesini E. Marcucci M. Young G. Bidlingmaier C. Brandao L.R. Ettingshausen C.E. Gringeri A. Kenet G. Knofler R. Kreuz W. Kurnik K. Manner D. Santagostino E. Mannucci P.M. Nowak‐Gottl U. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma‐derived or recombinant factor VIII concentrates: a systematic review.J Thromb Haemost. 2010; 8: 1256-65Crossref PubMed Scopus (236) Google Scholar, 29.Gouw S.C. van der Bom J.G. Marijke van den Berg H. Treatment‐related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study.Blood. 2007; 109: 4648-54Crossref PubMed Scopus (417) Google Scholar. For hemophilia B, the usual starting dose is 500 IU and the added protection of a double dose is slightly longer at ± 16 h 19.Bjorkman S. Shapiro A.D. Berntorp E. Pharmacokinetics of recombinant factor IX in relation to age of the patient: implications for dosing in prophylaxis.Haemophilia. 2001; 7: 133-9Crossref PubMed Scopus (100) Google Scholar. The first and most important step in initiation of prophylaxis is instruction of parents and caregivers to recognize bleeding symptoms and keep a detailed diary of both symptoms and treatment. To establish this, frequent contact (≥ 4× per year) with the clinic is recommended. Documentation of bleeding should include location of the bleed, the presence or absence of preceding trauma, and the treatment required until full functional recovery 30.Fischer K. Ljung R. Platokouki H. Liesner R. Claeyssens S. Smink E. van den Berg H.M. Prospective observational cohort studies for studying rare diseases: the European PedNet Haemophilia Registry.Haemophilia. 2014; 20: e280-6Crossref PubMed Scopus (48) Google Scholar. This information is essential and the prophylactic regimen should be reconsidered after each bleeding episode. The present recommendation of starting and/or intensifying prophylaxis according to bleeding is independent of factor levels. However, testing of factor trough levels and screening for inhibitors is warranted in the case of unexpected bleeding in a patient on ≥ 3× per week prophylaxis. Physical examination is most important for follow‐up after a bleed. Routine physical examination, even when using a validated scoring system, is of limited use for early monitoring as it is unlikely to pick up musculoskeletal changes in boys < 6 years 10.Astermark J. Petrini P. Tengborn L. Schulman S. Ljung R.C.R. Berntorp E. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized.Br J Haematol. 1999; 105: 1109-13Crossref PubMed Scopus (244) Google Scholar, 21.Manco‐Johnson M.J. Abshire T.C. Shapiro A.D. Riske B. Hacker M.R. Kilcoyne R. Ingram J.D. Manco‐Johnson M.L. Funk S. Jacobson L. Valentino L.A. Hoots W.K. Buchanan G.R. Dimichele D. Recht M. Brown D. Leissinger C. Bleak S. Cohen A. Mathew P. et al.Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia.N Engl J Med. 2007; 357: 535-44Crossref PubMed Scopus (1461) Google Scholar. Appropriate radiological evaluation of synovium and cartilage may therefore be necessary in those patients who have recurrent joint bleeds. Prophylaxis should be started no later than immediately or shortly after the first joint or muscle bleed. A detailed diary of bleeding events should be maintained and reviewed frequently (minimum 4× per year until full prophylaxis is reached) to ensure that all bleeds are reported and the intensity of prophylaxis is adjusted appropriately. Prophylaxis can be started with either once weekly or more frequent infusions, up to every other day. The initial dose can be 250–500 IU. If prophylaxis is started once weekly, we recommend that the frequency of infusions should be increased after each joint, muscle or other critical/significant bleeding episode, or sooner based on local practise, until a minimum of 3× per week (hemophilia A, or 2× per week for hemophilia B) is reached. Intensification of any prophylactic regimen should be considered if spontaneous significant bleeding occurs. The recommendations presented relate to use of standard FVIII/IX concentrates. The use of extended half‐life FVIII/IX concentrates does not affect the start of prophylaxis but may allow modification of the frequency of infusions in some cases. K. Fischer wrote the first draft of the manuscript, which was subsequently discussed during a face‐to‐face meeting of the Project Group (including K. Fischer, V. S. Blanchette, G. Young, M.C. Ozelo and A. Srivastava) and adapted according to the comments of the co‐authors in several rounds. All authors provided input for all versions of the manuscript. All authors reviewed and approved the final version of the recommendations for starting prophylaxis in boys with severe hemophilia without inhibitors. K. Fischer received speaker fees from Bayer, Baxter, CSL Behring, Octapharma, Pfizer and NovoNordisk; consultancy fees from Bayer, Baxter, Biogen, NovoNordisk and Pfizer; and research support from Bayer, Wyeth/Pfizer, Baxter and Novo Nordisk. P. Collins received consultancy fees and speaker fees from Baxter, Bayer, CSL Behring and Novo Nordisk; and research support from CSL Behring. M. Ozelo received consultancy fees and speaker fees from Baxter and Novo Nordisk; and research support from Bayer, Baxter, Biogen, CSL Behring and Novo Nordisk. A. Srivastava received advisory board and speaker fees from Bayer, Baxter, Novo Nordisk, Pfizer and Biotest; and research/grant support from Bayer, Baxalta and Novo Nordisk. G. Young received consultancy fees and speaker fees from Baxter, Bayer, Biogen, Kedrion and Novo Nordisk. V. S. Blanchette received consultancy, lecture and advisory board fees from Bayer, Baxter, Biotest, Novo Nordisk and Pfizer; and research support from CSL Behring and Baxter.