血友病患者に対する止血治療ガイドライン作成委員会編：血友病患者に対する止血治療ガイドライン 2019年補遺版ヘムライブラ（エミシズマブ）使用について、p95-96、日本血栓止血学会、2020.
Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, Carcao M, Mahlangu J, Ragni MV, Windyga J, Llinás A, Goddard NJ, Mohan R, Poonnoose PM, Feldman BM, Lewis SZ, van den Berg HM, Pierce GF; WFH Guidelines for the Management of Hemophilia panelists and co-authors.
WFH Guidelines for the Management of Hemophilia, 3rd edition.
Haemophilia. 2020 Aug;26 Suppl 6:1-158. doi: 10.1111/hae.14046. Epub 2020 Aug 3.
Abstract/Text
インヒビターのない血友病患者に対する止血治療ガイドライン作成委員会編：インヒビターのない血友病患者に対する止血治療ガイドライン 2013年改訂版、日本血栓止血学会、2013.
血友病患者に対する止血治療ガイドライン作成委員会編：血友病患者に対する止血治療ガイドライン 2019年補遺版. ヘムライブラ（エミシズマブ）使用について、FQ5.
Gouw SC, van der Bom JG, Ljung R, Escuriola C, Cid AR, Claeyssens-Donadel S, van Geet C, Kenet G, Mäkipernaa A, Molinari AC, Muntean W, Kobelt R, Rivard G, Santagostino E, Thomas A, van den Berg HM; PedNet and RODIN Study Group.
Factor VIII products and inhibitor development in severe hemophilia A.
N Engl J Med. 2013 Jan 17;368(3):231-9. doi: 10.1056/NEJMoa1208024.
Abstract/Text
BACKGROUND: For previously untreated children with severe hemophilia A, it is unclear whether the type of factor VIII product administered and switching among products are associated with the development of clinically relevant inhibitory antibodies (inhibitor development).
METHODS: We evaluated 574 consecutive patients with severe hemophilia A (factor VIII activity, <0.01 IU per milliliter) who were born between 2000 and 2010 and collected data on all clotting-factor administration for up to 75 exposure days. The primary outcome was inhibitor development, which was defined as at least two positive inhibitor tests with decreased in vivo recovery of factor VIII levels.
RESULTS: Inhibitory antibodies developed in 177 of the 574 children (cumulative incidence, 32.4%); 116 patients had a high-titer inhibitory antibody, defined as a peak titer of at least 5 Bethesda units per milliliter (cumulative incidence, 22.4%). Plasma-derived products conferred a risk of inhibitor development that was similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant products, 0.96; 95% confidence interval [CI], 0.62 to 1.49). As compared with third-generation full-length recombinant products (derived from the full-length complementary DNA sequence of human factor VIII), second-generation full-length products were associated with an increased risk of inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08 to 2.37). The content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development.
CONCLUSIONS: Recombinant and plasma-derived factor VIII products conferred similar risks of inhibitor development, and the content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Second-generation full-length recombinant products were associated with an increased risk, as compared with third-generation products. (Funded by Bayer Healthcare and Baxter BioScience.).
Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, Ingram JD, Manco-Johnson ML, Funk S, Jacobson L, Valentino LA, Hoots WK, Buchanan GR, DiMichele D, Recht M, Brown D, Leissinger C, Bleak S, Cohen A, Mathew P, Matsunaga A, Medeiros D, Nugent D, Thomas GA, Thompson AA, McRedmond K, Soucie JM, Austin H, Evatt BL.
Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia.
N Engl J Med. 2007 Aug 9;357(6):535-44. doi: 10.1056/NEJMoa067659.
Abstract/Text
BACKGROUND: Effective ways to prevent arthropathy in severe hemophilia are unknown.
METHODS: We randomly assigned young boys with severe hemophilia A to regular infusions of recombinant factor VIII (prophylaxis) or to an enhanced episodic infusion schedule of at least three doses totaling a minimum of 80 IU of factor VIII per kilogram of body weight at the time of a joint hemorrhage. The primary outcome was the incidence of bone or cartilage damage as detected in index joints (ankles, knees, and elbows) by radiography or magnetic resonance imaging (MRI).
RESULTS: Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P=0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups.
CONCLUSIONS: Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597 [ClinicalTrials.gov].).
Copyright 2007 Massachusetts Medical Society.
Gringeri A, Lundin B, von Mackensen S, Mantovani L, Mannucci PM; ESPRIT Study Group.
A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study).
J Thromb Haemost. 2011 Apr;9(4):700-10. doi: 10.1111/j.1538-7836.2011.04214.x.
Abstract/Text
BACKGROUND: Prevention of arthropathy is a major goal of hemophilia treatment. While studies in adults have demonstrated an impact of prophylaxis on the incidence of joint bleeds and patients' well-being in terms of improved quality of life (QoL), it is unclear whether or not prophylaxis influences the outcome and perception of well- of children with hemophilia.
OBJECTIVE: This randomized controlled study compared the efficacy of prophylaxis with episodic therapy in preventing hemarthroses and image-proven joint damage in children with severe hemophilia A (factor VIII <1%) over a 10-year time period.
METHODS: Forty-five children with severe hemophilia A, aged 1-7 years (median 4), with negative clinical-radiologic joint score at entry and at least one bleed during the previous 6 months, were consecutively randomized to prophylaxis with recombinant factor VIII (25 IU kg(-1) 3 × week) or episodic therapy with ≥25 IU kg(-1) every 12-24 h until complete clinical bleeding resolution. Safety, feasibility, direct costs and QoL were also evaluated.
RESULTS: Twenty-one children were assigned to prophylaxis, 19 to episodic treatment. Children on prophylaxis had fewer hemarthroses than children on episodic therapy: 0.20 vs. 0.52 events per patient per month (P < 0.02). Plain-film radiology showed signs of arthropathy in six patients on prophylaxis (29%) vs. 14 on episodic treatment (74%) (P < 0.05). Prophylaxis was more effective when started early (≤36 months), with patients having fewer joint bleeds (0.12 joint bleeds per patient per month) and no radiologic signs of arthropathy.
CONCLUSION: This randomized trial confirms the efficacy of prophylaxis in preventing bleeds and arthropathy in children with hemophilia, particularly when it is initiated early in life.
© 2011 International Society on Thrombosis and Haemostasis.
Berntorp E, Shapiro A, Astermark J, Blanchette VS, Collins PW, Dimichele D, Escuriola C, Hay CR, Hoots WK, Leissinger CA, Negrier C, Oldenburg J, Peerlinck K, Reding MT, Hart C.
Inhibitor treatment in haemophilias A and B: summary statement for the 2006 international consensus conference.
Haemophilia. 2006 Dec;12 Suppl 6:1-7. doi: 10.1111/j.1365-2516.2006.01359.x.
Abstract/Text
Participants in an international conference on the management of haemophilia patients with inhibitors developed a jointly authored summary of the findings and conclusions of the conference. Current knowledge of the genetic and immunologic mechanisms underlying inhibitor development was briefly summarized. Concerning the purported treatment-related risk factors, conference participants commented on the limitations of the available evidence and the need for more rigorous prospective research in a fully genotyped population. Other clinical considerations discussed included the unproved utility of routine surveillance, the need for assay standardization, the management of acute bleeding and approaches to joint disease prophylaxis and immune tolerance induction (ITI). A number of issues were identified as needing further investigation in larger prospective studies, ideally through international cooperation. Such studies should enroll cohorts that have been scrupulously defined in terms of mutation status and treatment exposure. Finally, conference participants urged their colleagues to participate in the currently ongoing international trials of ITI.
Hay CR, Brown S, Collins PW, Keeling DM, Liesner R.
The diagnosis and management of factor VIII and IX inhibitors: a guideline from the United Kingdom Haemophilia Centre Doctors Organisation.
Br J Haematol. 2006 Jun;133(6):591-605. doi: 10.1111/j.1365-2141.2006.06087.x.
Abstract/Text
The revised UKHCDO factor (F) VIII/IX Inhibitor Guidelines (2000) are presented. A schema is proposed for inhibitor surveillance, which varies according to the severity of the haemophilia and the treatment type and regimen used. The methodological and pharmacokinetic approach to inhibitor surveillance in congenital haemophilia has been updated. Factor VIII/IX genotyping of patients is recommended to identify those at increased risk. All patients who develop an inhibitor should be considered for immune tolerance induction (ITI). The decision to attempt ITI for FIX inhibitors must be carefully weighed against the relatively high risk of reactions and the nephrotic syndrome and the relatively low response rate observed in this group. The start of ITI should be deferred until the inhibitor has declined below 10 Bethesda Units/ml, where possible. ITI should continue, even in resistant patients, where it is well tolerated and so long as there is a convincing downward trend in the inhibitor titre. The choice of treatment for bleeding in inhibitor patients is dictated by the severity of the bleed, the current inhibitor titre, the previous anamnestic response to FVIII/IX, the previous clinical response and the side-effect profile of the agents available. We have reviewed novel dose-regimens and modes of administration of FEIBA (factor VIII inhibitor bypassing activity) and recombinant activated FVII (rVIIa) and the extent to which these agents may be used for prophylaxis and surgery. Bleeding in acquired haemophilia is usually treated with FEIBA or rVIIa. Immunosuppressive therapy should be initiated at the time of diagnosis with Prednisolone 1 mg/kg/d +/- cyclophosphamide. In the absence of a response to these agents within 6 weeks, second-line therapy with Rituximab, Ciclosporin A, or other multiple-modality regimens may be considered.
Rodriguez-Merchan EC, Rocino A, Ewenstein B, Bartha L, Batorova A, Goudemand J, Gringeri A, Joao-Diniz M, Lopaciuk S, Negrier C, Quintana M, Tagariello G, Tjonnfjord GE, Villar VA, Vorlova Z.
Consensus perspectives on surgery in haemophilia patients with inhibitors: summary statement.
Haemophilia. 2004 Sep;10 Suppl 2:50-2. doi: 10.1111/j.1365-2516.2004.00941.x.
Abstract/Text
Summary. Participants in an international workshop on surgery in haemophilia patients with inhibitors developed a consensus summary of the findings and conclusions of the meeting. In the consensus, participants agreed upon revised definitions for minor and major surgery, including an intermediate degree of surgery. An evaluation system of intraoperative and postoperative bleeding was developed. Recommended doses of FEIBA((R)) and rFVIIa (both in bolus injections and in continuous infusion) for surgery were agreed. Participants also agreed on the main blood tests to be performed peri-operatively. They also suggested the need of a prospective evaluation in the future. Finally, the approximate number of surgical procedures and costs performed on haemophilia patients with inhibitors were analysed.
Gringeri A, Mannucci PM; Italian Association of Haemophilia Centres.
Italian guidelines for the diagnosis and treatment of patients with haemophilia and inhibitors.
Haemophilia. 2005 Nov;11(6):611-9. doi: 10.1111/j.1365-2516.2005.01161.x.
Abstract/Text
The Italian Association of Haemophilia Centres reviewed and finally approved in November 2004 the new Italian Guidelines for the diagnosis and treatment of patients with clotting factor inhibitors. The recommendations have been based on the identification of levels of clinical evidence derived from the systematic review carried out in 2003 by the School of Health and Related Research, the University of Sheffield, UK, and further integrated by clinical studies published from 2003 to 2004. The Italian guidelines consist of six major domains concerning inhibitor definition, epidemiology, risk factors, diagnosis, inhibitor eradication, management of bleeding episodes, in patients with congenital and acquired coagulation disorders, with 121 statements, 59 synthesis and 54 recommendations. We report here recommendations and open issues concerning the diagnosis and monitoring of inhibitors, inhibitor eradication and the management of bleeding in patients with haemophilia A and B.
Rubinger M, Rivard GE, Teitel J, Walker H; Inhibitor Subcommittee of the Association of Hemophilia Clinic Directors of Canada.
Suggestions for the management of factor VIII inhibitors.
Haemophilia. 2000 Jul;6 Suppl 1:52-9.
Abstract/Text
Hay CR, Baglin TP, Collins PW, Hill FG, Keeling DM.
The diagnosis and management of factor VIII and IX inhibitors: a guideline from the UK Haemophilia Centre Doctors' Organization (UKHCDO).
Br J Haematol. 2000 Oct;111(1):78-90. doi: 10.1046/j.1365-2141.2000.02327.x.
Abstract/Text
日本血栓止血学会学術標準化委員会血友病部会血友病編：インヒビター保有先天性血友病患者に対する止血治療ガイドライン、日本血栓止血学会、2008.
血友病患者に対する止血治療ガイドライン作成委員会編：血友病患者に対する止血治療ガイドライン 2019年補遺版. ヘムライブラ（エミシズマブ）使用について、CQ1.
Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, Santagostino E, Kruse-Jarres R, Negrier C, Kessler C, Valente N, Asikanius E, Levy GG, Windyga J, Shima M.
Emicizumab Prophylaxis in Hemophilia A with Inhibitors.
N Engl J Med. 2017 Aug 31;377(9):809-818. doi: 10.1056/NEJMoa1703068. Epub 2017 Jul 10.
Abstract/Text
BACKGROUND: Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors.
METHODS: We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C.
RESULTS: A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (P<0.001). A total of 22 participants in group A (63%) had zero bleeding events, as compared with 1 participant (6%) in group B. Among 24 participants in group C who had participated in a noninterventional study, emicizumab prophylaxis resulted in a bleeding rate that was significantly lower by 79% than the rate with previous bypassing-agent prophylaxis (P<0.001). Overall, 198 adverse events were reported in 103 participants receiving emicizumab prophylaxis; the most frequent events were injection-site reactions (in 15% of participants). Thrombotic microangiopathy and thrombosis were reported in 2 participants each (in the primary analysis) who had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. No antidrug antibodies were detected.
CONCLUSIONS: Emicizumab prophylaxis was associated with a significantly lower rate of bleeding events than no prophylaxis among participants with hemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .).
血友病患者に対する止血治療ガイドライン作成委員会編：血友病患者に対する止血治療ガイドライン 2019年補遺版. ヘムライブラ（エミシズマブ）使用について、FQ1.
血友病患者に対する止血治療ガイドライン作成委員会編：血友病患者に対する止血治療ガイドライン 2019年補遺版. ヘムライブラ（エミシズマブ）使用について、FQ2.
血友病患者に対する止血治療ガイドライン作成委員会編：血友病患者に対する止血治療ガイドライン 2019年補遺版. ヘムライブラ（エミシズマブ）使用について、FQ3.
インヒビター保有先天性血友病患者に対する止血治療ガイドライン作成委員会編：インヒビター保有先天性血友病患者に対する止血治療ガイドライン 2013年改訂版、p13、日本血栓止血学会、2013.
Caram C, de Souza RG, de Sousa JC, Araújo Pereira T, do Amaral Cerqueira AM, van der Bom JG, Rezende SM.
The long-term course of factor VIII inhibitors in patients with congenital haemophilia A without immune tolerance induction.
Thromb Haemost. 2011 Jan;105(1):59-65. doi: 10.1160/TH10-04-0231. Epub 2010 Nov 5.
Abstract/Text
The development of alloantibodies that inhibit or neutralise the function of factor VIII is considered the most serious complication of the treatment of congenital haemophilia A. In order to describe their course without immune tolerance induction (ITI), we documented data on all performed inhibitor tests with dates as well as on clotting factor infusions of all consecutive patients who were treated in our centre between 1993 and 2006. Patients were tested every 7.1 months (95% confidence interval [CI], 6.6-7.8). A 'sustained negative inhibitor status' was defined as consistent non-positive inhibitor measurements for two years or longer. A total of 60/486 (12%) patients tested had a positive inhibitor titre in two or more occasions. Most of the patients (56%) with a maximum inhibitor titre of < 5 Bethesda unit (BU)/ml (named "low titre inhibitor") developed a sustained negative inhibitor status. Among patients with high (5-9.9 BU/ml) and very high (≥ 10 BU/ml) inhibitor titres, the proportions were 50% and 3%, respectively. Our findings suggest that ITI might not be needed for all patients with non-transient inhibitors, especially when their maximum inhibitor titre is below 10 BU/ml. Further studies in countries where ITI is not available are needed to examine predictors of the natural sustained negative inhibitor status.
