今日の臨床サポート

血友病(小児科)

著者: 石原卓 奈良県立医科大学 小児科

監修: 五十嵐隆 国立成育医療研究センター

著者校正/監修レビュー済:2022/06/23
参考ガイドライン:
  1. 日本血栓止血学会: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
  1. 日本血栓止血学会: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
  1. 日本血栓止血学会:血友病患者に対する止血治療ガイドライン、2014年補遺版
  1. 日本血栓止血学会:血友病患者に対する止血治療ガイドライン、2019年補遺版
患者向け説明資料

概要・推奨   

  1. 血友病患者の出血症状に補充療法を行う場合には、可能な限り速やかに投与することが勧められる。特に、頭蓋内出血などの生命に関与する重篤な出血が疑われる場合には、出血を確認するためのCTなどの検査を行うより先に凝固因子製剤の補充を行うことが勧められる(推奨度1)
  1. RICE処置(安静[Rest]、冷却[Ice]、圧迫[Compression]、拳上[Elevation] )による支持療法を並行して行うことが勧められる(推奨度1)
  1. トラネキサム酸(トランサミン)の投与は特に粘膜出血には有用な支持療法である(推奨度2)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
石原卓 : 特に申告事項無し[2022年]
監修:五十嵐隆 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 定期レビューを行い、近年承認された半減期延長型製剤や、バイスペシフィック抗体についての記載を追加した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 血液凝固因子の先天性欠乏・低下によって起こる凝固障害であり、第VIII因子の欠乏・低下が血友病A、第Ⅸ因子の欠乏・低下が血友病Bである。
  1. 第VIII因子、第IX因子ともにX染色体上に存在し、X連鎖劣性の遺伝形式をとるため、患者のほとんどは男性であり、女性は保因者となる。なお、非常に稀ではあるが、X染色体の不活化により女性血友病も存在する。
  1. 凝固因子活性<1%を重症血友病、1~5%を中等症血友病、5~40%を軽症血友病と診断する。
  1. 紫斑や関節出血、軟部組織出血や外傷後出血などの異常な出血がみられる。
  1. 家族歴に出血症状があることが多いが、約3分の1の症例では家族歴を認めない。
  1. 血友病の頻度は約10,000出生あたり1人程度と推定され、血友病Aが80~85%を占める。
  1. 血液凝固異常症全国調査(平成23年度)の集計によると、わが国の血友病Aは男性4,475人、女性29人、血友病Bは男性971人、女性13人が生存中であると報告されている。
  1. 凝固因子の補充が適切になされれば、正常な止血能力が得られる。
問診・診察のポイント  
  1. 先天性の凝固異常症であるため、初診以前の出血症状の有無を詳細に聴取する必要がある。ただし、1歳以前は運動量が少ないため、出血症状の既往がないことも多い。

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文献 

Jan Astermark, Sharyne M Donfield, Donna M DiMichele, Alessandro Gringeri, Steven A Gilbert, Jennifer Waters, Erik Berntorp, FENOC Study Group
A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study.
Blood. 2007 Jan 15;109(2):546-51. doi: 10.1182/blood-2006-04-017988. Epub 2006 Sep 21.
Abstract/Text The development of inhibitory antibodies to factor VIII is a serious complication of hemophilia. FEIBA (factor VIII inhibitor-bypassing activity), an activated prothrombin complex concentrate (aPCC), and NovoSeven, recombinant factor VIIa (rFVIIa), are used as hemostatic bypassing agents in treating patients with inhibitors. The FENOC study was designed to test equivalence of the products in the treatment of ankle, knee, and elbow joint bleeding. A prospective, open-label, randomized, crossover, equivalency design was used. The parameters of interest were the percentage of patients who reported efficacy in response to FEIBA and the percentage that reported efficacy in response to NovoSeven. A difference in these percentages of no more than 15% was determined to be a clinically acceptable magnitude for equivalence of the 2 products. The primary outcome was evaluation 6 hours after treatment. Data for 96 bleeding episodes contributed by 48 participants were analyzed. The criterion for declaring the 2 products equivalent at 6 hours was not met; however, the confidence interval of the difference in percentages of efficacy reported for each product only slightly exceeded the 15% boundary (-11.4%-15.7%), P=.059. FEIBA and NovoSeven appear to exhibit a similar effect on joint bleeds, although the efficacy between products is rated differently by a substantial proportion of patients. This trial was registered at www.clinicaltrials.gov as #NCT00166309.

PMID 16990605
Marilyn J Manco-Johnson, Thomas C Abshire, Amy D Shapiro, Brenda Riske, Michele R Hacker, Ray Kilcoyne, J David Ingram, Michael L Manco-Johnson, Sharon Funk, Linda Jacobson, Leonard A Valentino, W Keith Hoots, George R Buchanan, Donna DiMichele, Michael Recht, Deborah Brown, Cindy Leissinger, Shirley Bleak, Alan Cohen, Prasad Mathew, Alison Matsunaga, Desiree Medeiros, Diane Nugent, Gregory A Thomas, Alexis A Thompson, Kevin McRedmond, J Michael Soucie, Harlan Austin, Bruce L Evatt
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.
PMID 17687129
Johannes Oldenburg, Johnny N Mahlangu, Benjamin Kim, Christophe Schmitt, Michael U Callaghan, Guy Young, Elena Santagostino, Rebecca Kruse-Jarres, Claude Negrier, Craig Kessler, Nancy Valente, Elina Asikanius, Gallia G Levy, Jerzy Windyga, Midori Shima
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 .).

PMID 28691557
Steven W Pipe, Midori Shima, Michaela Lehle, Amy Shapiro, Sammy Chebon, Katsuyuki Fukutake, Nigel S Key, Agnès Portron, Christophe Schmitt, Maria Podolak-Dawidziak, Nives Selak Bienz, Cedric Hermans, Avrita Campinha-Bacote, Anna Kiialainen, Kathelijne Peerlinck, Gallia G Levy, Victor Jiménez-Yuste
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.
Lancet Haematol. 2019 Jun;6(6):e295-e305. doi: 10.1016/S2352-3026(19)30054-7. Epub 2019 Apr 16.
Abstract/Text BACKGROUND: Emicizumab, a subcutaneously administered, humanised, bispecific, monoclonal antibody, is approved to treat people with haemophilia A of all ages with and without coagulation factor VIII (FVIII) inhibitors. HAVEN 4 assessed emicizumab prophylaxis administered as one dose every 4 weeks in adults and adolescents with haemophilia A, regardless of FVIII inhibitor status.
METHODS: In this phase 3, multicentre, open-label, two-stage study, patients aged 12 years and older with severe congenital haemophilia A (<1% of normal FVIII activity in blood) or haemophilia A with FVIII inhibitors, undergoing treatment with either FVIII concentrates or bypassing agents were recruited from three sites in Japan and Spain for a run-in cohort, and from 17 sites in Australia, Belgium, Japan, Poland, Spain, and the USA for a subsequent expansion cohort. Participants in the run-in and expansion cohorts were given emicizumab subcutaneously 6 mg/kg every 4 weeks for 24 weeks or more; for patients in the expansion cohort this regimen was preceded by four loading doses of 3 mg/kg once weekly. In the run-in cohort, we assessed pharmacokinetics after single and multiple (every 4 weeks) subcutaneous administration of 6 mg/kg emicizumab and safety. In the expansion cohort, the efficacy endpoint was efficacy of prophylactic emicizumab in maintaining adequate bleed prevention, assessed in all patients who received at least one dose of emicizumab and reported as annualised bleed rates for treated bleeds, all bleeds (treated and untreated), treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds. Safety was assessed in all participants given emicizumab. This study is registered with ClinicalTrials.gov, number NCT03020160, and is ongoing.
FINDINGS: Between Jan 30, 2017, and Feb 27, 2017, seven patients were enrolled into the initial run-in cohort, which confirmed the expected pharmacokinetic profile and safety of the regimen based on model-based simulations, providing sufficient evidence for opening of the expansion cohort (n=41), which was recruited and enrolled between May 24, 2017, and June 30, 2017. The annualised rate of treated bleeds was 2·4 (95% CI 1·4-4·3). 23 (56·1%; 95% CI 39·7-71·5) of 41 reported no treated bleeds and 37 (90%; 76·9-97·3) reported zero to three treated bleeds. The annualised bleed rate was 4·5 (95% CI 3·1-6·6) for all bleeds, 0·6 (0·3-1·5), for treated spontaneous bleeds, 1·7 (0·8-3·7) for treated joint bleeds, and 1·0 (0·3-3·3) for treated target joint bleeds. The most frequent treatment-related adverse event was injection-site reaction (nine [22%] of 41 patients). We observed no thrombotic events or development of de-novo antidrug antibodies with neutralising potential or FVIII inhibitors.
INTERPRETATION: Emicizumab given once every 4 weeks showed clinically meaningful bleed control while being well tolerated. This regimen could improve patient care by decreasing treatment burden and increasing adherence to effective prophylaxis, potentially decreasing the development of secondary complications for people with haemophilia A.
FUNDING: F Hoffmann-La Roche and Chugai Pharmaceutical.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 31003963
Guy Young, Ri Liesner, Tiffany Chang, Robert Sidonio, Johannes Oldenburg, Victor Jiménez-Yuste, Johnny Mahlangu, Rebecca Kruse-Jarres, Michael Wang, Marianne Uguen, Michelle Y Doral, Lilyan Y Wright, Christophe Schmitt, Gallia G Levy, Midori Shima, Maria Elisa Mancuso
A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors.
Blood. 2019 Dec 12;134(24):2127-2138. doi: 10.1182/blood.2019001869.
Abstract/Text Emicizumab, a bispecific humanized monoclonal antibody, bridges activated factor IX (FIX) and FX to restore the function of missing activated FVIII in hemophilia A. Emicizumab prophylaxis in children with hemophilia A and FVIII inhibitors was investigated in a phase 3 trial (HAVEN 2). Participants, previously receiving episodic/prophylactic bypassing agents (BPAs), were treated with subcutaneous emicizumab: 1.5 mg/kg weekly (group A), 3 mg/kg every 2 weeks (group B), or 6 mg/kg every 4 weeks (group C). Pharmacokinetics, safety, and efficacy (including an intraindividual comparison of participants from a noninterventional study) were evaluated. Eighty-five participants aged <12 years were enrolled. In group A (n = 65), the annualized rate of treated bleeding events (ABRs) was 0.3 (95% confidence interval [CI], 0.17-0.50), and 77% had no treated bleeding events. Intraindividual comparison of 15 participants who previously took BPA prophylaxis showed that emicizumab prophylaxis reduced the ABR by 99% (95% CI, 97.4-99.4). In groups B (n = 10) and C (n = 10), ABRs were 0.2 (95% CI, 0.03-1.72) and 2.2 (95% CI, 0.69-6.81), respectively. The most frequent adverse events were nasopharyngitis and injection-site reactions; no thrombotic events occurred. Two of 88 participants developed antidrug antibodies (ADAs) with neutralizing potential, that is, associated with decreased emicizumab plasma concentrations: 1 experienced loss of efficacy, and, in the other, ADAs disappeared over time without intervention or breakthrough bleeding. All other participants achieved effective emicizumab plasma concentrations, regardless of the treatment regimen. Emicizumab prophylaxis has been shown to be a highly effective novel medication for children with hemophilia A and inhibitors. This trial was registered at www.clinicaltrials.gov as #NCT02795767.

© 2019 by The American Society of Hematology.
PMID 31697801
Johnny Mahlangu, Johannes Oldenburg, Ido Paz-Priel, Claude Negrier, Markus Niggli, M Elisa Mancuso, Christophe Schmitt, Victor Jiménez-Yuste, Christine Kempton, Christophe Dhalluin, Michael U Callaghan, Willem Bujan, Midori Shima, Joanne I Adamkewicz, Elina Asikanius, Gallia G Levy, Rebecca Kruse-Jarres
Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors.
N Engl J Med. 2018 Aug 30;379(9):811-822. doi: 10.1056/NEJMoa1803550.
Abstract/Text BACKGROUND: Emicizumab is a bispecific monoclonal antibody that bridges activated factor IX and factor X to replace the function of missing activated factor VIII, thereby restoring hemostasis. In a phase 3, multicenter trial, we investigated its use as prophylaxis in persons who have hemophilia A without factor VIII inhibitors.
METHODS: We randomly assigned, in a 2:2:1 ratio, participants 12 years of age or older who had been receiving episodic treatment with factor VIII to receive a subcutaneous maintenance dose of emicizumab of 1.5 mg per kilogram of body weight per week (group A) or 3.0 mg per kilogram every 2 weeks (group B) or no prophylaxis (group C). The primary end point was the difference in rates of treated bleeding (group A vs. group C and group B vs. group C). Participants who had been receiving factor VIII prophylaxis received emicizumab at a maintenance dose of 1.5 mg per kilogram per week (group D); intraindividual comparisons were performed in those who had participated in a noninterventional study.
RESULTS: A total of 152 participants were enrolled. The annualized bleeding rate was 1.5 events (95% confidence interval [CI], 0.9 to 2.5) in group A and 1.3 events (95% CI, 0.8 to 2.3) in group B, as compared with 38.2 events (95% CI, 22.9 to 63.8) in group C; thus, the rate was 96% lower in group A and 97% lower in group B (P<0.001 for both comparisons). A total of 56% of the participants in group A and 60% of those in group B had no treated bleeding events, as compared with those in group C, who all had treated bleeding events. In the intraindividual comparison involving 48 participants, emicizumab prophylaxis resulted in an annualized bleeding rate that was 68% lower than the rate with previous factor VIII prophylaxis (P<0.001). The most frequent adverse event was low-grade injection-site reaction. There were no thrombotic or thrombotic microangiopathy events, development of antidrug antibodies, or new development of factor VIII inhibitors.
CONCLUSIONS: Emicizumab prophylaxis administered subcutaneously once weekly or every 2 weeks led to a significantly lower bleeding rate than no prophylaxis among persons with hemophilia A without inhibitors; more than half the participants who received prophylaxis had no treated bleeding events. In an intraindividual comparison, emicizumab therapy led to a significantly lower bleeding rate than previous factor VIII prophylaxis. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 3 ClinicalTrials.gov number, NCT02847637 .).

PMID 30157389

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