Skip to main content
Erschienen in:

19.01.2022 | Original Article

Comparisons of global coagulation potential and bleeding episodes in emicizumab-treated hemophilia A patients and mild hemophilia A patients

verfasst von: Yuto Nakajima, Kuniyoshi Mizumachi, Naruto Shimonishi, Shoko Furukawa, Koji Yada, Kenichi Ogiwara, Masahiro Takeyama, Midori Shima, Keiji Nogami

Erschienen in: International Journal of Hematology | Ausgabe 4/2022

Einloggen, um Zugang zu erhalten

Abstract

Emicizumab reduces bleeding events in patients with severe hemophilia A (HA). The coagulation potential of emicizumab at a clinical dose appears to correspond to about 15 IU/dL of factor VIII activity (FVIII:C), the equivalent of converting from a severe to mild phenotype. However, the clinical and laboratory characteristics of HA patients receiving emicizumab (Emi-PwHA) compared with patients with mild HA (PwMHA) remain to be determined. We reviewed clinical data from Emi-PwHA (n = 63) and PwMHA (n = 15) and evaluated comprehensive coagulation function using Ca2+-triggered rotational thromboelastometry (ROTEM) and ellagic acid/tissue factor-triggered clot waveform analysis (modified CWA). The median FVIII:C in PwMHA was 13.0 (IQR 8.5–17.0) IU/dL. Bleeding patterns in both groups were similar and classified into three categories: (1) spontaneous bleeding, post-traumatic, (2) bleeding within 1–2 days, and (3) delayed bleeding after 1–2 weeks. The coagulation potential in Emi-PwHA with and without breakthrough bleeds was comparable. Furthermore, coagulation function in Emi-PwHA was equivalent to PwMHA, although time between treatment and hospitalization for breakthrough bleeds in PwMHA appeared to be longer than those in Emi-PwHA. The coagulation potential and bleeding patterns appeared to be similar in Emi-PwHA and PwMHA, indicating that emicizumab-driven coagulation potential reflected mild HA.
Literatur
1.
Zurück zum Zitat Luck JV Jr, Silva M, Rodriguez-Merchan EC, Ghalambor N, Zahiri CA, Finn RS. Hemophilic arthropathy. J Am Acad Orthop Surg. 2004;12:234–45.CrossRef Luck JV Jr, Silva M, Rodriguez-Merchan EC, Ghalambor N, Zahiri CA, Finn RS. Hemophilic arthropathy. J Am Acad Orthop Surg. 2004;12:234–45.CrossRef
2.
Zurück zum Zitat White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J. Factor VIII and factor IX subcommittee. Definitions in hemophilia. Recommendation of the Scientific Subcommittee on Factor VIII and Factor IX of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 2001;85:560.CrossRef White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J. Factor VIII and factor IX subcommittee. Definitions in hemophilia. Recommendation of the Scientific Subcommittee on Factor VIII and Factor IX of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 2001;85:560.CrossRef
3.
Zurück zum Zitat Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, et al. Treatment guidelines working group on behalf of the world federation of hemophilia. Guidelines management of hemophilia. Haemophilia. 2013;19:e1–47.CrossRef Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, et al. Treatment guidelines working group on behalf of the world federation of hemophilia. Guidelines management of hemophilia. Haemophilia. 2013;19:e1–47.CrossRef
4.
Zurück zum Zitat Den Uijl IE, Mauser Bunschoten EP, Roosendaal G, Schutgens RE, Biesma DH, Grobbee DE, et al. Clinical severity of haemophilia A: does the classification of the 1950s still stand? Haemophilia. 2011;17:849–53.CrossRef Den Uijl IE, Mauser Bunschoten EP, Roosendaal G, Schutgens RE, Biesma DH, Grobbee DE, et al. Clinical severity of haemophilia A: does the classification of the 1950s still stand? Haemophilia. 2011;17:849–53.CrossRef
5.
Zurück zum Zitat Ling M, Heysen JP, Duncan EM, Rodgers SE, Lloyd JV. High incidence of ankle arthropathy in mild and moderate haemophilia A. Thromb Haemost. 2011;105:261–8.CrossRef Ling M, Heysen JP, Duncan EM, Rodgers SE, Lloyd JV. High incidence of ankle arthropathy in mild and moderate haemophilia A. Thromb Haemost. 2011;105:261–8.CrossRef
6.
Zurück zum Zitat Di Minno MN, Ambrosino P, Franchini M, Coppola A, Di Minno G. Arthropathy inpatients with moderate hemophilia A: a systematic review of the literature. Semin Thromb Hemost. 2013;39:723–31.CrossRef Di Minno MN, Ambrosino P, Franchini M, Coppola A, Di Minno G. Arthropathy inpatients with moderate hemophilia A: a systematic review of the literature. Semin Thromb Hemost. 2013;39:723–31.CrossRef
7.
Zurück zum Zitat Kitazawa T, Igawa T, Sampei Z, Muto A, Kojima T, Soeda T, et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med. 2012;18:1570–4.CrossRef Kitazawa T, Igawa T, Sampei Z, Muto A, Kojima T, Soeda T, et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med. 2012;18:1570–4.CrossRef
8.
Zurück zum Zitat Sampei Z, Igawa T, Soeda T, Okuyama-Nishida Y, Moriyama C, Wakabayashi T, et al. Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactor activity. PLoS ONE. 2013;8:e57479.CrossRef Sampei Z, Igawa T, Soeda T, Okuyama-Nishida Y, Moriyama C, Wakabayashi T, et al. Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactor activity. PLoS ONE. 2013;8:e57479.CrossRef
9.
Zurück zum Zitat Shima M, Hanabusa H, Taki M, Matsushita T, Sato T, Fukutake K, et al. Factor VIII-mimetic function of humanized bispecific antibody in hemophilia A. N Engl J Med. 2016;374:2044–53.CrossRef Shima M, Hanabusa H, Taki M, Matsushita T, Sato T, Fukutake K, et al. Factor VIII-mimetic function of humanized bispecific antibody in hemophilia A. N Engl J Med. 2016;374:2044–53.CrossRef
10.
Zurück zum Zitat Shima M, Hanabusa H, Taki M, Matsushita T, Sato T, Fukutake K, et al. Long-term safety and efficacy of emicizumab in a phase 1/2 study in hemophilia A patients with or without inhibitors. Blood Adv. 2017;1:1891–9.CrossRef Shima M, Hanabusa H, Taki M, Matsushita T, Sato T, Fukutake K, et al. Long-term safety and efficacy of emicizumab in a phase 1/2 study in hemophilia A patients with or without inhibitors. Blood Adv. 2017;1:1891–9.CrossRef
11.
Zurück zum Zitat Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377:809–18.CrossRef Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377:809–18.CrossRef
12.
Zurück zum Zitat Young G, Liesner R, Chang T, Sidonio R, Oldenburg J, Jiménez-Yuste V, et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019;134:2127–38.CrossRef Young G, Liesner R, Chang T, Sidonio R, Oldenburg J, Jiménez-Yuste V, et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019;134:2127–38.CrossRef
13.
Zurück zum Zitat Mahlangu J, Oldenburg J, Paz-Priel I, Negrier C, Niggli M, Mancuso ME, et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N Engl J Med. 2018;379:811–22.CrossRef Mahlangu J, Oldenburg J, Paz-Priel I, Negrier C, Niggli M, Mancuso ME, et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N Engl J Med. 2018;379:811–22.CrossRef
14.
Zurück zum Zitat Pipe SW, Shima M, Lehle M, Shapiro A, Chebon S, Fukutake K, et al. 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;6:e295-305.CrossRef Pipe SW, Shima M, Lehle M, Shapiro A, Chebon S, Fukutake K, et al. 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;6:e295-305.CrossRef
15.
Zurück zum Zitat Shima M, Nogami K, Nagami S, Yoshida S, Yoneyama K, Ishiguro A, et al. A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors. Haemophilia. 2019;25:979–87.CrossRef Shima M, Nogami K, Nagami S, Yoshida S, Yoneyama K, Ishiguro A, et al. A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors. Haemophilia. 2019;25:979–87.CrossRef
16.
Zurück zum Zitat Barg AA, Livnat T, Budnik I, Avishai E, Brutman-Barazani T, Tamarin I, et al. Emicizumab treatment and monitoring in a paediatric cohort: real-world data. Br J Haematol. 2020;191:282–90.CrossRef Barg AA, Livnat T, Budnik I, Avishai E, Brutman-Barazani T, Tamarin I, et al. Emicizumab treatment and monitoring in a paediatric cohort: real-world data. Br J Haematol. 2020;191:282–90.CrossRef
17.
Zurück zum Zitat McCary I, Guelcher C, Kuhn J, Butler R, Massey G, Guerrera MF, et al. Real-world use of emicizumab in patients with haemophilia A: bleeding outcomes and surgical procedures. Haemophilia. 2020;26:631–6.CrossRef McCary I, Guelcher C, Kuhn J, Butler R, Massey G, Guerrera MF, et al. Real-world use of emicizumab in patients with haemophilia A: bleeding outcomes and surgical procedures. Haemophilia. 2020;26:631–6.CrossRef
18.
Zurück zum Zitat Barg AA, Avishai E, Budnik I, Levy-Mendelovich S, Barazani TB, Kenet G, et al. Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors-a single-center cohort. Pediatr Blood Cancer. 2019;66:e27886.CrossRef Barg AA, Avishai E, Budnik I, Levy-Mendelovich S, Barazani TB, Kenet G, et al. Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors-a single-center cohort. Pediatr Blood Cancer. 2019;66:e27886.CrossRef
19.
Zurück zum Zitat Misgav M, Brutman-Barazani T, Budnik I, Avishai E, Schapiro J, Bashari D, et al. Emicizumab prophylaxis in haemophilia patients older than 50 years with cardiovascular risk factors: real-world data. Haemophilia. 2021;27:253–60.CrossRef Misgav M, Brutman-Barazani T, Budnik I, Avishai E, Schapiro J, Bashari D, et al. Emicizumab prophylaxis in haemophilia patients older than 50 years with cardiovascular risk factors: real-world data. Haemophilia. 2021;27:253–60.CrossRef
20.
Zurück zum Zitat McCary I, Guelcher C, Kuhn J, Butler R, Guerrera FM, Massey G, et al. Peri-procedural management and outcomes of patients with hemophilia on emicizumab prophylaxis. Blood. 2019;134(Supplement_1):2396.CrossRef McCary I, Guelcher C, Kuhn J, Butler R, Guerrera FM, Massey G, et al. Peri-procedural management and outcomes of patients with hemophilia on emicizumab prophylaxis. Blood. 2019;134(Supplement_1):2396.CrossRef
21.
Zurück zum Zitat Ebbert PT, Xavier F, Seaman CD, Ragni MV. Emicizumab prophylaxis in patients with haemophilia A with and without inhibitors. Haemophilia. 2020;26:41–6.CrossRef Ebbert PT, Xavier F, Seaman CD, Ragni MV. Emicizumab prophylaxis in patients with haemophilia A with and without inhibitors. Haemophilia. 2020;26:41–6.CrossRef
22.
Zurück zum Zitat Lewandowska M, Randall N, Bakeer N, Maahs J, Sagar J, Greist A, et al. Management of people with haemophilia A undergoing surgery while receiving emicizumab prophylaxis: Real-world experience from a large comprehensive treatment centre in the US. Haemophilia. 2021;27:90–9.CrossRef Lewandowska M, Randall N, Bakeer N, Maahs J, Sagar J, Greist A, et al. Management of people with haemophilia A undergoing surgery while receiving emicizumab prophylaxis: Real-world experience from a large comprehensive treatment centre in the US. Haemophilia. 2021;27:90–9.CrossRef
23.
Zurück zum Zitat Muto A, Yoshihashi K, Takeda M, Kitazawa T, Soeda T, Igawa T, et al. Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation. J Thromb Haemost. 2014;12:206–13.CrossRef Muto A, Yoshihashi K, Takeda M, Kitazawa T, Soeda T, Igawa T, et al. Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation. J Thromb Haemost. 2014;12:206–13.CrossRef
24.
Zurück zum Zitat Nogami K, Matsumoto T, Tabuchi Y, Soeda T, Arai N, Kitazawa T, et al. Modified clot waveform analysis to measure plasma coagulation potential in the presence of the anti-factor IXa/factor X bispecific antibody emicizumab. J Thromb Haemost. 2018;16:1078–88.CrossRef Nogami K, Matsumoto T, Tabuchi Y, Soeda T, Arai N, Kitazawa T, et al. Modified clot waveform analysis to measure plasma coagulation potential in the presence of the anti-factor IXa/factor X bispecific antibody emicizumab. J Thromb Haemost. 2018;16:1078–88.CrossRef
25.
Zurück zum Zitat Nakajima Y, Tonegawa H, Noguchi-Sasaki M, Nogami K. Predicted coagulation potential using an in vitro simulated model of emicizumab prophylaxis and immune tolerance induction therapy in hemophilia A patients with inhibitor. Int J Hematol. 2021;113:789–96.CrossRef Nakajima Y, Tonegawa H, Noguchi-Sasaki M, Nogami K. Predicted coagulation potential using an in vitro simulated model of emicizumab prophylaxis and immune tolerance induction therapy in hemophilia A patients with inhibitor. Int J Hematol. 2021;113:789–96.CrossRef
26.
Zurück zum Zitat Yada K, Nogami K, Ogiwara K, Shida Y, Furukawa S, Yaoi H, et al. Global coagulation function assessed by rotational thromboelastometry predicts coagulation-steady state in individual hemophilia A patients receiving emicizumab prophylaxis. Int J Hematol. 2019;110:419–30.CrossRef Yada K, Nogami K, Ogiwara K, Shida Y, Furukawa S, Yaoi H, et al. Global coagulation function assessed by rotational thromboelastometry predicts coagulation-steady state in individual hemophilia A patients receiving emicizumab prophylaxis. Int J Hematol. 2019;110:419–30.CrossRef
27.
Zurück zum Zitat Furukawa S, Nogami K, Ogiwara K, Yada K, Minami H, Shima M. Systematic monitoring of hemostatic management in hemophilia A patients with inhibitor in the perioperative period using rotational thromboelastometry. J Thromb Haemost. 2015;13:1279–84.CrossRef Furukawa S, Nogami K, Ogiwara K, Yada K, Minami H, Shima M. Systematic monitoring of hemostatic management in hemophilia A patients with inhibitor in the perioperative period using rotational thromboelastometry. J Thromb Haemost. 2015;13:1279–84.CrossRef
28.
Zurück zum Zitat Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transpl. 2013;48:452–8.CrossRef Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transpl. 2013;48:452–8.CrossRef
30.
Zurück zum Zitat Franchini M, Favaloro EJ, Lippi G. Mild hemophilia A. J Thromb Haemost. 2010;8:421–32.CrossRef Franchini M, Favaloro EJ, Lippi G. Mild hemophilia A. J Thromb Haemost. 2010;8:421–32.CrossRef
31.
Zurück zum Zitat Broderick CR, Herbert RD, Latimer J, van Doorn N. Patterns of physical activity in children with haemophilia. Haemophilia. 2013;19:59–64.CrossRef Broderick CR, Herbert RD, Latimer J, van Doorn N. Patterns of physical activity in children with haemophilia. Haemophilia. 2013;19:59–64.CrossRef
32.
Zurück zum Zitat Niu X, Poon JL, Riske B, Zhou ZY, Ullman M, Lou M, et al. Physical activity and health outcomes in persons with haemophilia B. Haemophilia. 2014;20:814–21.CrossRef Niu X, Poon JL, Riske B, Zhou ZY, Ullman M, Lou M, et al. Physical activity and health outcomes in persons with haemophilia B. Haemophilia. 2014;20:814–21.CrossRef
33.
Zurück zum Zitat Bouskill V, Hilliard P, Stephens S, Zhang C, Whitney K, Carcao M. An institutional pilot study to investigate physical activity patterns in boys with haemophilia. Haemophilia. 2016;22:e383–9.CrossRef Bouskill V, Hilliard P, Stephens S, Zhang C, Whitney K, Carcao M. An institutional pilot study to investigate physical activity patterns in boys with haemophilia. Haemophilia. 2016;22:e383–9.CrossRef
34.
Zurück zum Zitat Hermans C, Giangrande PLF, O’Mahony B, de Kleijn P, Bedford M, Batorova A, European Haemophilia Consortium (EHC) and the European Association for Haemophilia and Allied Disorders (EAHAD), et al. European principles of inhibitor management in patients with haemophilia: implications of new treatment options. Orphanet J Rare Dis. 2020;15:219.CrossRef Hermans C, Giangrande PLF, O’Mahony B, de Kleijn P, Bedford M, Batorova A, European Haemophilia Consortium (EHC) and the European Association for Haemophilia and Allied Disorders (EAHAD), et al. European principles of inhibitor management in patients with haemophilia: implications of new treatment options. Orphanet J Rare Dis. 2020;15:219.CrossRef
35.
Zurück zum Zitat Tagliaferri A, Di Perna C, Riccardi F, Pattacini C, Rivolta GF, Franchini M. The natural history of mild haemophilia: a 30-year single centre experience. Haemophilia. 2012;18:166–74.CrossRef Tagliaferri A, Di Perna C, Riccardi F, Pattacini C, Rivolta GF, Franchini M. The natural history of mild haemophilia: a 30-year single centre experience. Haemophilia. 2012;18:166–74.CrossRef
Metadaten
Titel
Comparisons of global coagulation potential and bleeding episodes in emicizumab-treated hemophilia A patients and mild hemophilia A patients
verfasst von
Yuto Nakajima
Kuniyoshi Mizumachi
Naruto Shimonishi
Shoko Furukawa
Koji Yada
Kenichi Ogiwara
Masahiro Takeyama
Midori Shima
Keiji Nogami
Publikationsdatum
19.01.2022
Verlag
Springer Singapore
Erschienen in
International Journal of Hematology / Ausgabe 4/2022
Print ISSN: 0925-5710
Elektronische ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-021-03276-7

Neu im Fachgebiet Onkologie

Neue chemotherapiefreie Kombinationstherapie punktet bei CLL

Zwischenergebnisse der Phase-III-Studie AMPLIFY sprechen dafür, dass die zeitlich begrenzte Behandlung mit Acalabrutinib und Venetoclax fitte Personen mit chronischer lymphatischer Leukämie länger leben lässt als eine Chemoimmuntherapie.

Ab sofort gelten die neuen Verordnungsausnahmen für Lipidsenker

Freie Fahrt für Lipidsenker? Das nicht, doch mit niedrigerem Schwellenwert fürs Infarktrisiko und neuen Indikationen hat der G-BA die Verordnungs-Handbremse ein gutes Stück weit gelockert.

NRG1-Fusionen als neues, klinisch relevantes Target

Ergebnisse einer Phase-II-Studie deuten darauf hin, dass ein gegen HER3 und HER2 gerichteter Antikörper bei verschiedenen NRG1-Fusions-positiven Tumoren wirksam sein könnte. In den USA ist die Substanz bereits beschleunigt zugelassen worden.

Die aktuelle S3-Leitlinie zu CLL strotzt vor Neuerungen

Vor kurzem wurde eine neue, grundlegend überarbeite Version der S3-Leitlinie Chronische Lymphatische Leukämie (CLL) veröffentlicht.  Zu den wichtigsten Änderungen gehört, dass die Chemoimmuntherapie auf dem Rückzug ist.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.