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Hamostaseologie
DOI: 10.1055/a-2411-7416
Original Article

Expert Opinion for Defining a Severe Bleeding Phenotype to Guide Prophylaxis in Patients with Nonsevere Hemophilia

Christian Pfrepper
1   Division of Hemostaseology, University of Leipzig Medical Center, Leipzig, Germany
,
Carmen Escuriola Ettingshausen
2   Hemophilia Centre Rhein Main (HZRM), Frankfurt, Germany
,
Robert Klamroth
3   Vivantes Klinikum im Friedrichshain, Berlin, Germany
,
Johannes Oldenburg
4   Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany
,
Martin Olivieri
5   Pediatric Thrombosis and Hemostasis Center, Pediatric Hemophilia Center, Dr. von Hauner Children's Hospital, LMU Munich, Germany
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Abstract

Prophylaxis is the standard of care for patients with severe hemophilia, patients with moderate hemophilia, or those with another congenital bleeding disorder that is associated with a severe bleeding phenotype and/or a high risk of spontaneous life-threatening bleeding. Patients with nonsevere hemophilia (factor VIII [FVIII] ≥ 1%) may also have a bleeding phenotype that requires prophylaxis. To date, however, there are no clear criteria as to when prophylaxis is indicated in these patients. Also, the term “severe bleeding phenotype (SBPT)” is neither included in the definitions of the International Society on Thrombosis and Haemostasis (ISTH) nor specified in the World Federation of Hemophilia (WFH) guidelines. Based on our personal experience and available evidence, we propose the criteria we use to define an SBPT and when we consider offering prophylaxis in patients with nonsevere hemophilia. Our proposals can be the basis for discussions in the community about the assessment of SBPT and the initiation of prophylaxis in patients with nonsevere hemophilia without inhibitors.

Zusammenfassung

Für Patienten mit schwerer Hämophilie und für einige Patienten mit mittelschwerer Hämophilie oder mit einer anderen angeborenen Blutungsneigung, die mit einem schweren Blutungsphänotyp (SBPT) und/oder einem hohen Risiko für spontane lebensbedrohliche Blutungen einhergeht, ist die Prophylaxe die Standardbehandlung. Auch Patienten mit nicht-schwerer Hämophilie [Faktor VIII (FVIII) ≥ 1%] können einen Blutungsphänotyp haben, der eine Prophylaxe erfordert. Bisher gibt es aber keine klaren Kriterien, wann eine Prophylaxe bei diesen Patienten indiziert ist. Darüber hinaus ist der Begriff SBPT in den Definitionen der International Society on Thrombosis and Haemostasis (ISTH) nicht aufgeführt und in den World Federation of Hemophilia (WFH)-Guidelines nicht spezifiziert. Wir beschreiben anhand unserer persönlichen Erfahrungen und vorliegender Evidenz, anhand welcher Kriterien wir einen SBPT definieren und wann wir Patienten mit nicht-schwerer Hämophilie eine Prophylaxe anbieten. Unsere Vorschläge können als Basis einer Diskussion unter den Hämophiliebehandlern über die Einschätzung eines SBPT und den Prophylaxe-Beginn bei Patienten mit nicht-schwerer Hämophilie ohne Hemmkörper dienen.

Keywords

nonsevere hemophilia - moderate hemophilia - severe bleeding phenotype - prophylaxis - expert opinion

Schlüsselwörter

nicht-schwere Hämophilie - mittelschwere Hämophilia - schwerer Blutungsphänotyp - Prophylaxe - Expertenmeinung

Supplementary Material



Publication History

Received: 07 March 2024

Accepted: 06 September 2024

Article published online:
12 November 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 Srivastava A, Santagostino E, Dougall A. et al; WFH Guidelines for the Management of Hemophilia Panelists and Co-authors. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia 2020; 26 (6, Suppl 6): 1-158
    CrossrefPubMedSearch in Google Scholar
  • 2 Benson G, Auerswald G, Dolan G. et al. Diagnosis and care of patients with mild haemophilia: practical recommendations for clinical management. Blood Transfus 2018; 16 (06) 535-544
    PubMedSearch in Google Scholar
  • 3 Makris M, Oldenburg J, Mauser-Bunschoten EP, Peerlinck K, Castaman G, Fijnvandraat K. Subcommittee on Factor VIII, Factor IX and Rare Bleeding Disorders. The definition, diagnosis and management of mild hemophilia A: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (12) 2530-2533
    CrossrefPubMedSearch in Google Scholar
  • 4 Castaman G, Peyvandi F, De Cristofaro R, Pollio B, Di Minno DMN. Mild and moderate hemophilia A: neglected conditions, still with unmet needs. J Clin Med 2023; 12 (04) 1368
    CrossrefPubMedSearch in Google Scholar
  • 5 Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A. Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12 (11) 1935-1939
    CrossrefPubMedSearch in Google Scholar
  • 6 Rodeghiero F, Pabinger I, Ragni M. et al. Fundamentals for a systematic approach to mild and moderate inherited bleeding disorders: an EHA Consensus Report. HemaSphere 2019; 3 (04) e286
    CrossrefPubMedSearch in Google Scholar
  • 7 Rodeghiero F, Tosetto A, Abshire T. et al; ISTH/SSC joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working Group. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 8 (09) 2063-2065
    CrossrefPubMedSearch in Google Scholar
  • 8 Mancuso ME, Bidlingmaier C, Mahlangu JN, Carcao M, Tosetto A. Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders. The predictive value of factor VIII/factor IX levels to define the severity of hemophilia: communication from the SSC of ISTH. J Thromb Haemost 2018; 16 (10) 2106-2110
    CrossrefPubMedSearch in Google Scholar
  • 9 Verhagen MJA, van Heerde WL, van der Bom JG. et al. In patients with hemophilia, a decreased thrombin generation profile is associated with a severe bleeding phenotype. Res Pract Thromb Haemost 2023; 7 (02) 100062
    CrossrefPubMedSearch in Google Scholar
  • 10 Agosti P, Siboni SM, Scardo S, Torri A, Gualtierotti R, Peyvandi F. Minimum factor VIII levels to prevent joint bleeding in mild hemophilia A. Blood Adv 2023; 7 (23) 7209-7215
    CrossrefPubMedSearch in Google Scholar
  • 11 Verhagen MJA, van Balen EC, Blijlevens NMA. et al. Patients with moderate hemophilia A and B with a severe bleeding phenotype have an increased burden of disease. J Thromb Haemost 2024; 22 (01) 152-162
    CrossrefPubMedSearch in Google Scholar
  • 12 Thachil J, Connors JM, Mahlangu J, Sholzberg M. Reclassifying hemophilia to include the definition of outcomes and phenotype as new targets. J Thromb Haemost 2023; 21 (07) 1737-1740
    CrossrefPubMedSearch in Google Scholar
  • 13 Rejtő J, Kraemmer D, Grilz E. et al. Bleeding phenotype in nonsevere hemophilia by International Society on Thrombosis and Haemostasis bleeding assessment tool, bleeding frequency, and the joint status. Res Pract Thromb Haemost 2023; 7 (02) 100047
    CrossrefPubMedSearch in Google Scholar
  • 14 Négrier C, Mahlangu J, Lehle M. et al. Emicizumab in people with moderate or mild haemophilia A (HAVEN 6): a multicentre, open-label, single-arm, phase 3 study. Lancet Haematol 2023; 10 (03) e168-e177
    CrossrefPubMedSearch in Google Scholar
  • 15 Iorio A, Königs C, Reding MT. et al. Prophylaxis use of clotting factor replacement products in people with non-severe haemophilia: a review of the literature. Haemophilia 2023; 29 (01) 33-44
    CrossrefPubMedSearch in Google Scholar
  • 16 Kloosterman FR, Zwagemaker A-F, Bagot CN. et al. The bleeding phenotype in people with nonsevere hemophilia. Blood Adv 2022; 6 (14) 4256-4265
    CrossrefPubMedSearch in Google Scholar
  • 17 Zanon E, Pasca S, Demartis F. et al; REC Registry. Intracranial haemorrhage in haemophilia patients is still an open issue: the final results of the Italian EMO. J Clin Med 2022; 11 (07) 1969
    CrossrefPubMedSearch in Google Scholar
  • 18 Zwagemaker AF, Kloosterman FR, Hemke R. et al. Joint status of patients with nonsevere hemophilia A. J Thromb Haemost 2022; 20 (05) 1126-1137
    CrossrefPubMedSearch in Google Scholar
  • 19 Collins PW, Obaji SG, Roberts H, Gorsani D, Rayment R. Clinical phenotype of severe and moderate haemophilia: Who should receive prophylaxis and what is the target trough level?. Haemophilia 2021; 27 (02) 192-198
    CrossrefPubMedSearch in Google Scholar
  • 20 Jiménez-Yuste V, Álvarez-Román MT, Martín-Salces M. et al. Joint status in Spanish haemophilia B patients assessed using the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score. Haemophilia 2019; 25 (01) 144-153
    CrossrefPubMedSearch in Google Scholar
  • 21 Meunier S, d'oiron R, Chambost H, Dolimier E, Guillet B. ORTHem 15–25 Study Group. Choice of factor VIII/IX regimen in adolescents and young adults with severe or moderately severe haemophilia. A French national observational study (ORTHem 15–25). Thromb Res 2017; 151: 17-22
    CrossrefPubMedSearch in Google Scholar
  • 22 Chang CY, Li TY, Cheng SN. et al. Prevalence and severity by age and other clinical correlates of haemophilic arthropathy of the elbow, knee and ankle among Taiwanese patients with haemophilia. Haemophilia 2017; 23 (02) 284-291
    CrossrefPubMedSearch in Google Scholar
  • 23 Tosetto A, Castaman G, Rodeghiero F. Bleeders, bleeding rates, and bleeding score. J Thromb Haemost 2013; 11 (Suppl. 01) 142-150
    CrossrefPubMedSearch in Google Scholar
  • 24 Inaba H, Shinozawa K, Seita I. et al. Genotypic and phenotypic features of Japanese patients with mild to moderate hemophilia A. Int J Hematol 2013; 97 (06) 758-764
    CrossrefPubMedSearch in Google Scholar
  • 25 Den Uijl IE, Mauser Bunschoten EP, Roosendaal G. et al. Clinical severity of haemophilia A: does the classification of the 1950s still stand?. Haemophilia 2011; 17 (06) 849-853
    CrossrefPubMedSearch in Google Scholar
  • 26 Pergantou H, Platokouki H, Matsinos G. et al. Assessment of the progression of haemophilic arthropathy in children. Haemophilia 2010; 16 (01) 124-129
    CrossrefPubMedSearch in Google Scholar
  • 27 den Uijl IE, Fischer K, Van Der Bom JG, Grobbee DE, Rosendaal FR, Plug I. Clinical outcome of moderate haemophilia compared with severe and mild haemophilia. Haemophilia 2009; 15 (01) 83-90
    CrossrefPubMedSearch in Google Scholar
  • 28 Schulman S, Eelde A, Holmström M, Ståhlberg G, Odeberg J, Blombäck M. Validation of a composite score for clinical severity of hemophilia. J Thromb Haemost 2008; 6 (07) 1113-1121
    CrossrefPubMedSearch in Google Scholar
  • 29 Trossaërt M, Regnault V, Sigaud M, Boisseau P, Fressinaud E, Lecompte T. Mild hemophilia A with factor VIII assay discrepancy: using thrombin generation assay to assess the bleeding phenotype. J Thromb Haemost 2008; 6 (03) 486-493
    CrossrefPubMedSearch in Google Scholar
  • 30 Måseide RJ, Berntorp E, Astermark J. et al. Joint health and treatment modalities in Nordic patients with moderate haemophilia A and B - the MoHem study. Haemophilia 2020; 26 (05) 891-897
    CrossrefPubMedSearch in Google Scholar
  • 31 Scott MJ, Xiang H, Hart DP. et al. Treatment regimens and outcomes in severe and moderate haemophilia A in the UK: The THUNDER study. Haemophilia 2019; 25 (02) 205-212
    CrossrefPubMedSearch in Google Scholar
  • 32 den Uijl I, Biesma D, Grobbee D, Fischer K. Outcome in moderate haemophilia. Blood Transfus 2014; 12 (Suppl 1, Suppl 1): s330-s336
    PubMedSearch in Google Scholar
  • 33 [Cross-Sectional Guidelines of the German Medical Association for Therapy with Blood Components and Plasma Derivatives]. [Article in German]. 2020 . Accessed January 18, 2024 at: https://www.bundesaerztekammer.de/fileadmin/user_upload/_old-files/downloads/pdf-Ordner/MuE/Querschnitts-Leitlinien_BAEK_zur_Therapie_mit_Blutkomponenten_und_Plasmaderivaten-Gesamtnovelle_2020.pdf
    PubMedSearch in Google Scholar
  • 34 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
    CrossrefPubMedSearch in Google Scholar
  • 35 Schutgens REG, Jimenez-Yuste V, Escobar M. et al. Antithrombotic treatment in patients with hemophilia: an EHA-ISTH-EAHAD-ESO Clinical Practice Guidance. HemaSphere 2023; 7 (06) e900
    CrossrefPubMedSearch in Google Scholar
  • 36 Poston JN, Kruse-Jarres R. Perioperative hemostasis for patients with hemophilia. Hematology (Am Soc Hematol Educ Program) 2022; 2022 (01) 586-593
    CrossrefPubMedSearch in Google Scholar
  • 37 Warrilow G, Kirkham C, Ismail K, Wyatt K, Dimmock P, O'Brien P. Quantification of menstrual blood loss. Obstet Gynaecol 2004;
    CrossrefPubMedSearch in Google Scholar
  • 38 Kloosterman F, Zwagemaker AF, Abdi A, Gouw S, Castaman G, Fijnvandraat K. Hemophilia management: huge impact of a tiny difference. Res Pract Thromb Haemost 2020; 4 (03) 377-385
    CrossrefPubMedSearch in Google Scholar
  • 39 Pasca S, Linari S, Tagliaferri A, Santoro C, Zanon E. EMO.REC study group, REC Registry. Very high risk of intracranial hemorrhage and severe outcomes in adult patients with mild hemophilia: sub-analysis of the EMO. Thromb Res 2023; 221: 35-36
    CrossrefPubMedSearch in Google Scholar
  • 40 Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet 2003; 361 (9371) 1801-1809
    CrossrefPubMedSearch in Google Scholar
  • 41 Di Minno MN, Ambrosino P, Franchini M, Coppola A, Di Minno G. Arthropathy in patients with moderate hemophilia A: a systematic review of the literature. Semin Thromb Hemost 2013; 39 (07) 723-731
    Thieme ConnectPubMedSearch in Google Scholar
  • 42 Gualtierotti R, Solimeno LP, Peyvandi F. Hemophilic arthropathy: current knowledge and future perspectives. J Thromb Haemost 2021; 19 (09) 2112-2121
    CrossrefPubMedSearch in Google Scholar
  • 43 Di Minno MND, Napolitano M, Giuffrida AC. et al; Italian Association of Haemophilia Centres Musculoskeletal Working Group. Diagnosis and treatment of chronic synovitis in patients with haemophilia: consensus statements from the Italian Association of Haemophilia Centres. Br J Haematol 2022; 196 (04) 871-883
    CrossrefPubMedSearch in Google Scholar
  • 44 Rayment R, Chalmers E, Forsyth K. et al; British Society for Haematology. Guidelines on the use of prophylactic factor replacement for children and adults with haemophilia A and B. Br J Haematol 2020; 190 (05) 684-695
    CrossrefPubMedSearch in Google Scholar
  • 45 Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood 2015; 125 (13) 2038-2044
    CrossrefPubMedSearch in Google Scholar
  • 46 den Uijl IE, Fischer K, Van Der Bom JG, Grobbee DE, Rosendaal FR, Plug I. Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels. Haemophilia 2011; 17 (01) 41-44
    CrossrefPubMedSearch in Google Scholar
  • 47 Soucie JM, Monahan PE, Kulkarni R, Konkle BA, Mazepa MA. US Hemophilia Treatment Center Network. The frequency of joint hemorrhages and procedures in nonsevere hemophilia A vs B. Blood Adv 2018; 2 (16) 2136-2144
    CrossrefPubMedSearch in Google Scholar
  • 48 Peyvandi F, Berger K, Seitz R. et al. Kreuth V initiative: European consensus proposals for treatment of hemophilia using standard products, extended half-life coagulation factor concentrates and non-replacement therapies. Haematologica 2020; 105 (08) 2038-2043
    CrossrefPubMedSearch in Google Scholar
  • 49 Ahlberg A. Haemophilia in Sweden. VII. Incidence, treatment and prophylaxis of arthropathy and other musculo-skeletal manifestations of haemophilia A and B. Acta Orthop Scand Suppl 1965; 36 (77) 77 , 3–132
    PubMedSearch in Google Scholar
  • 50 Kempton CL. Prophylaxis in hemophilia: how much is enough?. Blood 2021; 137 (13) 1709-1711
    CrossrefPubMedSearch in Google Scholar
  • 51 Poulsen AL, Pedersen LH, Hvas AM, Poulsen LH, Thykjaer H, Ingerslev J. Assay discrepancy in mild haemophilia A: entire population study in a National Haemophilia Centre. Haemophilia 2009; 15 (01) 285-289
    CrossrefPubMedSearch in Google Scholar
  • 52 Rodgers SE, Duncan EM, Barbulescu DM, Quinn DM, Lloyd JV. In vitro kinetics of factor VIII activity in patients with mild haemophilia A and a discrepancy between one-stage and two-stage factor VIII assay results. Br J Haematol 2007; 136 (01) 138-145
    CrossrefPubMedSearch in Google Scholar
  • 53 Hemlibra. Summary of Product Characteristics. Roche Registration GmbH. Accessed January 18, 2024 at: https://www.ema.europa.eu/en/documents/product-information/hemlibra-epar-product-information_en.pdf
    PubMed
  • 54 Makris M. Emicizumab for non-severe haemophilia A. Lancet Haematol 2023; 10 (03) e158-e159
    CrossrefPubMedSearch in Google Scholar