Definitions in Hemophilia: Resolved and Unresolved Issues

Abstract

Definitions of clinical events and end points of care are important for disease characterization as well as documentation of outcomes in clinical practice and trials. Until recently, the only definitions in hemophilia that were provided through an international scientific organization related to disease severity and levels of inhibitors. Recently, the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis, through its Factor VIII and IX subcommittee, published consensus definitions for several other aspects of hemophilia management, including classification of disease severity; inhibitors; bleeding (and rebleeding) into muscles and joints; target joints; different forms of factor replacement therapy; and response to therapy for joint bleeding and surgical hemostasis. These definitions should help to bring greater uniformity in the documentation of critical clinical events and laboratory data that are reported both from clinical trials as well as real-world practice. This article describes these definitions in greater detail than the SSC short report and also addresses some of the unresolved issues. Wide dissemination of these concepts and definitions and their acceptance by relevant leading scientific societies, drug regulators, industry, and patient organizations will go a long way in ensuring their acceptance and use globally.

Keywords

definitions - prophylaxis - clinical events - therapy responses

• References

• 1 Srivastava A, Brewer AK, Mauser-Bunschoten EP , et al; Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia 2013; 19 (1) e1-e47
• 2 The WHOQOL Group. Development of the World Health Organization WHOQOL-BREF quality of life assessment. Psychol Med 1998; 28 (3) 551-558
• 3 Blanchette VS, O'Mahony B, McJames L, Mahlangu JN. Assessment of outcomes. Haemophilia 2014; 20 (Suppl. 04) 114-120
• 4 O'Mahony BN, Noone D, Tolley DK. An introduction to key concepts in health economics for hemophilia organizations. World Federation Hemophilia 2010; 11: 1-22
• 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. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12 (11) 1935-1939
• 6 Biggs R, MacFarlane RG. Haemophilia and related conditions: a survey of 187 cases. Br J Haematol 1958; 4 (1) 1-27
• 7 White II 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 (3) 560
• 8 Aledort LM, Haschmeyer RH, Pettersson H ; The Orthopaedic Outcome Study Group. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. J Intern Med 1994; 236 (4) 391-399
• 9 Tagariello G, Iorio A, Santagostino E , et al; Italian Association Hemophilia Centre (AICE). Comparison of the rates of joint arthroplasty in patients with severe factor VIII and IX deficiency: an index of different clinical severity of the 2 coagulation disorders. Blood 2009; 114 (4) 779-784
• 10 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 (6) 849-853
• 11 Donadel-Claeyssens S ; European Paediatric Network for Haemophilia Management. Current co-ordinated activities of the PEDNET (European Paediatric Network for Haemophilia Management). Haemophilia 2006; 12 (2) 124-127
• 12 Ota S, Mclimont M, Carcao MD , et al. Definitions for haemophilia prophylaxis and its outcomes: the Canadian consensus study. Haemophilia 2007; 13 (1) 12-20
• 13 Blanchette VS, McCready M, Achonu C, Abdolell M, Rivard G, Manco-Johnson MJ. A survey of factor prophylaxis in boys with haemophilia followed in North American haemophilia treatment centres. Haemophilia 2003; 9 (Suppl. 01) 19-26 , discussion 26 discussion
• 14 Kavakli K, Makris M, Zulfikar B, Erhardtsen E, Abrams ZS, Kenet G ; NovoSeven trial (F7HAEM-1510) investigators. Home treatment of haemarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. A multi-centre, randomised, double-blind, cross-over trial. Thromb Haemost 2006; 95 (4) 600-605
• 15 Verbruggen B, Novakova I, Wessels H, Boezeman J, van den Berg M, Mauser-Bunschoten E. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost 1995; 73 (2) 247-251
• 16 Giles AR, Verbruggen B, Rivard GE, Teitel J, Walker I ; Association of Hemophilia Centre Directors of Canada. Factor VIII/IX Subcommittee of Scientific and Standardization Committee of International Society on Thrombosis and Haemostasis. A detailed comparison of the performance of the standard versus the Nijmegen modification of the Bethesda assay in detecting factor VIII:C inhibitors in the haemophilia A population of Canada. Thromb Haemost 1998; 79 (4) 872-875
• 17 Meijer P, Verbruggen B. The between-laboratory variation of factor VIII inhibitor testing: the experience of the external quality assessment program of the ECAT foundation. Semin Thromb Hemost 2009; 35 (8) 786-793
• 18 Collins PW, Chalmers E, Hart DP , et al. Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia. 4th ed. UK Haemophilia Centre Doctors Organization. Br J Haematol 2013; 160: 153-170
• 19 Björkman S, Carlsson M, Berntorp E, Stenberg P. Pharmacokinetics of factor VIII in humans. Obtaining clinically relevant data from comparative studies. Clin Pharmacokinet 1992; 22 (5) 385-395
• 20 Dardikh M, Albert T, Masereeuw R , et al. Low-titre inhibitors, undetectable by the Nijmegen assay, reduce factor VIII half-life after immune tolerance induction. J Thromb Haemost 2012; 10 (4) 706-708
• 21 Miller CH, Platt SJ, Rice AS, Kelly F, Soucie JM ; Hemophilia Inhibitor Research Study Investigators. Validation of Nijmegen-Bethesda assay modifications to allow inhibitor measurement during replacement therapy and facilitate inhibitor surveillance. J Thromb Haemost 2012; 10 (6) 1055-1061
• 22 Berntorp E, Astermark J, Björkman S , et al. Consensus perspectives on prophylactic therapy for haemophilia: summary statement. Haemophilia 2003; 9 (Suppl. 01) 1-4
• 23 Astermark J, Petrini P, Tengborn L, Schulman S, Ljung R, Berntorp E. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized. Br J Haematol 1999; 105 (4) 1109-1113
• 24 Fischer K, van der Bom JG, Mauser-Bunschoten EP , et al. The effects of postponing prophylactic treatment on long-term outcome in patients with severe hemophilia. Blood 2002; 99 (7) 2337-2341
• 25 Manco-Johnson MJ, Abshire TC, Shapiro AD , et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357 (6) 535-544
• 26 Kraft J, Blanchette V, Babyn P , et al. Magnetic resonance imaging and joint outcomes in boys with severe hemophilia A treated with tailored primary prophylaxis in Canada. J Thromb Haemost 2012; 10 (12) 2494-2502
• 27 Gringeri A, Lambert T, Street A, Aledort L ; Adolescent/Adult Prophylaxis Expert Working Group of the International Prophylaxis Study Group. Tertiary prophylaxis in adults: is there a rationale?. Haemophilia 2012; 18 (5) 722-728