: SSC Communication
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Article type
Definitions in hemophilia: communication from the SSC of the ISTH
V.S. BLANCHETTE,* N.S. KEY, † L. R. LJUNG,‡ M.J. MANCO-JOHNSON, § H.M. VAN DEN BERG, ** A. SRIVASTAVA,††
*Pediatric Thrombosis and Hemostasis Program, Hospital for Sick Children, Department of Pediatrics, University of Toronto ,Toronto, ON, Canada; †Departments of Medicine and Pathology, UNC Hemophilia and Thrombosis Center Chapel Hill, NC, USA; ‡Lund University, Department of Paediatrics and Malmo Centre for Thrombosis and Haemostasis, Skanes Universitetssjukhus, Malmo, Sweden; §Hemophilia & Thrombosis Center, Univeristy of Colorado School of Medicine, Aurora, CO, USA; **Julius Center for Health Sciences and Primary Care, UMC Utrecht, The Netherlands; ††Department of Hematology, Christian Medical College, Vellore, India
Short running title: Definitions in Hemophilia
Correspondence: Dr. Victor S. Blanchette, Division of Hematology/Oncology, The Hospital for Sick Children, 555 University Avenue,
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an 'Accepted Article', doi: 10.1111/jth.12672 This article is protected by copyright. All rights reserved.
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Toronto, Ontario, M5G 1X8, Canada. Tel: + 1 416 813 5852 Fax: + 1 416 813 5327 E-mail: [email protected]
Background For the documentation and comparison of outcomes of clinical care in hemophilia, especially with different treatment protocols, as well as in clinical trials of new clotting factor concentrates, it is necessary to have clear definitions of disease related variables as well as the response to therapeutic interventions that are offered to treat or prevent bleeding. In 2001, White et al provided definitions for the severity of hemophilia and the levels for low and high response inhibitors on behalf of the Factor VIII and IX Subcommittee of the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH) [1]. With increasing emphasis on assessment of outcomes and creating evidence for clinical practice in hemophilia, it became necessary to revisit definitions in hemophilia. To this end, the Factor VIII, Factor IX and Rare Coagulation Disorders Subcommittee of the SSC of the ISTH established a Project Group to provide consensus definitions in the following areas: classification; inhibitors; regular factor replacement therapy (prophylaxis); bleeding (and re-bleeding) into joints and muscles; target joints; and response to therapy including surgical haemostasis.
Methods The Project Group was established on the basis of expertise in clinical care or experience in conducting major clinical trials and to provide an international perspective. In developing its recommendations, the group considered previously published definitions, other relevant
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literature and developed consensus opinion where data were inadequate. Apart from regular discussion between members, the group made presentations at several SSC and other international meetings and sought opinions from experts in academia and industry as well as patient groups. The final draft of the Project Group Report was posted on the SSC website for comments.
Classification of severity of hemophilia A and B The severity of hemophilia is currently classified based on plasma levels of factor VIII (FVIII) or IX (FIX) activity: severe if < 1%, moderate if between 1-5% and mild if > 5 and < 40% of normal. As this correlates well with clinical profiles in most cases, the Project Group recommended that this classification remain unaltered. It is recognized that a limitation of this classification is its failure to account for the clinical heterogeneity in bleeding that is observed in individuals with severe hemophilia [2], or between hemophilia A and B [3]. The classification of individuals with FVIII levels between 40-50% remains unresolved and may need to be addressed in the future.
Inhibitors Inhibitors are alloantibodies to FVIII or FIX that typically neutralize the function of infused clotting factor concentrates. Most inhibitors develop within 50 exposures [4]. An exposure is defined as any infusion of a FVIII/IX containing product in a 24 hour period. For inhibitors to be considered relevant, they should be documented on two separate occasions within a 1 to 4 week period and should have a level of > 0.6 Bethesda units (BU)/mL using the Nijmegen modification of the Bethesda assay [5]. This modification of the standard Bethesda assay was
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recommended by the Subcommittee on FVIII and FIX of the Scientific and Standardization Commmittee of the International Society on Thrombosis and Haemostasis at their meetings in 1996 [6]. Given the significant coefficient of variation of this assay [7], the Project Group recommended this value rather than a lower value of 0.5 BU but added that for inhibitors to be considered clinically significant, they should be associated with < 66% recovery of the particular product [8] on a blood sample obtained 10-15 minutes after completion of the factor infusion [9]. To take note of inhibitors that do not persist, a transient inhibitor is defined as a positive inhibitor that drops below the definition threshold within 6 months of initial documentation despite continuing antigenic challenge with FVIII or FIX. Patients whose inhibitor levels fall below 0.6 BU/mL but who show an inadequate clinical response to factor replacement therapy should have a pharmacokinetic study performed. A terminal half-life (t1/2) below 7 hours for conventional FVIII clotting factor concentrates should be considered as abnormal, and consistent with on-going inhibitory activity in the patient [8]. In the absence of any data suggesting otherwise, the Project Group proposed to retain the current definition of low (≤ 5 BU/mL) and high response (> 5 BU/mL) inhibitors. To avoid masking of low level inhibitors due to recent factor infusions, an infusion free period (“washout”) of at least 48 hours (FVIII deficient cases) or 72 hours (FIX deficient cases) is recommended prior to inhibitor testing allowing for at least five half-lives at the lower limit of normal of each factor to allow for its elimination. If this is not possible in patients receiving frequent infusions of FVIII/IX, test plasma should be pre-heated to inactivate any residual FVIII/IX before inhibitor testing is performed [10,11]. Clotting Factor replacement therapy All treatment with clotting factors in any form should be called replacement therapy. This may be on an episodic (“on-demand”) basis to treat bleeds or on a regular basis to avoid bleeds
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(Table 1). The latter has been termed prophylaxis [12]. Several definitions of prophylaxis have been proposed [13-15]. The Project Group proposed definitions for all clotting factor replacement therapy as presented in Table 1 taking into account relevant existing literature [1318]. Reference to frequency of infusions was avoided since the new long-acting clotting factor concentrates may be given less frequently for equivalent protection.
Joint bleeds Features of an acute joint bleed include some or all of the following: “aura”, pain, swelling, warmth over the joint, and decreased range of motion compared to baseline or loss of function. In patients with advanced arthropathy it may be difficult to distinguish pain-related arthritis from that associated with an acute bleed. Rapid resolution of pain following infusion of factor concentrates (typical of an acute hemarthrosis) or improvement of pain associated with activity soon after a period of rest (typical of chronic arthritis) can help distinguish between the two. While recognizing the subjective interpretation of some of these symptoms, the Project Group suggested the following definition for a joint bleed: an unusual sensation (“aura”) in the joint, in combination with any of the following: a) increasing swelling or warmth of the skin over the joint; b) increasing pain or c) progressive loss of range of motion or difficulty in using the limb as compared with baseline. In infants and young children, reluctance to use the limb alone may be indicative of a joint/muscle bleed.
Target joint A number of definitions for a target joint have been proposed by the Center for Diseases Control (CDC) Universal Data Collection (UDC) Program [19], the PEDNET (European Paediatric
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Network for Haemophilia Management) Group [13] and the Canadian Consensus Definition Group [14] all of which define a target joint as one in which at least 3 or 4 bleeds have occurred within a 3-6 month period. Such a joint is no longer considered a target joint when there has been no bleeding into that joint for 12 months. The definition of a target joint proposed by the Project Group is as follows: 3 or more spontaneous bleeds into a single joint within a consecutive 6 month period. Where there have been ≤ 2 bleeds into the joint within a consecutive 12 month period the joint is no longer considered a target joint.
Muscle bleeds Muscle bleeds can be difficult to diagnose. The Project Group proposed the following definition for a muscle bleed: an episode of bleeding into a muscle, determined clinically and/or by imaging studies, generally associated with pain and/or swelling and loss of movement over baseline. New bleed The definition of re-bleeding proposed by the PEDNET Group is endorsed by the Project Group and forms the foundation for the proposed definition of a new bleed, as follows: after an initial moderate to excellent response to treatment (as defined below), a new bleed is defined as a bleed occurring greater than 72 hours after stopping treatment for the original bleed for which treatment was initiated [13]. Response to treatment – acute hemarthrosis/muscle bleed and surgical hemostasis The assessment of response to treatment with clotting factor concentrates for the prevention/treatment of bleeding is challenging and not currently standardized. For the assessment of response to treatment of an acute hemarthrosis/muscle bleed and for surgical
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hemostasis, based on recently used definitions in clinical trials and after extensive discussions on these subjects, the Project Group has proposed definitions that are aimed at making them more objective and standardized. Proposed definitions are detailed in Table 2. Surgical procedures may be classified as major or minor depending on whether the planned duration of haemostatic support is more or less than 5 consecutive days.
Summary Consistent use of the definitions proposed in this Report from the Factor VIII, Factor IX and Rare Coagulation Disorders Subcommittee of the SSC of the ISTH will facilitate uniform documentation of outcomes in clinical studies, and will allow better comparison of data between different hemophilia treatment centers and clinical studies.
Addendum V. S. Blanchette participated in discussions of the Project Group, reviewed opinions from external consultants and assisted with preparation of all versions of the manuscript. A. Srivastava initiated the project, participated in discussions of the Project Group, reviewed opinions from external consultants and assisted with preparation of all versions of the manuscript. N. S. Key participated in discussions of the Project Group and reviewed and provided comments regarding the multiple versions of the manuscript. L. R. Ljung participated in discussions of the Project Group and reviewed and provided comments regarding the multiple versions of the manuscript. M. J. Manco-Johnson participated in discussions of the Project Group and reviewed and provided comments regarding the multiple versions of the manuscript. H. M. Van Den Berg participated in discussions of the Project Group and reviewed and provided comments regarding the multiple versions of the manuscript.
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All authors reviewed and approved the final submitted version of the Definitions in Hemophilia manuscript.
Acknowledgements The authors wish to express their gratitude to Alessandro Gringeri, Donna Di Michele, David Lillicrap, Nisha Jain, Anneliese Hilger, Connie Miller, Mike Soucie and several other scientific colleagues in academia and Industry for their useful input which helped prepare the final recommendations that were developed by the Project Group and that are presented in this SSC communication.
Conflicts of Interest A. Srivastava reports receiving fees for participation in educational symposia and advisory boards from Bayer, Baxter, Novo Nordisk, Pfizer and Biotest, and grant support from the Bayer Hemophilia Awards program.
V. Blanchette reports receiving consulting, lecture and advisory board fees from Bayer, Baxter, Biotest, Novo Nordisk and Pfizer, and grant support from CSL-Behring and Baxter. He is Chairman of the International Prophylaxis Study Group that is funded by grants from Bayer, Baxter, CSL-Behring, Novo Nordisk and Pfizer.
N. Key reports receiving fees for participation as a member of Data Safety Monitoring Boards for Bayer and CSL-Behring and a grant from Baxter Bioscience. He is Chairman of the Access Insight Grants Committee funded by Novo Nordisk.
M. Manco-Johnson reports receiving fees for participation in advisory boards for Baxter, Bayer, Biogen Idec, CSL-Behring and Novo Nordisk and grant support from Bayer Healthcare and CSLBehring.
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M. van den Berg reports receiving lecture fees from Bayer, Baxter, Novo Nordisk and Pfizer and grant support from Bayer, Baxter and Novo Nordisk. She serves as a clinical expert to the European Medicine Agency.
R. Ljung reports receiving fees for participating in educational symposia and advisory boards for Novo Nordisk, Baxter, Bayer, Octapharma and grant support from Bayer and Baxter.
References
1. White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J, on behalf of the 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.
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Aledort LM, Haschmeyer RH, Pettersson H and the Orthopaedic Outcome Study Group.
A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. J Intern Med 1994: 236: 391-9.
3. Tagariello G, Iorio A, Santagostino E, Morfini M, Bisson R, Innocenti M, Mancuso ME, Mazzucconi MG, Pasta GL, Radossi P, Rodorigo G, Santoro C, Sartori R, Scaraggi A, Solimeno LP, Mannucci PM on behalf of the 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: 779-84.
4. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003 9: 418-35.
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5. Verbruggen B, Novakova I, Wessels H, Boezeman J, van den Berg M, MauserBunschoten E. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost 1995; 73: 247-51.
6. Giles AR, Verbruggen B, Rivard GE, Teitel J, Walker I and the Association of Hemophilia Centre Directors of Canada. On behalf of the Factor VIII/IX Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 1998; 79: 872-5.
7. Meijer P, Verbruggen B. The between-laboratory variation of factor VIII inhibitor testing: the experience of the external quality assurance program of the ECAT Foundation. Sem Thromb Haemost 2009; 35: 786-93.
8. Collins PW, Chalmers E, Hart DP, Liesner R, Rangarajan S, Talks K, Williams M, Hay CR. Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition). Br J Haematol 2013: 160; 153-70.
9. Bjorkman S, Carlsson M, Berntorp E, Stenberg P. Pharmacokinetics of Factor VIII in humans. Obtaining clinically relevant data from comparative studies. Clin Pharmacokinet 1992: 22: 385-95.
10. Dardikh M, Albert T, Masereeuw R, Oldenburg J, Novakova I, Van Heerde WL, Verbruggen B. Low-titre inhibitors, undetectable by the Nijmegen assay, reduce factor VIII halflife after immune tolerance induction. J Thromb Haemost 2012; 10: 706-8.
11. Miller CH, Platt SJ, Rice AS, Kelly F, Soucie JM and the Hemophilia Inhibitor Research Study Investigators. Validation of the Nijmegen-Bethesda assay modifications to allow inhibitor measurement during replacement therapy and facilitate inhibitor surveillance. J Thromb Haemost 2012; 10: 1055-61.
12. Berntorp E, Astermark J, Bjőrkman S, Blanchette VS, Fischer K, Giangrande PLF, Gringeri A, Ljung RC, Manco-Johnson MJ, Morfini M, Kilcoyne RF, Petrini P, Rodriguez Merchan EC, Schramm W, Shapiro A, van den Berg HM, Hart C. Consensus perspectives on prophylactic therapy for haemophilia: summary statement. Haemophilia 2003; 9 (Suppl.1): 1-4.
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13 . Donadel-Claeyssens S, on behalf of the European Paediatric Network for Haemophilia Management. Current co-ordinated activities of the PEDNET (European Paediatric Network for Haemophilia Management). Haemophilia 2006; 12: 124-7.
14 . Ota S, McLimont M, Carcao MD, Blanchette VS, Graham N, Paradis E, Feldman BM. Definitions for haemophilia prophylaxis and its outcomes: The Canadian Consensus Study. Haemophilia 2007; 13: 12-20.
15 . Gringeri A, Lambert T, Street A, Aledort L. Tertiary prophylaxis in adults: Is there a rationale? Haemophilia 2012; 18: 727-8.
16. Fischer K, van den Bom JG, Mauser-Bunschoten EP, Rosendaal G, Prejs R, de Kleijn P, Grobbee DE, van den Berg M. The effects of postponing prophylactic treatment on long-term outcome in patients with severe hemophilia. Blood 2002; 99: 2337-41.
17. Gringeri A, Lundin B, Von Mackensen S, Mantovani L, Mannucci M, and the Esprit Study Group. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 2011; 9: 700-10.
18. 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, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357: 535-44.
19. 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.1): 19-26.
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Table 1 Definitions of replacement therapy with clotting factor concentrates
Factor replacement therapy
Definition
Episodic (“on demand”) replacement therapy
Replacement therapy given at the time of clinically evident bleeding
Regular replacement therapy
Replacement therapy given to prevent bleeding
•
Primary prophylaxis
•
Secondary prophylaxis
Regular continuous* replacement therapy started after 2 or more joint bleeds but before the onset of joint disease documented by physical examination and/or imaging studies
•
Tertiary prophylaxis
Regular continuous* replacement therapy started after the onset of joint disease documented by physical examination and plain radiographs of the affected joints
Intermittent (“periodic”) prophylaxis
Regular continuous* replacement therapy started in the absence of documented joint disease, determined by physical examination and/or imaging studies, and before the second clinically evident joint bleed and age 3 years
Replacement therapy given to prevent bleeding for periods not exceeding 45 weeks in a year
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* continuous is defined as the intent of treating for 52 weeks/year and receiving a minimum of an a priori defined frequency of infusions for at least 45 weeks (85%) of the year under consideration.
Table 2a: Assessment of treatment of acute joint / muscle bleeds*
Category
Response
Excellent
Complete pain relief within 8 hours and/or complete resolution of signs of bleeding after the initial injection and not requiring any further replacement therapy for relief of persistent symptoms and signs in the same joint within 72 hours
Good
Significant pain relief and/or improvement in signs of bleeding within approximately 8 hours after a single injection, but requiring more than one dose of replacement therapy within 72 hours for complete resolution
Moderate
Modest pain relief and/or improvement in signs of bleeding within approximately 8 hours after the initial injection and requiring more than one injection within 72 hours but without complete resolution
None
None or minimal improvement, or condition worsens, within approximately 8 hours after the initial injection
*Modifications may be required for studies where patients receive a priori multidose clotting factor concentrates infusions for treatment of acute joint/muscle bleeds as part of an enhanced episodic treatment program (18,19). However, outcomes after the first dose should be recorded and reported.
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Table 2b: Assessment of hemostatic response for surgical procedures* Category
Response
Excellent
Intra-operative and post-operative blood loss similar (within 10%) to the non-hemophilic patient with no extra (unplanned) doses of FVIII/FIX/ “bypassing agents” needed and blood component transfusions are similar to the non-hemophilic patient
Good
Intra-operative and/or post-operative blood loss slightly increased over expectation for the non-hemophilic patient (between 10-25% of expected), but the difference is judged by the involved surgeon/anaesthetist/relevant health care professional to be clinically insignificant as evidenced by no extra (unplanned) doses of FVIII/FIX/ ”bypassing agents” needed and blood component transfusions are similar to the non-hemophilic patient
Fair
Intra-operative and/or post-operative blood loss increased over expectation (25-50%) for the non-hemophilic patient and additional treatment is needed such as extra (unplanned) doses of FVIII/FIX/ ”bypassing agents” or increased blood component use (within 2 fold) of the anticipated transfusion requirement
Poor
Significant intra-operative and/or post-operative blood loss that is substantially increased over expectation (> 50%) for the non-hemophilic patient, requires intervention, and is not explained by a surgical/medical issue other than hemophilia, unexpected hypotension or unexpected transfer to an Intensive Care Unit due to bleeding or substantially increased blood component use (> 2 fold) of the anticipated transfusion requirement
* Hemostasis should be assessed by an involved surgeon and/or anaesthetist or other relevant health care professional (e.g. interventional radiologist) and reported within 72 hours following surgery. Apart from estimates of intra- and post-operative blood loss, including blood loss from drains, data on pre- and post-operative hemogloblin levels and the number of packed red blood cell units transfused should also be taken into account, if relevant, to estimate total blood loss.
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Article type
Definitions in hemophilia: communication from the SSC of the ISTH
V.S. BLANCHETTE,* N.S. KEY, † L. R. LJUNG,‡ M.J. MANCO-JOHNSON, § H.M. VAN DEN BERG, ** A. SRIVASTAVA,††
*Pediatric Thrombosis and Hemostasis Program, Hospital for Sick Children, Department of Pediatrics, University of Toronto ,Toronto, ON, Canada; †Departments of Medicine and Pathology, UNC Hemophilia and Thrombosis Center Chapel Hill, NC, USA; ‡Lund University, Department of Paediatrics and Malmo Centre for Thrombosis and Haemostasis, Skanes Universitetssjukhus, Malmo, Sweden; §Hemophilia & Thrombosis Center, Univeristy of Colorado School of Medicine, Aurora, CO, USA; **Julius Center for Health Sciences and Primary Care, UMC Utrecht, The Netherlands; ††Department of Hematology, Christian Medical College, Vellore, India
Short running title: Definitions in Hemophilia
Correspondence: Dr. Victor S. Blanchette, Division of Hematology/Oncology, The Hospital for Sick Children, 555 University Avenue,
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an 'Accepted Article', doi: 10.1111/jth.12672 This article is protected by copyright. All rights reserved.
Accepted Article
Toronto, Ontario, M5G 1X8, Canada. Tel: + 1 416 813 5852 Fax: + 1 416 813 5327 E-mail: [email protected]
Background For the documentation and comparison of outcomes of clinical care in hemophilia, especially with different treatment protocols, as well as in clinical trials of new clotting factor concentrates, it is necessary to have clear definitions of disease related variables as well as the response to therapeutic interventions that are offered to treat or prevent bleeding. In 2001, White et al provided definitions for the severity of hemophilia and the levels for low and high response inhibitors on behalf of the Factor VIII and IX Subcommittee of the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH) [1]. With increasing emphasis on assessment of outcomes and creating evidence for clinical practice in hemophilia, it became necessary to revisit definitions in hemophilia. To this end, the Factor VIII, Factor IX and Rare Coagulation Disorders Subcommittee of the SSC of the ISTH established a Project Group to provide consensus definitions in the following areas: classification; inhibitors; regular factor replacement therapy (prophylaxis); bleeding (and re-bleeding) into joints and muscles; target joints; and response to therapy including surgical haemostasis.
Methods The Project Group was established on the basis of expertise in clinical care or experience in conducting major clinical trials and to provide an international perspective. In developing its recommendations, the group considered previously published definitions, other relevant
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literature and developed consensus opinion where data were inadequate. Apart from regular discussion between members, the group made presentations at several SSC and other international meetings and sought opinions from experts in academia and industry as well as patient groups. The final draft of the Project Group Report was posted on the SSC website for comments.
Classification of severity of hemophilia A and B The severity of hemophilia is currently classified based on plasma levels of factor VIII (FVIII) or IX (FIX) activity: severe if < 1%, moderate if between 1-5% and mild if > 5 and < 40% of normal. As this correlates well with clinical profiles in most cases, the Project Group recommended that this classification remain unaltered. It is recognized that a limitation of this classification is its failure to account for the clinical heterogeneity in bleeding that is observed in individuals with severe hemophilia [2], or between hemophilia A and B [3]. The classification of individuals with FVIII levels between 40-50% remains unresolved and may need to be addressed in the future.
Inhibitors Inhibitors are alloantibodies to FVIII or FIX that typically neutralize the function of infused clotting factor concentrates. Most inhibitors develop within 50 exposures [4]. An exposure is defined as any infusion of a FVIII/IX containing product in a 24 hour period. For inhibitors to be considered relevant, they should be documented on two separate occasions within a 1 to 4 week period and should have a level of > 0.6 Bethesda units (BU)/mL using the Nijmegen modification of the Bethesda assay [5]. This modification of the standard Bethesda assay was
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recommended by the Subcommittee on FVIII and FIX of the Scientific and Standardization Commmittee of the International Society on Thrombosis and Haemostasis at their meetings in 1996 [6]. Given the significant coefficient of variation of this assay [7], the Project Group recommended this value rather than a lower value of 0.5 BU but added that for inhibitors to be considered clinically significant, they should be associated with < 66% recovery of the particular product [8] on a blood sample obtained 10-15 minutes after completion of the factor infusion [9]. To take note of inhibitors that do not persist, a transient inhibitor is defined as a positive inhibitor that drops below the definition threshold within 6 months of initial documentation despite continuing antigenic challenge with FVIII or FIX. Patients whose inhibitor levels fall below 0.6 BU/mL but who show an inadequate clinical response to factor replacement therapy should have a pharmacokinetic study performed. A terminal half-life (t1/2) below 7 hours for conventional FVIII clotting factor concentrates should be considered as abnormal, and consistent with on-going inhibitory activity in the patient [8]. In the absence of any data suggesting otherwise, the Project Group proposed to retain the current definition of low (≤ 5 BU/mL) and high response (> 5 BU/mL) inhibitors. To avoid masking of low level inhibitors due to recent factor infusions, an infusion free period (“washout”) of at least 48 hours (FVIII deficient cases) or 72 hours (FIX deficient cases) is recommended prior to inhibitor testing allowing for at least five half-lives at the lower limit of normal of each factor to allow for its elimination. If this is not possible in patients receiving frequent infusions of FVIII/IX, test plasma should be pre-heated to inactivate any residual FVIII/IX before inhibitor testing is performed [10,11]. Clotting Factor replacement therapy All treatment with clotting factors in any form should be called replacement therapy. This may be on an episodic (“on-demand”) basis to treat bleeds or on a regular basis to avoid bleeds
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(Table 1). The latter has been termed prophylaxis [12]. Several definitions of prophylaxis have been proposed [13-15]. The Project Group proposed definitions for all clotting factor replacement therapy as presented in Table 1 taking into account relevant existing literature [1318]. Reference to frequency of infusions was avoided since the new long-acting clotting factor concentrates may be given less frequently for equivalent protection.
Joint bleeds Features of an acute joint bleed include some or all of the following: “aura”, pain, swelling, warmth over the joint, and decreased range of motion compared to baseline or loss of function. In patients with advanced arthropathy it may be difficult to distinguish pain-related arthritis from that associated with an acute bleed. Rapid resolution of pain following infusion of factor concentrates (typical of an acute hemarthrosis) or improvement of pain associated with activity soon after a period of rest (typical of chronic arthritis) can help distinguish between the two. While recognizing the subjective interpretation of some of these symptoms, the Project Group suggested the following definition for a joint bleed: an unusual sensation (“aura”) in the joint, in combination with any of the following: a) increasing swelling or warmth of the skin over the joint; b) increasing pain or c) progressive loss of range of motion or difficulty in using the limb as compared with baseline. In infants and young children, reluctance to use the limb alone may be indicative of a joint/muscle bleed.
Target joint A number of definitions for a target joint have been proposed by the Center for Diseases Control (CDC) Universal Data Collection (UDC) Program [19], the PEDNET (European Paediatric
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Network for Haemophilia Management) Group [13] and the Canadian Consensus Definition Group [14] all of which define a target joint as one in which at least 3 or 4 bleeds have occurred within a 3-6 month period. Such a joint is no longer considered a target joint when there has been no bleeding into that joint for 12 months. The definition of a target joint proposed by the Project Group is as follows: 3 or more spontaneous bleeds into a single joint within a consecutive 6 month period. Where there have been ≤ 2 bleeds into the joint within a consecutive 12 month period the joint is no longer considered a target joint.
Muscle bleeds Muscle bleeds can be difficult to diagnose. The Project Group proposed the following definition for a muscle bleed: an episode of bleeding into a muscle, determined clinically and/or by imaging studies, generally associated with pain and/or swelling and loss of movement over baseline. New bleed The definition of re-bleeding proposed by the PEDNET Group is endorsed by the Project Group and forms the foundation for the proposed definition of a new bleed, as follows: after an initial moderate to excellent response to treatment (as defined below), a new bleed is defined as a bleed occurring greater than 72 hours after stopping treatment for the original bleed for which treatment was initiated [13]. Response to treatment – acute hemarthrosis/muscle bleed and surgical hemostasis The assessment of response to treatment with clotting factor concentrates for the prevention/treatment of bleeding is challenging and not currently standardized. For the assessment of response to treatment of an acute hemarthrosis/muscle bleed and for surgical
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hemostasis, based on recently used definitions in clinical trials and after extensive discussions on these subjects, the Project Group has proposed definitions that are aimed at making them more objective and standardized. Proposed definitions are detailed in Table 2. Surgical procedures may be classified as major or minor depending on whether the planned duration of haemostatic support is more or less than 5 consecutive days.
Summary Consistent use of the definitions proposed in this Report from the Factor VIII, Factor IX and Rare Coagulation Disorders Subcommittee of the SSC of the ISTH will facilitate uniform documentation of outcomes in clinical studies, and will allow better comparison of data between different hemophilia treatment centers and clinical studies.
Addendum V. S. Blanchette participated in discussions of the Project Group, reviewed opinions from external consultants and assisted with preparation of all versions of the manuscript. A. Srivastava initiated the project, participated in discussions of the Project Group, reviewed opinions from external consultants and assisted with preparation of all versions of the manuscript. N. S. Key participated in discussions of the Project Group and reviewed and provided comments regarding the multiple versions of the manuscript. L. R. Ljung participated in discussions of the Project Group and reviewed and provided comments regarding the multiple versions of the manuscript. M. J. Manco-Johnson participated in discussions of the Project Group and reviewed and provided comments regarding the multiple versions of the manuscript. H. M. Van Den Berg participated in discussions of the Project Group and reviewed and provided comments regarding the multiple versions of the manuscript.
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All authors reviewed and approved the final submitted version of the Definitions in Hemophilia manuscript.
Acknowledgements The authors wish to express their gratitude to Alessandro Gringeri, Donna Di Michele, David Lillicrap, Nisha Jain, Anneliese Hilger, Connie Miller, Mike Soucie and several other scientific colleagues in academia and Industry for their useful input which helped prepare the final recommendations that were developed by the Project Group and that are presented in this SSC communication.
Conflicts of Interest A. Srivastava reports receiving fees for participation in educational symposia and advisory boards from Bayer, Baxter, Novo Nordisk, Pfizer and Biotest, and grant support from the Bayer Hemophilia Awards program.
V. Blanchette reports receiving consulting, lecture and advisory board fees from Bayer, Baxter, Biotest, Novo Nordisk and Pfizer, and grant support from CSL-Behring and Baxter. He is Chairman of the International Prophylaxis Study Group that is funded by grants from Bayer, Baxter, CSL-Behring, Novo Nordisk and Pfizer.
N. Key reports receiving fees for participation as a member of Data Safety Monitoring Boards for Bayer and CSL-Behring and a grant from Baxter Bioscience. He is Chairman of the Access Insight Grants Committee funded by Novo Nordisk.
M. Manco-Johnson reports receiving fees for participation in advisory boards for Baxter, Bayer, Biogen Idec, CSL-Behring and Novo Nordisk and grant support from Bayer Healthcare and CSLBehring.
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Accepted Article
M. van den Berg reports receiving lecture fees from Bayer, Baxter, Novo Nordisk and Pfizer and grant support from Bayer, Baxter and Novo Nordisk. She serves as a clinical expert to the European Medicine Agency.
R. Ljung reports receiving fees for participating in educational symposia and advisory boards for Novo Nordisk, Baxter, Bayer, Octapharma and grant support from Bayer and Baxter.
References
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5. Verbruggen B, Novakova I, Wessels H, Boezeman J, van den Berg M, MauserBunschoten E. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost 1995; 73: 247-51.
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13 . Donadel-Claeyssens S, on behalf of the European Paediatric Network for Haemophilia Management. Current co-ordinated activities of the PEDNET (European Paediatric Network for Haemophilia Management). Haemophilia 2006; 12: 124-7.
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Table 1 Definitions of replacement therapy with clotting factor concentrates
Factor replacement therapy
Definition
Episodic (“on demand”) replacement therapy
Replacement therapy given at the time of clinically evident bleeding
Regular replacement therapy
Replacement therapy given to prevent bleeding
•
Primary prophylaxis
•
Secondary prophylaxis
Regular continuous* replacement therapy started after 2 or more joint bleeds but before the onset of joint disease documented by physical examination and/or imaging studies
•
Tertiary prophylaxis
Regular continuous* replacement therapy started after the onset of joint disease documented by physical examination and plain radiographs of the affected joints
Intermittent (“periodic”) prophylaxis
Regular continuous* replacement therapy started in the absence of documented joint disease, determined by physical examination and/or imaging studies, and before the second clinically evident joint bleed and age 3 years
Replacement therapy given to prevent bleeding for periods not exceeding 45 weeks in a year
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* continuous is defined as the intent of treating for 52 weeks/year and receiving a minimum of an a priori defined frequency of infusions for at least 45 weeks (85%) of the year under consideration.
Table 2a: Assessment of treatment of acute joint / muscle bleeds*
Category
Response
Excellent
Complete pain relief within 8 hours and/or complete resolution of signs of bleeding after the initial injection and not requiring any further replacement therapy for relief of persistent symptoms and signs in the same joint within 72 hours
Good
Significant pain relief and/or improvement in signs of bleeding within approximately 8 hours after a single injection, but requiring more than one dose of replacement therapy within 72 hours for complete resolution
Moderate
Modest pain relief and/or improvement in signs of bleeding within approximately 8 hours after the initial injection and requiring more than one injection within 72 hours but without complete resolution
None
None or minimal improvement, or condition worsens, within approximately 8 hours after the initial injection
*Modifications may be required for studies where patients receive a priori multidose clotting factor concentrates infusions for treatment of acute joint/muscle bleeds as part of an enhanced episodic treatment program (18,19). However, outcomes after the first dose should be recorded and reported.
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Table 2b: Assessment of hemostatic response for surgical procedures* Category
Response
Excellent
Intra-operative and post-operative blood loss similar (within 10%) to the non-hemophilic patient with no extra (unplanned) doses of FVIII/FIX/ “bypassing agents” needed and blood component transfusions are similar to the non-hemophilic patient
Good
Intra-operative and/or post-operative blood loss slightly increased over expectation for the non-hemophilic patient (between 10-25% of expected), but the difference is judged by the involved surgeon/anaesthetist/relevant health care professional to be clinically insignificant as evidenced by no extra (unplanned) doses of FVIII/FIX/ ”bypassing agents” needed and blood component transfusions are similar to the non-hemophilic patient
Fair
Intra-operative and/or post-operative blood loss increased over expectation (25-50%) for the non-hemophilic patient and additional treatment is needed such as extra (unplanned) doses of FVIII/FIX/ ”bypassing agents” or increased blood component use (within 2 fold) of the anticipated transfusion requirement
Poor
Significant intra-operative and/or post-operative blood loss that is substantially increased over expectation (> 50%) for the non-hemophilic patient, requires intervention, and is not explained by a surgical/medical issue other than hemophilia, unexpected hypotension or unexpected transfer to an Intensive Care Unit due to bleeding or substantially increased blood component use (> 2 fold) of the anticipated transfusion requirement
* Hemostasis should be assessed by an involved surgeon and/or anaesthetist or other relevant health care professional (e.g. interventional radiologist) and reported within 72 hours following surgery. Apart from estimates of intra- and post-operative blood loss, including blood loss from drains, data on pre- and post-operative hemogloblin levels and the number of packed red blood cell units transfused should also be taken into account, if relevant, to estimate total blood loss.
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