Definitions in hemophilia: communication from the SSC of the ISTH

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. 1 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). 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 hemostasis. 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 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. 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 and 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 and 50% remains unresolved and may need to be addressed in the future. 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-h period. For inhibitors to be considered relevant, they should be documented on two separate occasions within a 1–4 week period and should have a level of ≥ 0.6 Bethesda units (BU) per mL using the Nijmegen modification of the Bethesda assay 5. This modification of the standard Bethesda assay was recommended by the Subcommittee on FVIII and FIX of the Scientific and Standardization Committee 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 min 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−1 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 h 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−1) and high response (> 5 BU mL−1) inhibitors. To avoid masking of low level inhibitors due to recent factor infusions, an infusion-free period ‘washout’ of at least 48 h (FVIII-deficient cases) or 72 h (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. 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 (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 therapies as presented in Table 1, taking into account relevant existing literature 13-18. Reference to frequency of infusions was avoided because the new long-acting clotting factor concentrates may be given less frequently for equivalent protection. 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 with 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. 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 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 three or four 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: three 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 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. 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 > 72 h after stopping treatment for the original bleed for which treatment was initiated 13. 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 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 hemostatic support is more or < 5 consecutive days. 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. 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. All authors reviewed and approved the final submitted version of the Definitions in Hemophilia manuscript. The authors wish to express their gratitude to A. Gringeri, D. Di Michele, D. Lillicrap, N. Jain, A. Hilger, C. Miller, M. 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. 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 CSL-Behring. 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 and Octapharma and grant support from Bayer and Baxter.