Abstract Number: PB1002
Meeting: ISTH 2020 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical
Background: Hemophilia A (HA) severity is traditionally determined by clotting factor VIII (FVIII) levels, but up to 15% of individuals with severe hemophilia A (sHA, FVIII < 1%) have paradoxically mild clinical phenotypes. The Identification of these individuals is complicated by the lack of standardized methods for clinical phenotyping and the early initiation of prophylaxis that modifies phenotype. Identifying individuals with FVIII < 1% and a mild clinical phenotype may spare them from the burden of unnecessary treatment and reduce treatment cost, and studying this group of patients may lead to identification of novel genetic modifiers of bleeding and thrombosis.
Aims: To systematically review the literature of sHA for mild clinical phenotypes.
Methods: We conducted a systematic literature review of PubMed for publications from 1980 through 2020 with the search terms hemophilia A and phenotype. The reference lists of studies with relevant data were also reviewed. We extracted data on clinical phenotypes that may distinguish mild bleeders from non-mild bleeders in the era of prophylaxis.
Results: Our initial search yielded 434 studies. Nine clinical phenotype metrics were identified. Most of these do not account for treatment intensity or adherence, or pharmacokinetics, and none account for hemostatic risk behavior or inhibitor status. Additional characteristics of each metric are listed in table 1. The phenotype metrics varied widely based on the depth and complexity of phenotypic assessment and variations in the populations to which they apply.
Conclusions: There are limited data to identify and study patients with sHA and a mild clinical phenotype. Among the clinical phenotype metrics that were identified, there is wide methodological variation, evidenced by divergent assessment tools and non-standardized concepts. The lack of standardized methods for clinical phenotyping of sHA is a major obstacle to improved understanding and treatment and thus improved standardization is essential for further evaluation of this important patient population.
| Clinical phenotype metric | Measure of phenotype | Accounts for PPX intensity | Accounts for PPX PK and adherence | Effect of recall bias | Comments and reference |
| ISTH-BAT score | Composite score | – | – | +++ | Not validated in PPX-treated sHA. May lack power to differentiate mild from non-mild clinical phenotypes due to saturation of the score even with mild bleeding symptoms. Borhany et al., Transfus Apher Sci. 2018;57(4):556. |
| Hemophilia severity score | Composite score | + | – | +++ | Calculation of score is complex. Schulman et al., J Thromb Haemost. 2008 Jul;6(7):1113. |
| Age at first joint bleed before the initiation of PPX | Age (years) | N/A | N/A | + | Applicable only if PPX is initiated after the first bleeding event. Carcao et al. Blood. 2013;121(19):3946. |
| Joint severity score | Composite score | – | – | + | Affected by factors other than bleeding (e.g. inflammatory reaction). Aledort et al., J Intern Med. 1994 Oct;236(4):391. |
| Breakthrough bleeding event rate | Number of events per year | – | – | ++ | Bleeding events on PPX are very low in most individuals and the event rate may be affected by PPX dose or frequency adjustments in response to bleeding. Gringeri et al., J Thromb Haemost. 2011 Apr;9(4):700. |
| Breakthrough bleeding event rate with trough level-adjusted PPX | Number of events per year | + | + | ++ | Bleeding events on PPX are very low in most individuals and the event rate may be affected by PPX dose or frequency adjustments in response to bleeding or low trough levels. Petrini et al., Haemophilia. 2001;7(1):99. |
| Lowest intensity PPX regimen (dose and frequency) with no breakthrough bleeding events | Dosing regimen | + | – | + | Applicable only to dose-escalated PPX-treated individuals. Feldman et al., Lancet Haematol. 2018 Jun;5(6):e252. |
| FVIII consumption | FVIII consumption (IU/kg) per year | + | – | ++ | Van dijk et al., Haemophilia 2005;11:438. |
| Bleeding event rate after stopping prophylaxis | Number of events per year | N/A | N/A | + | Applicable only in patients who discontinue prophylaxis, such as adults. Fischer et al., Haemophilia. 2001;7:544. |
[Clinical phenotypes that may identify individuals with FVIII <1% and mild bleeding in the era of prophylaxis. PPX-prophylaxis. PK-pharmacokinetics.]
To cite this abstract in AMA style:
Bentur OS, Coller BS. Dissecting the Paradox of “Severe” Hemophilia A (Clotting Factor VIII < 1%) with a Mild Clinical Phenotype in the Era of Prophylaxis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/dissecting-the-paradox-of-severe-hemophilia-a-clotting-factor-viii-1-with-a-mild-clinical-phenotype-in-the-era-of-prophylaxis/. Accessed September 29, 2023.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/dissecting-the-paradox-of-severe-hemophilia-a-clotting-factor-viii-1-with-a-mild-clinical-phenotype-in-the-era-of-prophylaxis/