A Systematic Review of Definitions and Reporting of Bleeding Outcome Measures in Hemophilia

Chatree Chai-Adisaksopha, Christopher M. Hillis, Lehana Thabane and Alfonso Iorio


Background: Bleeding frequency is an important outcome commonly used in hemophilia studies. There is variation in practice in how bleeding is measured and defined. We therefore performed a systematic review of the studies reporting bleeding frequency in hemophilia patients.

Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Control Trials were searched from January 1990 to January 2014. We included all published studies that included patients with hemophilia A and/or B and reported some measure of bleeding. Two reviewers independently performed title and abstract screening, full-text review and data abstraction of the identified studies.

Results: A total of 118 studies fulfilled the inclusion criteria. Study designs were randomized controlled trials [RCT] (16/118: 14%), cohort (80/118: 68%), cross-sectional (6/118: 5%) and others design (13/118: 11%). The median duration of follow-up (first quartile [Q1], third quartile [Q3]) was 20 (7.9, 50) months. Joint bleeding is the most common site of reported bleeding (66.9%). We found 10 different bleeding outcomes reported (absolute number of bleeding 60 (50.8%) studies, annualized bleeding rate 60 (50.8%) studies, bleed per month 10 (8.5%) studies and others (bleed per patient-year, bleed per week, bleed per season, etc.) 11 (9.3%) studies). Of these, 32 studies (27%) reported only mean or median without dispersion and 33 (28%) studies did not report any measures of central tendency (dispersion).

Conclusions: There is substantial variation in definitions and measures of bleeding outcomes in the hemophilia literature. This creates difficulty and limitations in comparing the outcomes between studies and in performing meta-analysis. The hemophilia research community needs to develop a consensus definition of bleeding and how to address the limitations associated with variations in measures of bleeding between centers and studies.

Bleeding outcome measuresn , (%)
1. Bleeding frequency#
Absolute number of bleeds60 (50.8)
Annualized bleeding rate60 (50.8)
Bleed per month10 (8.5)
Bleed per 100 days4 (3.4)
Others (bleed per patient-year, bleed per week, bleed per 5 years, etc.)11 (9.3)
2. Central tendency and dispersion#
Mean with standard deviation33 (28.0)
Median with range or interquartile range35 (27.0)
Only mean or median32 (27.1)
Not reported33 (28.0)
Table 1.

Measures of bleeding frequency used in the studies

#Studies could include more than one level of characteristics.

Disclosures No relevant conflicts of interest to declare.

  • * Asterisk with author names denotes non-ASH members.