Table 1. Bleeding phenotype.

Bleeding phenotype
➢ Defined by severity, number, and spontaneity of bleeds
➢ Influenced by:
Genetic factors:
- Directly: F8 / F9 variants
- Indirectly: variants influencing procoagulant/anticoagulant pathways, joint bleeding-triggered inflammatory processes, and pharmacokinetics of factor concentrates
Nongenetic factors:   - Physical activity (type, level)   - Functional ability/physical coordination (e.g., strength, flexibility, stability, etc.)   - Risk-taking behaviors   - Muscle/joint status   - Occurrence of trauma
➢ Assessed by:
- HSS, a composite score of the sum of 3 components: 12 a
o Bleeding score: average value of annual incidence of joint bleeds in the last 10 years divided by 20
o Joint score: last score obtained during the 10-year period divided by the maximum possible score of 86 (patient examined independently by one physician and one physiotherapist) b
o Factor score: average annual amount of factor used during the 10-year period divided by mean body weight in that period and divided by 6 kIU/kg (maximum consumption of regular prophylaxis) c
- Severity scoring system of the ISTH-SCC, whose severity criteria are: 13 d
o First spontaneous bleeding before age 6 months, 2 points
o Spontaneous joint bleeding before age 2 years, 2 points
o Unprovoked intracranial hemorrhage, 3 points
o Spontaneous s.c. hematomas: at least one palm-sized or multiple (> 3) coin-sized, 1 point
A phenotype is severe when a score > 3 is reached by the age of 3 years
- Global hemostasis assessment methods (validation pending) 14
Limitations and unmet needs
➢ There is no reliable score to assess severity of bleeding: HSS requires 10 years of data collection and does not use imaging techniques to assess joint status; ISTH-SSC score considers neither joint status nor physical activity and requires availability of bleeding data from earliest childhood
➢ There is an urgent need to establish a consensus concept of severe bleeding phenotype in patients on prophylaxis so that specific guidelines for therapy adjustment can be developed

Abbreviations: HSS, Hemophilia Severity Score; ISTH-SSC, Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis; ln, natural logarithm; s.c., subcutaneous.

^aEach component has a maximum value of 1. Worst composite value is 3.

^b Requires adjustment by the age at the start of prophylaxis: the joint score is multiplied by log(age at start of prophylaxis + 10) ⁻¹ . Age is set at 50 for those never in prophylaxis beforehand.

^c Requires adjustment for late start of prophylaxis: the factor score is multiplied by ln(age at start of prophylaxis + 1.72) ⁻¹ .

^dThese criteria are the result of a consensus reached during the ISTH-SSC meeting that was held in Toronto (Canada) in 2015.