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G. Castaman and D. Matino et al.
ical studies have now provided several lines of evidence of the ability of FIX to distribute extravascularly,37 of binding to the extracellular matrix38 (and in particular to type IV collagen39), an in vivo effect of the binding to collagen IV,40 and of tissue distribution of FIX.41 Although there is some
evidence of tissue distribution in humans,42,43 in hemophil- ia patients, the extravascular compartment is not readily accessible and further studies are needed in order to obtain robust evidence of the clinical impact of these specific characteristics of FIX.
Table 1. Summary of main clinical findings reported in the studies.
Patients with severe hemophilia
Patients with moderate hemophilia
Ludlam et al.19a
N of patients
Hospital admission rate (bed days/pt/year)
Biss et al.21
N of patients
N of patients receiving prophylaxis (%)
Schulman et al.15
N of patients
Bleeding score, median (IQR) Joint score, median (IQR) Factor score, median (IQR) HSS, median (IQR)
Tagariello et al.17
N of patients
Rate of patients undergoing arthroplasty, % (95% CI) Odds of undergoing arthroplasty, OR (95% CI)
Den Uijl et al.
N of patients 29
Incidence of arthroplasty (%)
st th th
Age at 1 treatment (years), medians (5 -95 percentiles)
st th th
Age at 1 joint bleed (years), medians (5 -95 percentiles)
Patients on prophylaxis, N (%) Annualjointbleedingfrequency,medians(5-95 percentiles)
Hemophilia A
99 7.3
681
424/617 (32)
37
0.15 (0.1–0.25) 0.079 (0.033–0.144) 0.15 (0.086–0.267) 0.50 (0.41–0.68)
1770
14.3% (12.7%-15.9%) 3.38 (1.97-5.77)
252
78 (31%) 1.1 (0.2-2.7) 1.9 (0.5-5.9) 194 (77%) 4.3(0.3-16.3) 1560 (286-3644)
61
15 (25) 12 (12–36) 24 (24–48) 11 (2–25)
582
0.42 (3 days–0.88) 0.81(0.43–1.11) 0.82 (0.50–1.12) 105 (17.5) 1280 (369–2170) 13 (6–20)
28 (20–45)
58 2 800 1 491
70
11 (15.7) 16 (22.8) 43 (61.4) 6.81±3.99 36.6±21.6 10.91±4.05
Hemophilia B
24 3.1o
Hemophilia A
69 3.5
250
43/244 (18)
21
0.05 (0–0.15) 0.020 (0–0.033) 0.004 (0.001–0.015) 0.073 (0.024–0.253)
Na Na Na
Na Na Na Na Na Na Na
Na Na Na Na Na
97
0.77 (2 days–1.62) 1.42(0.90–2.92) 1.47 (0.98–2.82) 34 (34.7)
Na
Na
Na
10 138 Na
Na
Na Na Na
Hemophilia B
33 2.1o
th th Annual factor use (IU Kg-1) , medians (5 -95
Santagostino et al.
N of patients 3
Mild bleeding phenotype, N (%)
Median age at first bleed, months (IQR) Median age at first joint bleed, months (IQR) Median number of bleeds per year (IQR)
percentiles)
42/131 (32) o 6
9/187 (5) o 8
134
188
0.12 (0.6–0.19) T 0.057 (0.024–0.122) T 0.039 (0.028–0112)* 0.29 (0.23–0.45)*
0.05 (0.019–0.11) T 0.054 (0.016–0.096) T 0.004 (0.002–0.011) T 0.115 (0.039–0.349) T
th th
319
4.7% (2.4%-7.0%) 1**
30o
9 (30%)T
1.3 (0.6-2.9) T 2.4 (0.9-5.5) T 22 (73%)T 3.8(0.4-17.8)T 1260 (302-5826) T
11o
7 (64) *
24 (12–48) T 66 (51–102) ** 0 (0–12)*
76
0.43 (0 days–0.88)T 0.88(0.60–1.18)T 0.88 (0.60–1.19)T 12 (15.4)T
333 (38–487)** 5 (2–9)*
23 (9–31) T
15 502o 332o
35
15 (42.9) ** 3 (8.5) ** 17 (48.6)* 5.64±4.02T 20.2±14.6** 4.34±3.39**
Na Na Na
Na Na Na Na Na Na Na
Na Na Na Na Na
26o
2.5 days (0 days–1.17)T 1.74(0.99–4.10)T 1.76 (0.94–3.23)T 15 (57.7)*
Na
Na
Na
5o 16o Na
Na
Na Na Na
Clausen et al.
N of patients 23
Age at diagnosis (years) Ageat1 treatment
st
Age at 1st bleed
Patients without bleeding without prophylaxis < 2 years of age, N Median factor (IU Kg-1/year) (IQR)
Median orthopedic joint score (range)
Median Pettersson score (range)
Nagel et al.14
N of patients
Total bleeds over 36 months, N Joint bleeds, N
Melchiorre et al.26
N of patients Hemarthrosis, N (%)
<10 10-50 >50
Pettersson score, mean ± SD WFH score, mean ± SD
US score, mean ± SD
a
Severe hemophilia was defined as a factor VIII/IX level of <2 U/dL; moderate hemophilia was defined as 2-9 U/dL. +Number (N) of patients at study end in 1994. *P≤0.05, HA
versus HB. **P≤0.001, HA versus HB. TNS: not statistically significant, HA versus HB. oComparison of HA versus HB not available. IQR: interquartile range; CI: Confidence Interval; HSS: Hemophilia Severity Score; Pt: patient; SD: Standard Deviation; WFH: World Federation of Hemophilia; US: ultrasound; Na: not available.
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haematologica | 2019; 104(9)