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J.I. Loomans et al.
Table 5. Previous studies on 1-Deamino-8-D-ArgininVasoPressin (desmopressin; DDAVP) response in moderate hemophilia A (HA) patients.
Author, year
Stoof et al. 2014
Knöfler et al. 2012
N
17
2
Study design
Retro- spective
Retro- spective
Intervention Age (median
years, IQR)
Test 28
and (8–67)* treatment
Test 32.5 (16.7–48.2)
Investigated DDAVP dose determinanƗ ts (μg/kg) and
of DDAVP administration response route
Time FVIII:C measurement (min)
0; 60; 180; 600
0; 30; 60; 120; 240
Pre-DDAVP FVIII:C (IU/dL)
1-5*
2.6 (1.7–3.5)
After DDAVP FVIII:C (IU/dL)
uk
14.75 (14– 15.5)
Partial response
uk
0
0
0
0
2 (25%) 1 (50%) 0
3 (5%)
At least complete response
8 (47%)
0
1(8%)
0
0
3 (38%) 0
0
12 (21%)
Blood group O, mutations, age, route of administration Age, administration route
IV and IN
0.4 IV and 0.4 SC
Searyetal. 13 Retro- Test <18 Age, 0.3IV 0;60;240 1-5* uk
2012
Revel-Vilk et al. 11 2002
spective
Retro- spective
Prospective Prospective Prospective Prospective
and treatment disease severity, mutations
and 0.3 SC 0.3 IV
0.3 SC 0.3 IV 0.3 IV
and 0.4 IV 2.0 IN
Ghirardini et al. 1988
De La Fuente et al. 1985 Mariana et al. 1984
Warrier et al. 1983
Total
2
8
2
1
56
Age, disease severity, blood group O uk
uk
uk
0; 60
0; 60
0; 15; 30; 60; 180; 300; 1440 0; 60
0; 15; 90; 180; 270
1-5 *
3.5 (3–4) 3.5 (2–5) 4.8 (4.5–5) 2
uk
11.5 (9–14) 24 (7–47) 15.7 (11.3–20) 13
Test 2.8 (0.13–9.75)**
Treatment uk
Test and 30 treatment (2–66) Treatment uk
Test and 23
treatment (10–45)*** route
Administration
ƗUnderlined factors were identified determinants.*Age is not specific for moderate patients,but for complete study population including mild HA patients.**Age is not specific for moderate HA patients, but for non-responders. ***Age is not specific for moderate HA patients, but for all patients with IN administration of DDAVP. IV: intravenous; IN: intranasal; SC: subcutaneous; uk: unknown; IQR: interquartile range; FVIII:C: factor VIII.
556
from these studies are also included in our cohort. Unexpectedly, we observed a discordance in DDAVP response among patients with the same mutation that was not due to differences in route of administration (Figure 2). Four mutations present in at least three patients were also identified in the INSIGHT cohort as high-risk mutations for inhibitor development (Arg550Cys, Arg612Cys, Arg2150His and Trp2248Cys HGVS numbering).23 As Figure 2 and Table 3 show, half of the patients with these mutations in our cohort showed at least a complete response to DDAVP. This is of clinical importance as these patients may be successfully treated with DDAVP in order to reduce hazardous exposure to FVIII concentrates.
Limitations and strengths
This large, international cohort study provides data on the response to DDAVP in moderate HA patients. Our study is unique owing to the large number of patients included, thus increasing the statistical power.
As lifetime lowest and pre-DDAVP FVIII:C was not measured in a standardized manner, this may have led to an overestimation of patients who were once classified as moderate, but who were not defined as moderate at the time of the DDAVP test. This can be seen in Table 1, where patients with complete and excellent responses have a higher pre-DDAVP FVIII:C irrespective of their lowest life- time FVIII:C.
With respect to our outcome variables, it is important to state that the biological response is only a proxy of the clin- ical response to DDAVP. Additional data are warranted to establish when and to which extent desmopressin can be clinically used to treat patients with moderate HA.
As only 32% of the moderate patients from our source population were tested or treated with DDAVP, this might lead to an overestimation of patients with a good response. The proportion of moderate patients receiving DDAVP per hemophilia treatment center ranged from 19 to 50. Moderate patients who received DDAVP had higher lowest lifetime FVIII:C compared to those who did not. For these reasons, caution is needed when extrapolating these results to all moderate HA patients.
Although our study is unique in terms of its size, we still lacked the power to further analyze the effect of mutations on DDAVP response in moderate HA patients. As the F8 genotype is known to influence baseline FVIII:C, and there- by DDAVP response, the effect of mutations via baseline FVIII:C may contribute to clarifying 35% of the unex- plained variation in peak FVIII:C levels.33
For further functional analyses of genotype, it would have been informative to have, in addition, the FVIII anti- gen (FVIII:Ag) levels. Castaman et al. demonstrated that the presence of a dysfunctional FVIII molecule (Antigen>Activity) per se does not prevent a response to DDAVP.34
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