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J.I. Loomans et al.
Our observation that higher pre-DDAVP FVIII:C predicts higher peak FVIII:C in moderate HA patients is supported by other studies.15,18
Our finding that younger age predicted higher peak FVIII:C in our cohort of moderate HA patients is inconsis- tent with the literature reporting moderate patients. Stoof et al. and Knöfler et al. did not find an effect of age on DDAVP response, which they both attribute to the fact that the age of their population was higher than in the studies of Seary et al. and Revel-Vilk et al. (Table 5).15-18 Both Seary et al. and Revel-Vilk et al. found that responders had a higher mean age compared to non-responders, however, they did not adjust for pre-DDAVP FVIII:C. Furthermore, their study was performed exclusively in children whereas our study focuses predominantly on adults (Table 5).15,18
Determinants of incremental response
We identified four predictors of the incremental response; DVWF:Ag, pre-DDAVP VWF:Ag and lifetime lowest FVIII:C levels increase the incremental response. Furthermore, a smaller product of the interaction term age*pre-DDAVP FVIII:C predicted a higher incremental response. The interaction term indicates that the effect of pre-DDAVP FVIII:C on the incremental change of FVIII fol- lowing DDAVP varies for age, or that the effect of age on the incremental change of FVIII following DDAVP is altered by pre-DDAVP FVIII:C.
This is the first study which used incremental response as an outcome variable reflecting the biological mechanisms underlying DDAVP response. Unlike for peak FVIII:C, for incremental response the pre-DDAVP is not a predictor and
DVWF:Ag was the second strongest predictor of peak FVIII:C. In consistency with this finding, we identified lower pre-DDAVP VWF:Ag as a predictor of peak FVIII:C. We can only speculate on the biological mechanism explaining this observation. Potentially, the stronger increase in VWF provides more binding sites for FVIII released upon DDAVP administration. Some patients may have higher pre-DDAVP VWF:Ag due to stress. Stress is known to increase endogenous FVIII:C and VWF. Hence, patients may have already released some of their stored VWF due to stress, with with less potential for VWF to rise further with DDAVP. Finally, it is conceivable that some patients have a phenotype of “greedy” endothelium, whereby VWF stores (or storage compartments) are only depleted upon extra (DDAVP) stimulation. There is still more to learn about the exact sources and secretion of both FVIII and VWF upon DDAVP stimulation, and how they interact.
It is important to stress that DVWF:Ag is derived from a post hoc parameter (DDAVP-induced rise in VWF:Ag), and can therefore not be used by the clinician to predict response adequacy in advance.
We do not have an explanation for the lower peak VWF:Act which predicts a higher FVIII:C peak. This finding is inconsistent with the DVWF:Ag finding.
Figure 1. Patient selection of 169 moderate hemophilia A (HA)
patients with ArgininVasoPressin (desmopressin; DDAVP) administration. The 169 patients are from 23 different hemo- philia treatment centers. *Reason for treatment was unknown for one patient.
1-Deamino-8-D-
Table 3. Mutations in at least three patients. Number of
patients (%)
No Response
Partial Complete Excellent Response Response Response
Pro149Arg 6(4) 1 2 3 0 Tyr450Asn 3(2) 3 0 0 0 Arg550Cys 3 (2) 0 111 Arg612Cys 3 (2) 0 012 Arg1960Gln 3(2) 0 1 1 1 Gly1979Val 3(2) 0 0 3 0 Arg2169His 21 (12) 2 3115 Trp2248Cys 3 (2) 1 020 Gln2265Arg 3(2) 1 1 0 1
Total 48 (28) 8 8 22 10
*Human Genome Variation Society nomenclature was used. Mutations in bold were additionally identified as high-risk mutations for inhibitor development.
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haematologica | 2018; 103(3)