Page 191 - Haematologica3

DDAVP response in moderate hemophilia A
DDAVP is a synthetic vasopressin analogue and can be administered intravenously, subcutaneously or intranasally. The drug increases endogenous FVIII plasma concentra- tions by an average of three- to five-fold by inducing the release of von Willebrand factor (VWF), the carrier protein of FVIII, and the direct release of FVIII from Weibel-Palade bodies (WPBs) in endothelial cells.4,5 FVIII is primarily syn- thesized in liver sinusoidal endothelial cells.6 Extrahepatic FVIII is believed to be made by cells in the spleen, by lym- phatic tissue, and especially by endothelial cells.7-11 The effect of DDAVP is dependent on the vasopressin type 2 receptor which is highly expressed in lung endothelial cells, but not in other populations of vascular endothelial cells.12 It is currently unknown from which sites FVIII and VWF are released upon DDAVP stimulation. Interestingly, liver trans- plantation in HA patients eliminates DDAVP response for FVIII but not for VWF, suggesting that extrahepatic FVIII synthesis may be necessary for DDAVP response.13
Large inter-individual variation in the response to DDAVP is observed. The variability of biological response within the same individual is smaller than between individ- uals.14 Although the relative increase in VWF and FVIII lev- els may be similar between non-severe HA patients, as moderates start at a much lower baseline FVIII:C, they may not reach a sufficient peak FVIII level to allow for treatment of minor procedures or trauma. Nevertheless, peak FVIII:C levels reaching 30 IU/dL may be clinically relevant for minor procedures or bleeding events.
Several single-center studies described DDAVP in moder- ate HA.15-22 A total of 21% of the moderate patients who were tested showed an increase of FVIII:C to at least 30 IU/dL and identified the following predictors of response: age, route of administration, blood group, disease severity, and F8 mutations.
However, these studies were hampered by small sample sizes and provided heterogeneous outcomes due to differ- ences in patient characteristics and route of administration. Moreover, VWF was not studied as a potential determinant and the outcome variable which was principally studied was peak FVIII:C. In addition to the peak FVIII:C, the incre- mental response (proportional rise) may reveal important information on the biological mechanisms underlying DDAVP response, with possibly different predictors.
We aim to describe the response to DDAVP in moderate HA patients and to identify predictors in a large, interna- tional cohort of moderate HA patients. Our results show that DDAVP provides a valuable treatment option in a large proportion of patients with moderate HA.
Methods
Study population
We selected data on all 169 patients with moderate HA from the multicenter Response to DDAVP In non-severe hemophilia A patients: in Search for dEterminants (RISE) cohort study, consisting of 1,474 non-severe HA patients from 24 hemophilia treatment centers (Figure 1). The aim of the RISE project was to assess the predictive value of clinical and genetic factors on the DDAVP response in non-severe HA patients. This international retrospec- tive cohort study includes all consecutive non-severe HA patients with DDAVP administration between 1980 and 2012.
Participating centers (listed in the Online Supplementary Appendix) were located in Canada, Australia and ten European countries. The institutional review boards of all centers approved the study. Since
this project involves retrospective data collection, all review boards indicated that informed consent was not required. This study was conducted in accordance with the Declaration of Helsinki.
Data collection
We collected demographic and clinical data from available med- ical records using a standardized electronic case report form. The following data on baseline characteristics were collected: date of birth, ethnicity, ABO blood group, family history of DDAVP response, F8 mutation (Human Genome Variation Society [HGVS] numbering was used), reason for DDAVP administration, lifetime lowest FVIII:C (one-stage clotting assay), pre-DDAVP FVIII:C, pre- DDAVP VWF antigen (VWF:Ag) and activity (VWF:Act), date of DDAVP response, DDAVP dose, Body Mass Index (BMI), inhibitor status, route of administration, FVIII:C/VWF:Ag/VWF:Act after DDAVP, and potential side effects. In cases where the patient was treated to prevent or stop bleeding, we also collected information on the reason for treatment, location and severity of bleeding and therapeuticresponse.
Patient selection
We selected patients from the RISE study with moderate disease severity. Patients were defined as moderate if one of the available FVIII:C measurements was 5 IU/dL or lower (lifetime lowest FVIII:C). In case of multiple DDAVP administrations, we selected the most recent DDAVP administration.
It is important to mention that 13 patients from Seary et al. and 17 patients from the study conducted by Stoof et al. with FVIII:C ≤5 IU/dL are also included in our population.15,16 We explored selec- tion bias of our study population by comparing the RISE popula- tion to 357 moderate patients from the Intervention as a Goal in Hypertension Treatment (INternational Study on etiology of inhibitors in patients with a moderate or mild form of hemophilia A, influences of Immuno Genetic & Hemophilia Treatment factors ([INSIGHT]) study population that did not receive DDAVP.23 We compared: FVIII:C, inhibitors, cumulative exposure days to FVIII, date of birth, and age.
Definition of response
The main study outcome is the peak FVIII:C after DDAVP (in IU/dL). We classified peak response as none (<20), partial (20-29), complete (30-49) or excellent (≥50). With these classifications we were able to compare our findings to previously reported response rates. For further univariate analyses of the determinants of response, we compared patients with inadequate response to patients with at least a complete response.
Incremental response was calculated by dividing peak FVIII:C by pre-DDAVP FVIII:C. Data was collected on the therapeutic response, which is defined in Online Supplementary Table S1.
Statistical analyses
Summary statistics include frequencies and percentages for cat- egorical variables and medians and interquartile ranges for contin- uous variables. An unpaired t-test and χ2 test were used to compare means between patients with inadequate response and at least a complete response. Furthermore, we used multiple linear regres- sion to model relationships between potential explanatory vari- ables and peak FVIII:C and incremental response in the patients tested for DDAVP responsiveness. Potential explanatory variables included in the model were: blood group, route of administration, dose, lifetime lowest FVIII:C, age, pre-DDAVP FVIII:C/VWF:Ag/VWF:Act, peak VWF:Ag/VWF:Act, and DVWF:Ag. DVWF:Ag was defined as peak VWF:Ag minus pre- DDAVP VWF:Ag. We restricted multivariate analyses to DDAVP test results as only nine patients were exclusively treated with
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