The von Willebrand’s disease (VWD) is the most common inherited bleeding disorder (IBD), with an estimated prevalence of approximately 1% in the general population.1,2 The prevalence of symptomatic VWD has been estimated to be 1:1000 to1:10,000 individuals.3,4 The diagnostic criteria of VWD include a personal bleeding history associated with laboratory abnormalities and family history of bleeding.5 The VWD classification consists of types 1, 2 and 3, of which type 2 has 4 subtypes, 2A, 2B, 2 M and 2N.4,6 Types 1 and 3 are quantitative defects of the von Willebrand factor (VWF) and type 2 and its subtypes are functional defects.4,6 The diagnosis of VWD is challenging, due its heterogeneity, variations in diagnostic criteria and requirement for complex laboratory tests.4–6

The standard treatment of VWD consists of increasing VWF levels above 50% in the course of bleeding episodes or for prophylaxis in case of surgery and other interventions.7–10 Most bleeding episodes in patients with VWD can be effectively treated with desmopressin acetate [DDAVP (1-desamino-8-d-arginine vasopressin)], a synthetic analog of the natriuretic hormone.11 The DDAVP induces the release of the von Willebrand factor (VWF) from its storage sites in the endothelial cells and increases plasma levels of factor VIII (FVIII).11–13 In patients with VWD, DDAVP is the treatment of choice for mild to moderate bleeding and for prophylaxis of minor surgeries in responsive patients, except for subtype 2B and type 3,5–10,14 A good response to DDAVP has usually been defined as an increase in plasma VWF and FVIII levels of three to five times above the basal levels within 30−60 min after intravenous injection, or 60−90 min after subcutaneous (SC) injection of DDAVP, at a dose of 0.3 µg/kg.7–11 The type and severity of VWD, documented response9 and potential risks of therapy need to be considered. For non-responding patients, for those presenting VWD types 2B and 3, or any subtype with severe bleeding or requiring prophylaxis for major surgeries, factor VIII-containing VWF (VWF/FVIII) concentrate is recommended.7–10

In Brazil, health care for people with hemophilia, VWD and other IBDs is publicly funded and patients are attended at hemophilia treatment centers (HTCs) by a multidisciplinary team.15 According to the Brazilian Ministry of Health data, in 2016, a total of 2,808/7811 patients 35.9%) who are registered with VWD used one or more types of procoagulant agents for treatment of any bleeding episode.16 Most of these patients (52.4%) used VWF/FVIII concentrates, followed by 40.3% and 7.3% who used tranexamic acid and DDAVP, respectively.16 This finding has alerted us to a possible underuse of DDAVP in Brazil and led us to seek for reasons why DDAVP has not been more frequently prescribed.

Therefore, the aim of this study was to evaluate the use of DDAVP by medical doctors in the management of VWD patients. We also aimed to investigate the reasons for not using the product when it was indicated and the awareness of participants of the indications and contraindications of DDAVP. For this, we implemented a survey targeting medical doctors working with VWD patients.

We developed a survey on the use of DDAVP by Brazilian medical doctors who are involved in the management of VWD. We found that DDAVP is underused in Brazil for the management of bleeding episodes of VWD, with most participants reporting not having used DDAVP, either subcutaneously or intravenously, in the past 12 months of the survey. Instead, approximately 70% of participants reported having used VWF/FVIII concentrate to treat VWD in the past 12 months.

Most participants were hematologists who had treated patients with VWD in the previous year. More than half of them work at HTCs, mostly located in southeastern Brazil. However, only approximately 25% reported attending to a larger number of patients (>11 patients) per month.

The main reasons supplied for not using DDAVP were (i) the unavailability of DDAVP; (ii) the lack of laboratory tests to monitor the response, and; (iii) the current practice in the participant’s institution to use VWF/FVIII concentrate to treat patients with VWD. It was surprising that one of the main reasons for not using DDAVP was the unavailability of the drug. Indeed, this reflects a lack of information on the part of the participants, as DDAVP for intravenous use (4 µg/ml) has been purchased since 2004 for the treatment of patients with IBD in Brazil. More recently, the Ministry of Health (MoH) initiated the purchase of SC DDAVP (15 µg/ml). This corroborates that the underuse of DDAVP in Brazil is not related to the mode of administration of the drug. Furthermore, it is somewhat surprising that reference centers for the treatment of IBD have adopted the current practice of using VWF/FVIII concentrate to treat patients with VWD in clinical situations in which this is not the main indication. We found that most participants were knowledgeable on the main indications for DDAVP.

According to the last registry of patients with IBD in Brazil,16 there were 7811 patients with VWD, accounting for 32.2% of all IBD diagnosed in 2016. In spite of major efforts towards incrementing the appropriate diagnosis of VWD in Brazil, only 21.8% 1,703/7811 of patients have been classified according to types/subtypes. This might be partially explained by the difficulty in accessing laboratory reagents to perform tests for the VWD diagnosis, especially in some less developed Brazilian states. However, this can also be due to the lack of informed data by the HTCs in the Hemovidaweb Coagulopatias, which is the database system for patients with IBD in Brazil. In this survey, approximately one-quarter of the participants who answered the question regarding reasons for not using DDAVP while required informed the lack of laboratory reagents to monitor the DDAVP test. Therefore, this is likely to be the common reason for both problems, of the diagnosis of the disease and the performance of the DDAVP test. These limitations in the diagnosis of VWD due to the unavailability of diagnostic facilities were also reported in other developing countries, such as Pakistan and India.17–19,23

Currently, for the treatment of VWD in Brazil, there are available tranexamic acid, DDAVP for intravenous (4 µg/ml) or subcutaneous (15 µg/ml) use and plasma-derived VWF/FVIII concentrate. In 2016, 35.9% of patients registered with VWD in Brazil 2,808/7811 used one or more types of procoagulant for the treatment of any bleeding.16 Surprisingly, most of the patients (52.3%) used VWF/FVIII concentrate, followed by 42.1% and 7.6%, who used tranexamic acid and DDAVP, respectively.16 This reflects the results of the present survey, in which 82.5% vs 39.0 % or 24.0 % of the participants reported the use of VWF/FVIII concentrate vs DDAVP IV or SC in the last 12 months, respectively. This suggests that patients with an indication to use DDAVP are instead using VWF/FVIII concentrate. Our data is different from that in Windyga et al., who reported the results of a European survey conducted by The European Haemophilia Therapy Strategy Board (EHTSB). They assessed hematologists of centers across Europe, regarding clinical use of DDAVP in VWD patients, and showed that 61.5% and 53.8% of hematologists used DDAVP and VWF/FVIII concentrates, respectively, as prophylaxis for surgery in VWD.14 In this European survey, only one out of 13 participants who completed the survey did not have access to DDAVP for the treatment of VWD, due to unlicensed DDAVP in Slovakia, and 85% of the hematologists performed a DDAVP test in a non-bleeding state.14

Despite the underuse of DDAVP in Brazil, most participants showed a good general knowledge of the indications and contraindications of the drug, although some contraindications were less recognized, such as the use in coronary artery diseases. Most participants recognized the appropriate use of DDAVP as a test to evaluate responsiveness and to treat responsive VWD type 1. Physicians who recognized DDAVP as an indication for VWD Type 1 more often had prescribed DDAVP in last year (p = 0.03). However, fewer participants (about half) considered the indication of DDAVP for responsive VWD type 2 and this should be a target for education. Concerning contraindications, most participants indicated correctly that “hyponatremia, seizures, hypertension and children under 3 years” and “VWD type 2 with thrombocytopenia” are contraindications for DDAVP use. But only 42.5% considered “Coronary artery disease” as a contraindication for DDAVP use, compared with 80% of participants in the European survey who recognized coronary disease as a contraindication14. In our study, more than one-third (35.9%) of the participants considered pregnancy as a contraindication for DDAVP use. This likely reflects the controversies about the use of DDAVP before labor due to concern about the potential risk of placental insufficiency related to arterial vasoconstriction and the increase in the risk of miscarriage due to an oxytocic effect and to maternal and/or neonatal hyponatremia.20,21 This explains why some experts recommend the use of DDAVP only after the clamping of the umbilical cord.20,21 Regarding age, it is general practice to avoid DDAVP in children under three years, but there is some controversy about DDAVP use in the elderly, with variability in the recommendations.14,22 In Brazil, the MoH recommends avoidance of DDAVP in children under the age of three.22

This study poses some limitations. We only assessed participants who attended the congress instead of assessing medical doctors treating VWD in the entire country and it is to be expected that medical doctors attending a congress be more likely to be updated on medical subjects. Furthermore, most of the participants worked in southeastern Brazil, which is the most developed region of the country. Therefore, this impairs the generalizability of our study. Finally, we did not include in the survey a question inquiring whether participants currently use VWF/FVIII concentrates instead of DDAVP in clinical situations, such as major surgery, children < 3 years of age, elderly patients with a history of heart disease, in which DDAVP is contraindicated.

In conclusion, we showed that DDAVP is currently underused in Brazil, as opposed to the excessive use of VWF/FVIII concentrates in VWD patients. The reasons for not using it were varied and mainly included lack of reagents, laboratory facilities and of skills in using DDAVP. Participants are well-acquainted with the indications and contraindications of DDAVP. We suggest that measures targeting the adoption of communication strategies, as well as an educational program and the availability of laboratory reagents, are key to increment the correct use of DDAVP.

This study was partially funded by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) which included the Doctorate degree of MSSNL.