Looking at the map illustrating the geographical distribution of C1-INH-HAE patients in Belarus, it is evident as most of them live in Minsk, where the Research Centre of Borovlyani is located. This indicates that patients living in or near Minsk can more easily reach the centre in order to undergo the necessary examinations and/or to have easier access to care. Also, Minsk and neighbouring areas have in their disposition a greater pathology knowledge base, access to relevant trainings and better developed health services. At the same time, in the Grodno region Belarussian National Public Organization "HAE Patients Care" is located, whose members actively help patients with provisional HAE come to Minsk for the diagnosis, with reflected in the number of patients identified in the Grodno region. The quantity is identical to the number of patients identified in the Minsk region. The remaining parts of Belarus report the lack of knowledge about HAE as well as ability to timely diagnose. This situation results in lower prevalence and increased diagnostic delay compared to data from surveys conducted in other countries [10,11,12,13,14,15,16,17,18,19,20,21,22].
Despite this situation, a high number of patients have been diagnosed in the last three years. The collaboration with Italian HAE centre of Milan, marked a significant improvement in the management of HAE.
Genetic data indicate that, although numerous and various SERPING1 variants have been already reported in C1-INH-HAE, given the high number of novel variants identified in our study, the spectrum of variants responsible for this rare pathology is not completely characterized yet. Moreover, splicing defects amounted to 25%, which differs from the world data (about 10%) .
Data extrapolated from the answers to the questionnaire regarding therapeutic possibilities, suggest a serious deficiency in Belarus in accessing preventive therapy with Danazol: only 9 patients, indeed, declared to carry on a prophylactic treatment with such drug.
Evaluating the number of attacks reported by patients in the questionnaire, at least 11 out of 32 patients without prophylaxis had a number of attacks greater than 2 per month, above which the attenuated androgen therapy is indicated . Furthermore, no patient reported short-term prophylactic therapy with attenuated androgens before surgical intervention, particularly in the oral cavity.
Regarding ODT for acute attacks, it is important to consider how a third of the patients (11 out of 38) did not answer the question about drugs used during acute attacks. This could be a result of inadequate patient training about the effective drugs for the treatment of HAE. Analysing 27 answers of the patients, it becomes obvious the poor adherence to guidelines for therapeutic management of acute attacks in Belarus. In fact, as many as 18 patients were treated with ineffective drugs for HAE: antihistamine, steroid, tranexamic acid. Only 9 patients were treated with appropriate drugs, 2 with icatibant or i.v. C1-INH concentrate and 7 with fresh frozen plasma infusion.
Icatibant or i.v. C1-INH concentrate are not available even at the national hospitals and not refunded by Belarusian Health System. Hence, the patients have to import the drugs from abroad on their own expense. Therefore, danazol, tranexamic acid and fresh frozen plasma infusion are used as the primary maintenance treatment in Belarus.
Our data show a lack of knowledge of on-demand HAE effective drugs both by patients and by health personnel. Lack of proper knowledge and education on patients' pathology lead to a condition of extreme vulnerability of the patients even in protected settings such as hospitals. Indeed, during the hereditary history taking, patients with HAE reported 12 deaths of their blood relatives due to laryngeal edema. Moreover, unfortunately, one patient, out of 64 presented in this study, died of angioedema in the hospital, because the provided therapy was not effective due to the lack of necessary medications.