Methodological recommendations for surgical care in patients with hemophilia A receiving prophylactic therapy with emicizumab. Recommendations of the expert group. Moscow, 2024.

Введение. Гемофилия — наследственное генетическое заболевание, связанное с дефицитом факторов свертывания крови, приводящим к кровотечениям различных локализаций. Основным принципом лечения гемофилии является специфическая заместительная терапия дефицитными факторами свертывания крови. Цель исследования: изучить динамику клинических и лабораторных показателей у пациентов с гемофилией А после перевода с лечения препаратами фактора свертывания крови VIII (FVIII) со стандартным периодом полувыведения на эфмороктоког альфа при наблюдении в течение 12 месяцев. Материалы и методы. В открытое многоцентровое несравнительное наблюдательное исследование в одной группе в условиях обычной медицинской практики были включены 30 пациентов в возрасте от 12 до 35 лет с гемофилией A любой тяжести, в возрасте от 12 до 33 лет, со среднегодовой частотой кровотечений ≥ 2, находящиеся на профилактической терапии препаратами FVIII на протяжении не менее одного года. Пациенты были разделены на 2 группы: 12–16 лет (n = 8) и 17–35 лет (n = 22). Для каждого пациента сбор данных проводился в рамках 5 визитов на протяжении 12 месяцев. Результаты. Лечение эфмороктокогом альфа, препаратом с пролонгированным периодом полувыведения, в течение 12 месяцев продемонстрировало улучшение клинических и лабораторных показателей у пациентов с гемофилией А, переведенных с лечения FVIII со стандартным периодом полувыведения. В возрастной группе 12–16 лет у 3 пациентов наблюдался как минимум один эпизод кровотечения, причем в течение первых 6 месяцев произошло в общей сложности 5 кровотечений. Среднегодовая частота кровотечений составила 0,6. В возрастной группе 17–35 лет у 10 пациентов наблюдался как минимум один эпизод кровотечения, в общей сложности 31 кровотечение за период исследования. Среднегодовая частота кровотечений составила 1,44. Серьезных нежелательных явлений зарегистрировано не было. Заключение. Положительная динамика наблюдалась уже в первые 6 месяцев исследования в обеих возрастных группах и включала изменения в частоте кровотечений, количестве инвазивных процедур и хирургических вмешательств, а также в состоянии суставов. Полученные результаты подтверждают высокую эффективность и безопасность эфмороктокога альфа при профилактическом лечении пациентов с гемофилией А. Introduction. Hemophilia is a hereditary genetic disease associated with a deficiency of blood clotting factors, which results in bleeding in various locations. The fundamental tenet of hemophilia treatment is specific replacement therapy with deficient blood clotting factors. Аim: to study changes in clinical and laboratory parameters in patients with hemophilia A after switching from standard half-life factor VIII (FVIII) preparations to efmoroctocog alfa for 12 months. Materials and Methods. An open, multicenter, non-comparative, observational single-arm study was conducted in a routine clinical setting. The study included 30 patients with hemophilia A of any severity aged 12 to 35 years with an average annual bleeding frequency of ≥ 2 episodes and prophylactic therapy with FVIII for at least one year. The patients were divided into two groups: 12–16 years (n = 8) and 17–35 years (n = 22). For each patient, data were collected during 5 visits over 12 months. Results. Treatment with fmoroctocog alfa, a prolonged-half-life agent, for 12 months resulted in improvements in clinical and laboratory parameters in patients with hemophilia A switched from a standard-half-life FVIII. In the 12–16-year age group, three patients experienced at least one bleeding episode, with a total of 5 bleeds occurring during the first 6 months. The mean annualized bleeding rate was 0.6. In the 17–35-year age group, 10 patients experienced at least one bleeding episode, with a total of 31 bleeds during the study period. The mean annualized bleeding rate was 1.44. No serious adverse events were reported. Conclusion. Positive changes were observed already in the first 6 months of the study in both age groups and included changes in bleedings frequency, the number of invasive procedures and surgeries, as well as improvements in joints condition. The results obtained confirm the high efficacy and safety of efmoroctocog alfa in the prophylactic treatment of patients with hemophilia A.

Introduction. In 2018 emicizumab was approved in Russia for prophylactic treatment in patients with hemophilia A (HA) with inhibitors and in 2019 for patients with severe HA without inhibitors. A significant amount of data has been accumulated from clinical trials and real-world data, which allow us to resolve most of the questions that hematologists may have when to prescribe emicizumab. Aim - to provide information on the management of patients on emicizumab. Results. The recommendations accumulated the currently available information and world experience in the management of patients receiving emicizumab in order to facilitate decision-making when prescribing and using emicizumab. Information on the use of emicizumab in patients with HA with FVIII inhibitors and severe HA without FVIII inhibitors is presented. Possible complications and measures for their prevention and treatment are presented.

Despite availability of prophylactic therapy for hemophilia A with factor VIII concentrates with a standard half-life, patients continue to experience episodes of bleeding and joint damage. The reasons for this may be the relatively short half-life of the factor VIII drug and the low adherence of patients to treatment. The appearance of clotting factor concentrates with an extended half-life makes it possible to reduce the frequency of infusions and increase the residual activity of the deficient factor. The article presents clinical observations of the use of Efmoroctocog alfa (recombinant human coagulation factor VIII, Fc fusion protein (rFVIIIFc)) in a 16-year-old adolescent and a 7-year-old child with severe and moderate forms of hemophilia A. In order to select the most rational therapy regimen and evaluate the effectiveness of treatment, the authors have conducted individual assessments of patients’ pharmacokinetic (PK) parameters. The drug administration in both patients was twice per week. To assess individual PK, the WAPPS-Hemo was used in order to calculate individual PK parameters based on a small plasma samples collected during routine prophylactic treatment. During the PK study, 3 blood samples were taken to determine the level of factor VIII in a one-step method. In a 16-year-old patient, the half-life of Efmoroctocog alfa (t1/2) was 24.25 hours. The activity of factor VIII prior to the next injection was 7.4%. In addition, 81% of time the factor VIII activity was above 15%. In a 7-year-old patient, the t1/2 of the drug was 12.75 hours. The minimum residual activity of factor VIII was 2.1%, 86% of time the activity of factor VIII was above 3%. Conclusion: high efficacy and safety were demonstrated based on the results of the use of Efmoroctocog alfa in routine clinical practice in previously treated pediatric and adolescent patients with severe and moderate hemophilia A, as well as the reduction in the frequency of infusions per week from 3 to 2.

Цель исследования: сбор и анализ данных о результатах применения нонакога альфа (Иннонафактор) при лечении больных с тяжелой и среднетяжелой формой гемофилии B в возрасте от 12 лет и старше в условиях рутинной клинической практики. Материалы и методы. В проспективное многоцентровое открытое наблюдательное исследование был включен 51 пациент в возрасте от 16 до 59 (32,9 ± 9,5) лет. Среди них было 39 (76,5%) пациентов с тяжелой формой и 12 (23,5%) пациентов со среднетяжелой формой гемофилии В. Эффективность лечения оценивали по числу спонтанных кровотечений, возникших в течение 72–96 ч после введения нонакога альфа, их степени тяжести и числу инъекций для купирования одного эпизода кровотечения. Безопасность оценивали по частоте и характеру нежелательных явлений (НЯ). Результаты. В группепациентов, завершивших исследование по протоколу, зарегистрировано 41 (63%) спонтанное и 24 (37%) посттравматических кровотечения. Медиана (Ме) числа спонтанных кровотечений в течение 72–96 ч после введения нонакога альфа была равна 2, межквартильный диапазон (англ. interquartile range, IQR) –6. Средняя профилактическая доза составила 28,25 ± 12,24 МЕ/кг (Me = 26,3 МЕ/кг; IQR = 24,4 МЕ/кг). Для купирования возникших кровотечений на фоне профилактического лечения требовалось в среднем 1,9 ± 1,8 введения в средней разовой дозе 2137 ± 790 МЕ (Me = 2000 МЕ; IQR = 1000 МЕ). По результатам оценки реакции на лечение острого гемартроза по шкале Всемирной федерации гемофилии (англ. World Federation of Hemophilia, WFH) в группе профилактического лечения в 16 (32,0%) эпизодах реакция была оценена как «отличная», в 31 (62,0%) эпизоде — как «хорошая» и в 3 (6,0%) эпизодах – как «умеренная». В группе лечения по требованию в 10 (100%) эпизодах реакция была оценена как «хорошая». Было зарегистрировано 26 НЯ у 14 пациентов, из которых только 2 НЯ (дисгевзия и кашель) у одного пациента имели связь с применением нонакога альфа. Заключение. Полученные результаты свидетельствуют об эффективности и безопасности нонакога альфа как для профилактического лечения, так и для купирования возникших кровотечений у обследованных пациентов с тяжелой и среднетяжелой формой гемофилии B в условиях рутинной клинической практики. Objectives: to analyze the results of the nonacog alfa (Innonafactor) use in patients aged 12 years and older with severe and moderate hemophilia B in routine clinical practice. Patients/Methods. A prospective multicenter open, observational study included 51 patients aged 16 to 59 (32.9 ± 9.5) years. Among them 39 (76.5%) patients had severe hemophilia B and 12 (23.5%) patients had moderate hemophilia B. Treatment efficacy was assessed by the number of spontaneous bleedings occurring within72–96 hours after nonacog alfa administration, bleeding severity and number of injections to stop one bleeding episode. Safety was assessed by the frequency and type of adverse events (AEs). Results. Forty one (63%) spontaneous and 24 (37%) post-traumatic bleedings were registered in patients completed the study according to protocol. The spontaneous bleedings incidence was 2 (Me; IQR = 6) within 72–96 hours after nonacog alfa administration. The mean prophylactic dose was 28.25 ± 12.24 IU/kg (Me = 26.3 IU/kg; IQR = 24.4 IU/kg). About 1.9 ± 1.8 injections were required to stop a bleeding appeared during prophylactic treatment, an average single dose was of 2137 ± 790 IU (Me = 2000 IU; IQR = 1000 IU). Basing on World Federation of Hemophilia (WFH) scale the response to treatment of acute hemarthrosis was considered as “excellent” in 16 (32.0%), “good” in 31 (62.0%), and “moderate” in 3 (6.0%) for patients with prophylactic treatment, and as “good” in 10 (100%) in the on-demand treated group. AEs incidence was as 26 in 14 patients, of which only patient performed 2 AEs (dysgeusia and cough) associated directly with the nonacog alfa administration. Conclusions. The results lets know nonacog alfa as effective and safe for prevention and to stop bleedings in patients with severe and moderate hemophilia B in routine clinical practice.

Hemophilia B is a hereditary disease of the blood clotting system caused by a deficiency or molecular abnormalities of blood clotting factor IX. The main method of treatment is intravenous administration of coagulation factor IX concentrates. To optimize treatment and increase patient adherence to therapy, concentrates with a prolonged half-life have been developed.

Болезнь Виллебранда — наследственное заболевание свертывающей системы крови, обусловленное дефицитом или молекулярными аномалиями фактора Виллебранда (vWF). Верификация диагноза проводится на основе оценки данных семейного и личного анамнеза, клинических проявлений и результатов лабораторных исследований. Основной метод лечения — заместительная терапия — внутривенное введение препаратов vWF, содержащих vWF и фактор свертывания крови VIII (FVIII). Залогом успешного лечения пациентов с болезнью Виллебранда является подбор оптимального препарата с учетом индивидуальных потребностей пациента и фармакокинетических свойств концентратов Von Willebrand disease is a hereditary disease of blood coagulation system caused by a defi ciency or molecular abnormalities of von Willebrand factor (vWF). Verification of the diagnosis is based on the assessment of anamnesis, family and personal data, clinical manifestations and the results of complex laboratory tests. The main method of treatment is replacement therapy — intravenous administration of vWF concentrates containing blood coagulation factor VIII (FVIII) and vWF. The key to successful treatment of patients with von Willebrand disease is the selection of the optimal drug, taking into account the individual needs of the patient and the pharmacokinetic properties of the concentrates.

Relevance. Immune tolerance induction (ITI) is the only approach proven to eradicate inhibitors in hemophilia A patients. ITI with Octanate® (human VWF-stabilized FVIII) has been shown to be effective at eradicating inhibitors, even in poor-prognosis patients. Here we report interim data from two observational, prospective studies on the use of Octanate® for ITI in patients in Russia. Purposes of research. The primary objective was to assess the efficacy of ITI. Secondary objectives included assessment of time to ITI success and inhibitor eradication. Patients and methods. Patients of any age with any severity of hemophilia A and a FVIII inhibitor  0.6 BU/mL were eligible. The ITI regimen was at the discretion of the treating physician. Results. The analysis included 73 patients. ITI outcomes were assessed in 63 patients who had completed the study, of whom 56 (89 %) had  1 poor prognostic factors. Inhibitor eradication was achieved by 77.1 % (37/48) of primary ITI patients and 71.4 % (45/63) of all patients, in a median of 2.4 months (range – 0.0–27.4) for both groups. Complete success was achieved by 72.9 % (35/48) of primary ITI patients in a median of 8.9 months (range – 2.4–28.0) and 66.7 % (42/63) of all patients in a median of 10.5 months (range – 2.4–28.0). No relapses were reported after complete or partial ITI success. Of the patients with  1 poor prognostic factors, 67.9 % achieved inhibitor eradication and 62.5 % complete success. Conclusions. ITI with Octanate® in a real-world setting showed rapid and sustained success, even in patients with poor prognostic factors.

Relevance. Immune tolerance induction (ITI) is the only approach proven to eradicate inhibitors in hemophilia A patients. ITI with Octanate® (human VWF-stabilized FVIII) has been shown to be effective at eradicating inhibitors, even in poor-prognosis patients. Here we report interim data from two observational, prospective studies on the use of Octanate® for ITI in patients in Russia.Purposes of research. The primary objective was to assess the efficacy of ITI. Secondary objectives included assessment of time to ITI success and inhibitor eradication.Patients and methods. Patients of any age with any severity of hemophilia A and a FVIII inhibitor  0.6 BU/mL were eligible. The ITI regimen was at the discretion of the treating physician.Results. The analysis included 73 patients. ITI outcomes were assessed in 63 patients who had completed the study, of whom 56 (89 %) had  1 poor prognostic factors. Inhibitor eradication was achieved by 77.1 % (37/48) of primary ITI patients and 71.4 % (45/63) of all patients, in a median of 2.4 months (range – 0.0–27.4) for both groups. Complete success was achieved by 72.9 % (35/48) of primary ITI patients in a median of 8.9 months (range – 2.4–28.0) and 66.7 % (42/63) of all patients in a median of 10.5 months (range – 2.4–28.0). No relapses were reported after complete or partial ITI success. Of the patients with  1 poor prognostic factors, 67.9 % achieved inhibitor eradication and 62.5 % complete success.Conclusions. ITI with Octanate® in a real-world setting showed rapid and sustained success, even in patients with poor prognostic factors.

Relevance.The development of a new recombinant blood coagulation factor VIII preparation is a promising step towards optimizing the treatment of hemophilia A. An introduction of a new medication into clinical practice precedes a clinical trials to evaluate the efficacy and safety.Materials and methods.The efficacy and safety of the domestic recombinant B-domain deleted blood coagulation factor VIII (FVIII) (moroctocog alfa, Octofactor®, JSC “GENERIUM”) were studied in the preventive treatment of 31 patients aged 21 to 52 years with severe haemophilia A. The Octofactor was administered in doses of 40 ± 5 IU/kg 3 times per week at intervals of at least 48 hours for 21 ± 1 weeks.Results.The efficacy of therapy was evaluated in 30 patients, since 1 patient refused to participate in the trial after the first injection of the study medication. There were registered 43 episodes of bleeding among 11 patients in the course of the preventive treatment with Octofactor. The average number of bleeding episodes was 1.4 ± 2.58. There were 43 bleeding episodes, 9 (20.9 %) of them were posttraumatic, 34 (79.1 %) of them were spontaneous. The average number of the spontaneous bleeding episodes (a major criterion of the efficacy) was 1.13 ± 2.19, which showed a low incidence of exacerbations of the hemorrhagic syndrome in the course of preventive treatment with Octofactor. Among all registered bleeding episodes there were 6 (14 %) mild episodes, 37 (86 %) moderate episodes. Among all spontaneous bleedings there were 6 mild episodes (17.6 %), 28 (82.4 %) moderate episodes. All posttraumatic bleedings were moderate. The vast majority (36, or 83.7 %) of bleeding episodes were stopped with administration of the Octofactor. The average number of administrations of the Octofactor for arresting 1 bleeding episode was 1.2 ± 0.56, for 1 spontaneous bleeding episode – 1.2 ± 0.59. On average, it was required to administer 3534.9 ± 2329.02 IU of the Octofactor to stop 1 episode of bleeding. In the vast majority of patients with severe hemophilia A (83.3–86.7 %), the remaining activity FVIII was 1 % or more after the administration of the Octofactor in 48 hours. The total amount of the Octofactor, introduced for the prevention of bleeding, was 6,107,000 IU, to stop bleeding – 152,000 IU. The safety of therapy was evaluated in 31 patients. There were recorded 25 adverse events (AE) in 17 patients. Among them the laboratory ones prevailed in 23 (92 %) cases, which is not associated with the use of the trial medication. There were noted nausea and an unpleasant aftertaste in the mouth in 1 patient during the first administration of the Octofactor, and therefore he refused to continue to participate in the trial. Causality 2 AE with the study drug was regarded as definite. Such AE are expected and described in the instructions to the preparation. All AE were not serious and mild and resolved without outcomes. There were no presented thromboembolic events and immunogenic reactions.Conclusions.The obtained data testify to the efficacy and safety of the Octofactor both for preventive measures and for stopping bleeding in adult patients with severe hemophilia A.

Результаты многоцентрового, проспективного, открытого, неконтролируемого исследования эффективности и безопасности препарата Иннонафактор у пациентов в возрасте 12 лет и старше с тяжелой и среднетяжелой гемофилией В

Von Willebrand disease (vWD) is a heritable disease, which can be inherited by either autosomal dominant or autosomal recessive, caused by qualitative or quantitative deficiency of von Willebrand factor (vWF) and characterized by excessive bleeding. In Russia 2013 was announced as a year of von Willebrand disease. For elaboration of guidelines on improvement of specific care of children and adults suffering from vWD we carried out a retrospective study. Information regarding the patients registered by regional haematologists with diagnosis of vWD (ICH-10 code D 68.0) was collected. There were examined 86 patients suspected for vWD. The diagnosis was confirmed in 52 (61.6%) patients. This data supported opinion that present status of laboratory service in the Russian regions is not satisfactory for detection of coagulation disorders and final diagnosis justification. Factor VIII concentrate is relatively novel but rare for Russian practice therapeutic approach for bleeding treatment in the patients with vWD. According to the results of the study it was effective in all the cases.

Von Willebrand disease (vWD) is a heritable disease, which can be inherited by either autosomal dominant or autosomal recessive, caused by qualitative or quantitative deficiency of von Willebrand factor (vWF) and characterized by excessive bleeding. In Russia 2013 was announced as a year of von Willebrand disease. For elaboration of guidelines on improvement of specific care of children and adults suffering from vWD we carried out a retrospective study. Information regarding the patients registered by regional haematologists with diagnosis of vWD (ICH-10 code D 68.0) was collected. There were examined 86 patients suspected for vWD. The diagnosis was confirmed in 52 (61.6%) patients. This data supported opinion that present status of laboratory service in the Russian regions is not satisfactory for detection of coagulation disorders and final diagnosis justification. Factor VIII concentrate is relatively novel but rare for Russian practice therapeutic approach for bleeding treatment in the patients with vWD. According to the results of the study it was effective in all the cases.