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

Introduction. Replacement therapy with coagulation factor VIII concentrates remains the standard of care for patients with hemophilia A. In 2023, the drug Eytoplasm, the first modern plasma-derived coagulation factor VIII concentrate developed in the Russian Federation, was authorized for medical use in the Russian Federation. Aim: to study the efficacy, safety, immunogenicity, and pharmacokinetic properties of Eytoplasm. Methods. A multicenter, prospective, open-label clinical trial was conducted in 55 patients over 12 years of age with severe hemophilia A who had previously received treatment with coagulation factor VIII concentrates (at least 150 exposure days). All patients received the drug for prophylactic treatment 2-3 times a week; the treatment duration was 6 months (at least 50 exposure days). In addition, the drug was used to treat bleeding. Ten patients underwent 10 surgical interventions (2 major and 8 minor). Pharmacokinetic parameters were determined after the first administration of the drug to patients and after 6 months of therapy. Results. Eytoplasm pharmacokinetics properties are comparable with other plasma-derived coagulation factor VIII concentrates. No bleeding was recorded in 75.9% of patients. In 92.3 % of patients, a single administration of the drug was sufficient to stop an episode of bleeding. In all participants who completed the study, the residual activity of coagulation factor VIII 48-72 hours after drug administration was at least 1 %. Positive dynamics of APTT was showed during the study. Serious adverse events, allergic reactions, thrombotic and thromboembolic complications were absent in patients. In 3 patients, 4 adverse events associated with the use of the drug were registered: 2 cases of increased serum concentration of direct bilirubin and 2 cases of headache. An inhibitor to coagulation factor VIII was not detected in any patient. In none of the patients who did not have antibodies to parvovirus B19 before the first dose of Eytoplasm, antibodies were detected after 6 months of therapy. Conclusion. Eytoplasm is an effective option for the prevention and treatment of bleeding, and during surgical interventions, including major ones, in patients with hemophilia A. The drug has a favorable safety profile; its use was not associated with the formation of inhibitory antibodies, allergic reactions, thrombotic and thromboembolic complications.

Introduction. Hemophilia is an X-linked hereditary blood clotting disorder caused by insufficiency of blood clotting factor VIII or IX that affects mainly men. In extremely rare cases, the disease can be observed in women, which is most often associated with asymmetric inactivation of the X chromosome. The severity of hemophilia in women does not differ from that in men. Aim – to present a clinical observation of surgical treatment of stage 4 hemophilic arthropathy in a woman with severe hemophilia A. Main findings. Female patient T., 39 years old, was admitted to the National Medical Research Center for Hematology with a preliminary diagnosis: hereditary deficiency of factor VIII. She had an extension of the APTT to 68.8 sec, a high level of Willebrand factor activity — 222 %, and the concentration of Willebrand factor antigen of 178.1 mg/l, and a decrease in the level of factor VIII to 1.6 %. According to molecular genetic analysis, intron 22 inversion associated with severe hemophilia A was detected in the F8 gene. Throughout the patient’s life, hemarthrosis of the knee, ankle and elbow joints were observed, which led to the development of severe arthropathy of varying severity. The woman underwent total knee arthroplasty and arthrolysis of the left ankle joint. The postoperative period proceeded without complications. Hemostatic replacement therapy was performed with a recombinant factor VIII.

ОБОСНОВАНИЕ Наличие ингибиторов к факторам свертывания крови осложняет течение заболевания у 15—32% больных гемофилией. Любое оперативное вмешательство у пациентов этой группы сопряжено с высоким риском развития тяжелых геморрагических осложнений как во время операции, так и в послеоперационном периоде, что требует обеспечения надежного гемостаза и четкого лабораторного контроля эффективности проводимой гемостатической терапии. ЦЕЛЬ ИССЛЕДОВАНИЯ Обозначить проблемы обеспечения гемостаза при выполнении хирургического вмешательства у больных ингибиторной формой гемофилии. МАТЕРИАЛ И МЕТОДЫ Осуществлен анализ 5 хирургических вмешательств у больных с ингибиторной формой гемофилии. Все операции проведены в ФГБУ НМИЦ гематологии в 2016—2020 гг. Медиана возраста составила 46 лет. Все хирургические вмешательства выполнены на органах брюшной полости: 4 операции с использованием лапароскопического доступа (1 холецистэктомия, 2 герниопластики, 1 уретеролитотомия) и 1 «открытое» оперативное вмешательство — герниопластика. Гемостатическая терапия осуществлялась препаратами антиингибиторного коагулянтного комплекса и rFVIIa. РЕЗУЛЬТАТЫ Осложнения в послеоперационном периоде зафиксированы у 4 больных: у 3 были геморрагические осложнения, у 1 — тромботические. Геморрагические осложнения наблюдались в 1-е сутки после операции и требовали коррекции гемостатической терапии. Решающим фактором критического тромбоза селезеночной артерии одного из пациентов явилось повышение коагуляционного потенциала крови при введении rFVIIa на фоне истощения фибринолитической системы (удлинение XIIa-зависимого фибринолиза с 25 до 75 мин) и снижения концентрации антитромбина III, участвующего в инактивации FVIIa, до 81%. ЗАКЛЮЧЕНИЕ Применение стандартных протоколов гемостатической терапии не обеспечивает надежного и безопасного гемостаза при ингибиторной форме гемофилии. При назначении гемостатической терапии больным гемофилией необходимо учитывать индивидуальные характеристики каждого конкретного пациента: компенсаторные механизмы свертывающей системы, сочетанную патологию, изменение клинической ситуации. Для персонализированного подбора схемы гемостатической терапии и контроля системы гемостаза в реальных физиологических условиях необходимо до хирургического вмешательства и на протяжении периоперационного периода оценивать результаты всех возможных гемостазиологических тестов, как общепринятых, так и интегральных, для снижения риска развития геморрагических и тромботических осложнений.

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.

Background. Combined injuries involving brain damage represent the most severe and life-threatening conditions in hemophilia patients. These injuries are characterised by specific situational and behavioural circumstances indicating the presence of victim behaviour in such patients.Aim. To analyse the influence of victim behaviour in hemophilia patients on the formation of combined neurosurgical trauma and the choice of neurosurgical and traumatological treatment approaches.Materials and methods. Twenty five patients (20 patients with hemophilia A and 5 patients with hemophilia B) were included in the study. The patients suffered the following injuries: craniocerebral injuries — 68 (100.0 %); bone fractures — 18 (26.6 %); hematomas of the soft tissues of the face, upper and lower extremities, as well as bruised, lacerated wounds — 50 (73.4 %).Results. The following types of victim behaviour were identified in the hemophilia patients: paranoid — 7 (28.0 %), dependent — 8 (32.0 %), dissociative — 6 (24.0 %) and antisocial — 4 (16.0 %). The patients underwent hemostatic therapy with coagulation factor VIII or IX concentrates and surgical (neurosurgical and/or traumatological) treatment of the injuries associated with victim behaviour. In 51 (75.0 %) cases there was delayed medical care, which was the reason for the complicated course of the post-traumatic period. It was revealed that the best treatment results in patients with severe injuries, including craniocerebral traumas, were achieved in cases where medical assistance was provided in the first three hours after injury. As a result of the treatment, the majority of the patients demonstrated regression of the clinical manifestations of the injury.Conclusions. The proposed tactics for the diagnosis and neurosurgical/traumatological treatment of hemophilia patients with signs of victim behaviour, in whom combined brain injuries are detected, includes a comprehensive assessment of medical history data, clinical and laboratory examination, as well as determination of diagnostic criteria for the choice of patient-specific surgical techniques. It is proposed to use the number of patients’ return visits related to their victim behaviour as a quantitative assessment of the degree of victimization.Conflict of interest: the authors declare no conflict of interest.

Objective was to study genetic markers of thrombophilia in patients with hemophilia, which can affect the course of the disease and contribute to thrombotic complications. Material and methods. The study included 96 patients with severe hemophilia: 75 (78.1 %) – hemophilia A, 16 (16.7 %) – hemophilia B, 5 (5.2 %) – hemophilia with inhibitor form. All patients were with severe hemophilic arthropathyand and underwent knee or hip replacement. The average age of patients was 39.6 years. All patients were examined for markers of thrombophilia. Results. Ninety three patients had either a heterozygous or homozygous form of thrombophilia marker polymorphism. One of thrombophilia markers was present in 15 (15.6 %) patients and in 78 (81.3 %) there was a combination of several markers. In patients with hemophilia B homozygous mutations in the MTHFR gene (A1298C and C677T) were more than 2 times more frequent than in patients with hemophilia A. Conclusion. The frequency of occurrence of polymorphism of FV (G1691A), MTHFR (C677T) and PAI-1 in the studied group of patients with hemophilia is higher than in the general Russian population.

We measured specific volume and hematocrit of blood clots prepared from the whole blood of patients with hemophilia A and healthy male volunteers. It was shown that in the hematocrit range of 43.5-52.5%, specific volume of the blood clot in hemophilia patients with low level of factor VIII (1-4%) was higher than in volunteers. After injection of factor VIII, specific volume of blood clots in hemophilia patients decreased. Hematocrit of the blood clots derived from the whole blood linearly depended on the mean erythrocyte density in both volunteers (r=-0.74, p=0.01) and patients with factor VIII level of 1-4% (r=-0.95, p<0.0001). The increase in the mean erythrocyte density led to a decrease in blood clot hematocrit. The curve describing blood clot hematocrit as a function of the mean erythrocyte density in hemophilia patients was lower than in healthy volunteers. The increase in factor VIII level was associated with an increase in blood clot hematocrit. The results showed that blood clot hematocrit depends on the mean erythrocyte density, and therefore, hematocrit of the blood clot can be changed by modulating the properties of erythrocyte population.

Background. There are no clinical guidelines in Russia regarding the use of central venous access devices in hemophilia despite venous access being crucial for hemophilia treatment. Objective. To analyse different long-term vascular access options in hemophilia patients. Materials and methods. We reviewed 12 cases (11 hemophilia patients and 1 patient with von Willebrand disease) in which long-term vascular access was established. All patients were treated in the National Research Center for Hematology between 2014 and 2018. Results. In total, 17 long-term central venous devices (LTCVD) were implanted in 12 patients (11 peripherally inserted central catheters, PICCs, and 6 ports). The PICCs were implanted in 7 patients of whom 4 had FVIII inhibitors. Median PICC dwell time was 214 days (7 to 464 days); the incidence of catheter-associated bloodstream infections was 0.41 per 1000 PICC days. The ports were implanted in 6 patients (3 via internal jugular veins, 2 via subclavian veins, and 1 via femoral vein in a patient with stenosis and thrombosis of the superior vena cava system). The incidence of catheter-associated thrombosis in this group was 0.15 per 1000 port days, and the incidence of catheter-associated bloodstream infections was 0.15 per 1000 port days. Conclusion. In inhibitor hemophilia patients and hemophilia patients who need intravenous therapy other than with clotting factors, PICCs are a good choice. It is necessary to estimate the demand for LTCVDs in hemophilia patients in Russia and to develop national guidelines regarding their use.

Введение. Проблемой применения рекомбинантного активированного фактора свертывания крови VII (rFVIIa) при ингибиторной гемофилии является сложность лабораторной оценки терапии. Стандартные клоттинговые тесты изменяются, однако, как правило, не нормализуются. Цель работы – изучить возможность использования стандартных клоттинговых тестов (активированного частичного тромбопластинового времени (АЧТВ), протромбинового времени (ПВ)) для оценки эффективности гемостатической терапии rFVIIa у больных с ингибиторной гемофилией. Материалы и методы. В исследование были включены 20 взрослых больных с ингибиторной гемофилией. На момент включения в исследование у пациентов не было признаков кровотечения, FVIII в плазме был < 1 %, ингибитор к FVIII – в титре от 5 БЕ/мл до 463 БУ/мл. Больные получали однократно rFVIIa (Коагил-VII) в дозе 90 мкг/кг. До введения rFVIIa, а затем через 15, 30 и 60 мин, 2 и 24 ч исследовали АЧТВ, ПВ, эндогенный тромбиновый потенциал (ЭТП), проводили тромбоэластографию (ТЭГ). Результаты. Исходно у всех больных было удлиненное АЧТВ, которое уменьшилось через 15 мин после введения rFVIIa и сохранялось значимо меньше до 120 мин, но оставалось почти в 2 раза выше нормы. ПВ также значимо уменьшилось через 15 мин после rFVIIa. На ТЭГ до введения rFVIIa сгусток не образовывался, через 15 мин после инъекции параметры ТЭГ приблизились к норме, гемостатический эффект сохранялся 2 ч. ЭТП повысился через 15 мин после применения rFVIIa, повышение сохранялось в течение 60 мин. Имелась сильная корреляция между временем от начала измерения до образования первых волокон фибрина (R) и АЧТВ (r = 0,74; p = 0,001), максимальной амплитудой (МА) и АЧТВ (r = –0,70), между ПВ и R (r = 0,79; p = 0,01), ПВ и МА (r = –0,76, p = 0,01). Не было корреляции между ЭТП и АЧТВ, ЭТП и R. С помощью ROC-анализа установлено, что укорочение АЧТВ после введения rFVIIa на 17 с и более или на 22 % и более от исходной величины ассоциируется с нормализацией R и МА. Изменения ПВ хуже позволяли дискриминировать нормальные значения ТЭГ. Заключение. Укорочение АЧТВ после введения rFVIIa у больных с ингибиторной гемофилией на 17 с и более или на 22 % и более от исходной величины может быть использовано для оценки эффективности гемостатической терапии rFVIIa в случаях, когда невозможно или недоступно выполнение ТЭГ.

We report our experience of 675 (616 primary, 59 revision) joint replacements in 425 patients performed in one hospital.There were 383 patients with hemophilia A and 42 patients with hemophilia B (age from 18 to 76 years). Inhibitor was detected in 18 hemophilia patients. 90% of patients had positive antibodies to hepatitis C (anti-HCV+), 3 patients had HIV infection.There were 552 knee, 115 hip, 5 shoulder and 3 elbow replacements. 23 knee and 3 hip replacements were performed in hemophilia patients with inhibitor. The average follow-up of implants was 6 years (from 4 months to 20 years). There were revision replacements in 8.8% of cases: 5.5% patients with aseptic loosening and 3% patients-with deep infections. In hemophilia patients deep infection occurred much more frequent - 11%. The significantly higher rate of complications (11%) was observed in patients with inhibitors. In spite of elevated risks for the development of complications in hemophilia patients joint replacement is the only effective procedure in the treatment of end-stage arthropathy. Hemophilia patients need an individualized approach in providing hemostasis and prophylactic antibacterial therapy.

The hemorrhagic syndrome is the relative contraindication for the central venous access. However, in the clinical practice, many patients with hemorrhagic syndrome need a long-term vascular access. Purpose of the study was to investigate the use of Peripherally Inserted Central Catheters (PICC) in patients with severe hemostatic disorders. Results. In total, 16 PICCs were implanted in 12 patients with hemorrhagic syndrome (6 hemophilia patients, 4 of them with inhibitor to FVIII, 1 patient with breast cancer and Willebrand disease, 3 patients with acute promyelocytic leukemia, 1 patient with multiple myeloma and 1 patient with myelodysplastic syndrome). Hemostasis was provided by recombinant activated factor VII (rFVlla), platelet and cryoprecipitate transfusions. The period of use of PICCs varied from 5 days to 1 year and 3 months. There were no thrombotic and infectious complications. PICC can be considered as a method of choice for long-term vascular access in patients with hemorrhagic syndrome.

We examined HCV+ and HCV- hemophilia A patients with knee arthropathy and hematocrit above 38.5%. The mean density of erythrocytes was studied by the phthalate method, intraoperative blood loss was assessed gravimetrically. The volume of blood loss in HCV+ patients with manifest adhesive process and chronic synovitis varied from 300 to 1900 ml, in patients with moderate adhesive process from 400 to 1500 ml. The volume of blood loss in HCV- patients was 300-800 ml. A positive correlation between the blood loss volume and mean density of erythrocytes was detected. Blood loss > 1000 ml during total knee arthroplasty can be expected in patients with hemophilia A with HCV and high mean density of erythrocytes. Blood loss > 1000 ml is unlikely in HCV- and HCV+ patients with the mean density of erythrocytes not surpassing the normal values.

The paper describes 4 clinical cases of thrombotic events (pulmonary embolism, deep vein thrombophlebitis, acute myocardial infarction, ischemic stroke) that have occurred in patients with hemophilia. It discusses the possible causes of their development and methods for their prevention and treatment. Controlled natural hypocoagulation, in which the dose of an administered deficient factor decreases to such an extent that in order to maintain the safe level of hypocoagulation (plasma factor activity is 15-20%; activated partial thromboplastin time is 1.5-2 times normal values), is proposed as one of the treatment options.

Intraoperative blood loss during total knee arthroplasty in patients with hemophilia varies over a wide range (from 300 to 3000 ml). The reasons have not been clarified yet. We studied the dependence of intraoperative blood loss during total knee arthroplasty in patients with hemophilia A on hematocrit and mean erythrocyte density. Intraoperational blood loss ≥1000 ml was observed in patients with hematocrit <38.5%. In patients with hematocrit >38.5% this parameter depended on the mean erythrocyte density: in patients with increased erythrocyte density, the risk of intraoperational blood loss ≥1000 ml was higher. The increase in erythrocyte density can serve as an indicator of pathological processes, including the processes modulating hemostasis. It can also be assumed that erythrocytes with higher density change blood flow, which affects platelet adhesion to the damaged endothelium. Hematocrit below the threshold level and mean density of erythrocytes above the normal level can be regarded as risk factor for increased intraoperational blood loss.

Hairy cell leukemia (HCL), a chronic B-cell lymphoproliferative disease with special villous morphology and immunophenotypic markers of lymphoid cells, is characterized by the involvement of bone marrow and spleen. The paper describes a case of a 29-year-old female patient without abnormal clinical blood tests and myelograms, with normal spleen sizes, in whom the only manifestation of HCL was massive scrotal injury with a soft tissue component in the small pelvic cavity.

The hemostatic effect of rFVIIa (Coagil-VII) was evaluated in patients with thrombocytopenia and ineffective platelet transfusions. rFVIIa was used in the treatment of 31 hemorrhagic syndrome episodes in 20 patients with thrombocytopenia. Control group consisted of 10 hemophilia patients with a factor VIII inhibitor without signs of hemorrhage. All hemophilia patients received a single dose of rFVIIa (120 mu g/kg). Indications for use of rFVIIa in thrombocytopenia were: gastrointestinal hemorrhages (14), intracranial hemorrhages (5), before insertion of the central venous catheter (5), abdominal bleeding (1), bleeding from the femoral artery (1), epistaxix (2), bleeding after massive blood loss (1), before lumbar puncture (1), and pulmonary hemorrhage (1 episode). The doses of rFVIIa varied from 50 to 144 mu g/kg (median 79 mu g/kg). No hemorrhagic complications developed after injection of rFVIIa before invasive manipulations. Use of rFVIIa in the therapy for the hemorrhagic syndrome was effective in 51%, partially effective in 44% patients; no effect was attained in 4% patients. Injection of rFVIIa led to shortening of activated partial thromboplastin time, increase of prothrombin level and of plasma FVII activity, to shortening of periods K and R in thromboelastogram, and to increase of the maximum amplitude. In contrast to hemophilia, in thrombocytopenia the maximum hemostatic effect was obtained only after 1 h. Complications were recorded in 4 patients. rFVIIa can be used for therapy of thrombocytopenia patients with the hemorrhagic syndrome, but its hemostatic effect is unpredictable in some cases.

The development of allogenic antibodies to factor VIII (FVIII) or FIX is one of the most grave complications of substitute therapy for hemophilia. Therapy of bleedings in these patients is carried out by drugs with the shunting mechanisms of action, such as anti-inhibitory coagulant complex (Faiba(circle dot), Baxter, Austria) or recombinant activated factor VII (NovoSeven, Coagulyl VII). Both drugs effectively arrest hemorrhagic episodes in patients with inhibitory hemophilia. Today a preventive approach to therapy of hemorrhages in patients with inhibitory hemophilia is actively introduced. It consists in the use of drugs with the shunting mechanism of action. Two international clinical studies have demonstrated that preventive haemostatic therapy with Faiba is safe and effective in patients with inhibitory hemophilia, reducing significantly the number of spontaneous hemorrhages and thus preventing the developmentor progress of hemophilic arthropathy and improving the patients' quality of life.