Hemophilia: Clinical Guidelines

List of Abbreviations

aPTT – activated partial thromboplastin time

APCC – anti-inhibitor coagulant complex

BU – Bethesda Unit

HA – hemophilia A

HB – hemophilia B

ID – infusion day

GI – gastrointestinal tract

ITI – immune tolerance induction

CT – computed tomography

MRI – magnetic resonance imaging

NSAIDs – non-steroidal anti-inflammatory and antirheumatic drugs (M01A according to the ATC classification)

PT – prothrombin time

TT – thrombin time

FVIII – coagulation factor VIII

FIX – coagulation factor IX

FXI – coagulation factor XI

FXII – coagulation factor XII

CNS – central nervous system

COX-2 – cyclooxygenase-2

Terms and Definitions

Hemarthrosis – bleeding into the joint cavity

Hematoma – localized accumulation of blood in closed or open injuries of organs and tissues with vascular rupture, resulting in the formation of a cavity containing liquid or clotted blood

Hematuria – presence of red blood cells in the urine above physiological norms

Hemostasis – blood coagulation system

Hemostatic therapy – therapy aimed at stopping bleeding

Hemophilia A – hereditary deficiency of coagulation factor VIII

Hemophilia B – hereditary deficiency of coagulation factor IX

Inhibitors – antibodies produced against an exogenously administered protein

Coagulogram (screening test of the hemostatic system) – investigation of the blood coagulation system

Coagulopathy – blood coagulation disorder

Bypassing agents – specific products from the group of coagulation factors (B02BD coagulation factors according to the ATC classification): anti-inhibitor coagulant complex** and eptacog alfa (activated)**

Coagulation factor – a protein found in blood plasma and platelets that ensures blood clotting

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hemophilia is an X-linked congenital disorder of plasma hemostasis resulting from the deficiency or absence of coagulation factor VIII (FVIII) — hemophilia A, or coagulation factor IX (FIX) — hemophilia B.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Hemophilia is inherited in an X-linked recessive manner. Approximately 70% of patients have a positive family history of the disease. Hemophilia is caused by mutations in the gene encoding FVIII (Xq28) or the gene encoding FIX (Xq27). In 30–35% of cases, sporadic mutations may occur without a family history of the disease.

1.3 Epidemiology of the Disease or Condition

The prevalence of hemophilia in the general population is 1:10,000 individuals. Hemophilia A (HA) is more common than hemophilia B (HB) and accounts for 80–85% of all cases. The vast majority of hemophilia patients are male. Isolated cases of hemophilia in women are known when inheriting the gene simultaneously from an affected father and a carrier mother, or in a woman with a gene mutation on one chromosome when the gene on the other is inactive (Turner syndrome, etc.). Some female carriers of FVIII or FIX gene mutations may also have clinical manifestations of hemophilia [1].

1.4 Features of Coding the Disease or Condition

D66 – Hereditary factor VIII deficiency

D67 – Hereditary factor IX deficiency

1.5 Classification of the disease or condition

The classification of hemophilia by severity is based on the determination of FVIII and FIX activity (Table 1) [1–3].

Table 1. Classification of hemophilia by severity

About 60–70% of all diagnosed hemophilia cases are severe forms of the disease, characterized by spontaneous hemorrhagic episodes (predominantly hemarthrosis and soft tissue hematomas of various locations). The severity of blood coagulation disorders and clinical manifestations in hemophilia generally depends on the level of factor activity in the blood; however, in clinical practice, there is not always a direct correlation between laboratory and clinical phenotypes of the disease.

1.6 Clinical presentation of the disease or condition

The main manifestation of hemophilia is bleeding and hemorrhage occurring spontaneously or as a result of trauma (Table 2). HA and HB have a similar clinical presentation [1,3].

Table 2. Clinical manifestations of hemophilia

Severe hemophilia is characterized by the onset of hemorrhagic syndrome during the first year of life with the beginning of the child's active period (soft tissue hematomas, post-traumatic mucosal bleeding, hemarthrosis). The large joints are primarily affected: knee, ankle, elbow, and hip joints.

Moderate hemophilia has similar manifestations. The first signs typically develop after one year of age. Patients with factor activity greater than 2% less frequently experience joint hemorrhages, retroperitoneal hematomas, and hematuria. Post-traumatic hematomas and prolonged bleeding are most typical, especially in case of mucosal injuries.

Mild hemophilia may remain asymptomatic throughout life. Hemorrhagic syndrome usually occurs as a result of major trauma or surgical treatment. Musculoskeletal involvement is extremely rare.

2. Diagnostics, medical indications and contraindications for diagnostic methods

To establish the diagnosis of hemophilia in a patient with a history of hemorrhagic syndrome or a burdened family history, diagnostic criteria for hemophilia are used (the diagnosis is established if at least two of the three criteria are met) [1,3]:

• absence of acquired coagulopathies;

• decrease in FVIII/FIX activity below 50%;

• presence of FVIII or FIX gene mutations.

2.1 Complaints and Anamnesis

Diagnosis of hemophilia begins with identifying the presence of a hemorrhagic syndrome in the anamnesis of the patient and family members.

• All patients with suspected hemophilia are recommended to undergo a history and symptom taking for blood and hematopoietic system disorders [1,3].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: when taking the disease history and family history, investigate the presence of manifestations of hemorrhagic syndrome: complaints of easily developing ecchymoses and hematomas in early childhood; occurrence of spontaneous bleeding (especially into joints, muscles, and soft tissues); prolonged bleeding after trauma or surgery.

Family history data in approximately 2/3 of patients contain indications of hemorrhagic manifestations in close maternal relatives (in males, less frequently in females). Personal history data may contain information about hemorrhagic manifestations in the patient. When taking the disease history, it is necessary to pay attention to the presence of hemorrhagic manifestations in the neonatal period in the form of cephalhematomas, intracranial hemorrhages, bleeding, and prolonged healing of the umbilical cord stump; in infants – ecchymoses not associated with significant trauma, soft tissue hematomas after minor bruises or spontaneous ones. In some children, bleeding may be absent in the first year of life until the child starts walking [4,5]. It is important to pay attention to the discrepancy between the severity of hemorrhagic manifestations and the severity of the preceding trauma, relapses of bleeding after primary cessation not associated with re-trauma, massive and (or) multiple hematomas, systemic nature of hemorrhagic manifestations (manifestations of various localizations), and "spontaneous hemorrhagic manifestations." In mild hemophilia, bleeding may be absent until the first trauma or surgical intervention. Taking complaints and anamnesis will help determine the scope of patient examination.

2.2 Physical Examination

• All patients with suspected hemophilia, as well as all patients with an established diagnosis of hemophilia at every medical appointment, are recommended to undergo visual inspection, palpation, and percussion for blood and hematopoietic system disorders [1,3].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5)

Comments: it is necessary to pay attention to the presence of cutaneous hemorrhagic syndrome of varying severity in the form of multiple ecchymoses and hematomas, which are possible in severe and moderate forms of hemophilia. It is highly probable to detect signs of joint damage in the form of deformation, edema, and local skin temperature elevation (acute hemarthrosis) and/or signs of impaired mobility, range of motion, muscle hypotrophy of the limb on the side of the affected joint, and gait disturbance (deforming arthropathy). This allows determining the severity of the patient's condition and the need for specific replacement and/or hemostatic therapy.

2.3 Laboratory Diagnostics

Obtaining the maximum amount of laboratory data contributes to verifying the diagnosis and ruling out acquired deficiencies of blood coagulation factors VIII/IX, as well as ruling out deficiencies of other blood coagulation factors.

• Patients with suspected hemophilia, as well as patients with verified hemophilia at each visit to a hematologist, are recommended to undergo a coagulogram (exploratory study of the hemostasis system), with the mandatory inclusion of the following parameters: activated partial thromboplastin time (APTT), determination of prothrombin (thromboplastin) time in blood or plasma, determination of thrombin time in blood, and study of fibrinogen levels in blood to monitor the state of the blood coagulation system [1,3,6].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: hemophilia is characterized by an isolated increase in APTT while other parameters remain within normal limits. It should be kept in mind that screening in patients with mild hemophilia may show normal APTT values.

For emergency monitoring of treatment efficacy, it is necessary to use the APTT test (normal or subnormal values must be obtained); however, these data do not allow differentiation of activity values above 30-50% and do not reflect a direct correlation with factor VIII and IX activity.

• Patients with suspected hemophilia are recommended to undergo a complete blood count (CBC) and platelet count to monitor blood parameters [1,3,6].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with hemorrhagic syndrome upon detection of an isolated APTT prolongation with suspected hemophilia are recommended to undergo blood testing for the diagnosis of congenital coagulation factor deficiency, including determination of factor VIII activity in blood serum, determination of factor IX activity in blood serum, determination of factor XI activity in blood serum, determination of factor XII activity in blood serum, study of von Willebrand factor activity and properties in blood, and study of von Willebrand factor antigen [1,3,6].

Level of Evidence CGrade of Recommendation 5Level of Evidence C (reliability of evidence – 5)

Comments: at the second stage, the activity of plasma hemostasis factors — FVIII, FIX, XI, and XII, von Willebrand factor activity (vWF:RCo), and vWF-ag are determined.

• Patients with suspected or established hemophilia are recommended determination of inhibitor activity to factor VIII and/or factor IX in blood plasma using the Nijmegen-modified Bethesda assay to assess the state of the coagulation system and monitor the efficacy of ongoing treatment in the following situations [1,3,7–13]:

• in children – every 5 days for the first 20 exposure days (EDs), every 10 days from the 21st to the 50th ED, and then at least 2 times a year up to 100 EDs.

• in patients with more than 100 EDs to the product – once a year and additionally in the following situations: decreased efficacy of factor replacement therapy when administering adequate doses, appearance or increase in the number of bleeding episodes on prophylactic therapy, absence of a sufficient increase in factor activity in the blood after drug administration.

• before surgical interventions and postoperatively if there is no adequate increase in factor activity in the blood after drug administration.

• 4 weeks after the completion of intensive therapy.

GCR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

Comments: confirmation of inhibitor presence and titer determination are performed in a coagulology laboratory. In patients receiving emicizumab** prophylaxis, a chromogenic assay with bovine clotting factors should be used to determine FVIII inhibitor titers.

Inhibitor classification:

- inhibitor titer < 5 BU – low titer inhibitor (low responder)

- inhibitor titer ≥ 5 BU – high titer inhibitor (high responder)

Low titer inhibitors can be transient and disappear within 6 months. High titer inhibitors are usually permanent. With prolonged absence of replacement therapy, their titer may decrease, but upon resumption of therapy, an anamnesistic reaction may develop within 3–5 days.

At a very low titer (<0.6 BU), the inhibitor may not be detected by the Bethesda assay, but may cause a shortening of the half-life and recovery of the factor.

• Patients with suspected hemophilia and detected decreased factor IX activity are recommended determination of factor IX inhibitor activity in blood plasma [8].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Patients with hemorrhagic syndrome when it is impossible to perform a comprehensive coagulological examination are recommended to undergo thromboelastography to identify and monitor disorders in the blood coagulation system [14].

Level of Evidence CGrade of Recommendation 5Level of Evidence C (reliability of evidence – 5)

Comments: in a portion of patients with an established diagnosis, global hemostasis tests can be performed, such as thromboelastography. The results of global tests can indicate the direction of blood coagulation disorders. They cannot be used to establish a diagnosis or to determine treatment drugs and their administration regimens. The use of global tests may be possible in certain cases as a screening tool when coagulological testing is unavailable, as well as to monitor ongoing therapy.

2.4 Instrumental Diagnostics

Instrumental studies may allow visualization of bleeding/hemorrhage of various localizations, as well as identification of complications developed as a result of hemorrhagic manifestations.

• In all patients with suspected or established hemophilia presenting with suspected gastrointestinal bleeding/hemorrhage, it is recommended to perform esophagogastroduodenoscopy and/or small bowel/colon video capsule endoscopy to determine the severity of hemophilia manifestations and localize the bleeding [15,16].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5)

• In all patients with suspected or established hemophilia presenting with suspected joint bleeding/hemorrhage, it is recommended to perform joint ultrasound, radiography of the affected joint, or magnetic resonance imaging of the joint to determine the severity of hemophilia manifestations and localize the bleeding [1,3].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5)

• In all patients with suspected or established hemophilia presenting with suspected abdominal and/or retroperitoneal bleeding/hemorrhage, it is recommended to perform a comprehensive ultrasound of the abdominal cavity and retroperitoneal space to determine the severity of hemophilia manifestations and localize the bleeding [1,3].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5)

• In all patients with suspected or established hemophilia presenting with suspected urinary tract bleeding/hemorrhage, it is recommended to perform urinary tract ultrasound to determine the severity of hemophilia manifestations and localize the bleeding [17].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5)

• In all patients with suspected or established hemophilia presenting with suspected thoracic bleeding/hemorrhage, it is recommended to perform chest computed tomography to determine the severity of hemophilia manifestations and localize the bleeding [18,19].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5)

• In all patients with suspected or established hemophilia presenting with suspected cerebral bleeding/hemorrhage, it is recommended to perform computed tomography or magnetic resonance imaging of the brain to determine the severity of hemophilia manifestations and localize the bleeding [1,3].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5)

2.5 Other Procedures

• In all patients with suspected or established hemophilia presenting with suspected hemorrhagic manifestations or their consequences, it is recommended to consult relevant specialists depending on the bleeding localization to determine functional impairments in various organs and systems resulting from past or ongoing bleeding/hemorrhage [1,3]:

• traumatologist-orthopedist

• surgeon

• urologist

• neurologist

• otorhinolaryngologist

• dentist

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5)

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 General principles of treatment

• In all patients with hemophilia, it is recommended to administer specific replacement therapy with blood coagulation factors [1,3].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: specific replacement therapy with blood coagulation factors is indicated for patients with any severity of the disease. The choice of treatment regimen (on-demand or prophylactic) depends on the clinical phenotype of the disease. Blood coagulation factors are administered intravenously. Modern hemophilia therapy is based on the principle of "home treatment" (prophylactic or on-demand). Mandatory conditions for "home treatment" include: the patient has stocks of blood coagulation factors (the drug is located where the patient is), the decision to administer the drug is made by the patient or their relatives in accordance with the recommendations of a hematologist, and the patient and/or their relatives are trained in the rules of drug storage and administration.

It is necessary to use purified, virus-inactivated products made from human donor plasma belonging to the group "Blood coagulation factors" (ATC classification B02BD) – plasma-derived (blood coagulation factor VIII**, blood coagulation factor IX**, blood coagulation factor VIII + von Willebrand factor**, anti-inhibitor coagulant complex**), or recombinant (octocog alfa**, moroctocog alfa**, nonacog alfa**, eptacog alfa (activated)**, simoctocog alfa (human recombinant blood coagulation factor VIII)**, lonoctocog alfa, turoctocog alfa), or extended half-life recombinant blood coagulation factor VIII/IX concentrates (efmoroctocog alfa**, rurioctocog alfa pegol, albutrepenonacog alfa) [1,3].

In previously untreated patients, it is advisable to administer therapy with blood coagulation factors derived from donor plasma or recombinant coagulation factor VIII/IX concentrates without switching therapy for 100 exposure days (provided no inhibitor develops). Currently, there is no basis to prefer one group of blood coagulation factors over another: plasma-derived (containing or not containing von Willebrand factor) or recombinant. Given satisfactory efficacy and tolerability of the specific therapy received by the patient, switching the INN of coagulation factor VIII or IX throughout life is inadvisable.

Preference should be given to the product that, with equal efficacy, is best tolerated by the patient, has better individual pharmacokinetic profiles, and is most convenient to use based on specific objective conditions. For individual dose selection, some patients may undergo a pharmacokinetic study [20,21].

Changing the INN in a specific patient in the absence of registered adverse events to the administered drug and with a satisfactory clinical response to therapy is possible after 100 exposure days of blood coagulation factor administration.

The use of unpurified products for the prevention or treatment of bleeding in hemophilia – blood components (fresh frozen plasma or coagulation factor VIII** in the dosage form of solution for infusion [frozen]) – is possible only when coagulation factor is unavailable and should not be a routine practice [20,21].

3.2 Treatment of bleeding

The calculation of blood coagulation factor dose and treatment duration is carried out based on the target level of deficient factor activity and the type of bleeding (see Appendix A3.1).

In all cases, it is necessary to immediately use an adequate dose and adhere to the administration frequency [3,22]

The use of inadequately low doses and non-compliance with the administration regimen leads to reduced efficacy, clinical deterioration, and increased drug consumption. An inadequately high dose can lead to thrombosis and unjustifiably increases drug consumption.

• In all patients with hemophilia for whom individual pharmacokinetic data are not available, it is recommended to use the average doses given below [1,3,22–24]:

• calculation of the dose of coagulation factor VIII**/octocog alfa**, moroctocog alfa**, simoctocog alfa (recombinant human coagulation factor VIII)**, turoctocog alfa, lonoctocog alfa, efmoroctocog alfa**, rurioctocog alfa pegol for patients older than 1 year: dose (IU) = body weight x (target activity – baseline activity) x 0.5.

• calculation of the dose of coagulation factor VIII**/octocog alfa**, moroctocog alfa**, simoctocog alfa (recombinant human coagulation factor VIII)**, turoctocog alfa, efmoroctocog alfa**, rurioctocog alfa pegol in infants in the first year of life: dose (IU) = body weight x (target activity – baseline activity).

• calculation of the dose of coagulation factor IX**/nonacog alfa**/albutrepenonacog alfa: dose (IU) = body weight x (target activity – baseline activity).

• upon administration of 1 IU/kg of the patient's body weight, FVIII activity increases by an average of 2% (in patients older than 1 year) (FVIII recovery activity - recovery test = 2), and FIX by an average of 1% (recovery test = 1).

• In infants in the first year of life, the degree of FVIII activity increase may be lower – 1%.

Level of Evidence CGrade of Recommendation 5Level of Evidence C (reliability of evidence – 5)

Comments: in products with a standard half-life, the half-life of FVIII** is about 8–12 hours, and the half-life of FIX** is about 24 hours. The half-life of FVIII** in extended half-life products is increased by 1.3 times or more [25], while the half-life of albutrepenonacog alfa is increased by 3.5–4 times (up to 95.3 hours in adults and up to 86–89 hours in children of various ages). The use of extended half-life products on an on-demand basis is permitted only for patients receiving regular prophylactic replacement therapy with these products (in the event of bleeding or during invasive procedures) [26].

In some cases, for example, due to individual pharmacokinetic characteristics in the absence of an inhibitor to FVIII or FIX, higher doses of coagulation factors (B02BD according to the ATC classification) may be used to stop bleeding.

Considering the variability of pharmacokinetic parameters in each individual patient, replacement therapy requires clinical and, if necessary, laboratory monitoring. Clinical monitoring must be performed continuously by a hematologist upon patient visits, as well as by the parents and the patient themselves. Clinical monitoring is based on assessing the dynamics of hemorrhagic manifestations and comparing it with the ongoing replacement therapy. Laboratory monitoring is performed routinely once a year and includes determining aPTT, the activity of the deficient factor in the blood, and the presence of its inhibitor. Unscheduled laboratory monitoring is performed when a patient seeks medical attention due to a decrease in the efficacy of ongoing therapy and includes determining aPTT, the activity of the deficient factor in the blood before and 30 minutes after administration of the calculated dose of the product (recovery test), and the presence of an inhibitor. In some cases, a pharmacokinetic study is additionally performed by determining FVIII/FIX activity at multiple time points to determine the half-life of the product. To evaluate the effectiveness of hemostatic therapy, some patients may undergo an integral test—thromboelastography [1,3].

3.3. Prophylactic treatment

Prophylactic therapy is a prerequisite for maintaining the physical and psychological health of patients with severe and moderate hemophilia.

Prophylaxis consists of the systematic administration of coagulation factors or emicizumab** (the latter only for patients with severe hemophilia A) to prevent bleeding and the development of hemophilic arthropathy. Prophylactic therapy that begins in the absence of signs of joint damage, before the age of three, and at least before the second hemarthrosis episode, is called primary.

Primary prophylaxis is the most effective way to prevent musculoskeletal damage. The decision to start continuous prophylactic replacement therapy must be made taking into account the state of venous access. If necessary, the issue of placing a central venous catheter can be addressed, which may be implanted and used only if it is possible to ensure adequate provision of necessary consumables, care, and monitoring of the patient at their place of residence.

Secondary prophylaxis begins after two or more hemarthroses in the presence of minimal signs of joint damage. Tertiary prophylaxis is prescribed at any age in the presence of damage to one or more joints. It can be continuous or short-term (periodic).

Prophylactic therapy does not eliminate already developed joint damage, but it reduces the frequency of bleeding and can slow down the progression of arthropathy and improve quality of life.

Indications for continuous prophylactic replacement therapy with coagulation factors (B02BD according to the ATC classification) are: severe hemophilia, moderate hemophilia with the development of at least one episode of hemarthrosis or severe hemorrhagic manifestations of another localization. Patients with a factor activity of ≥5% require continuous or long-term prophylactic treatment in case of recurrent joint hemorrhages, the appearance of signs of synovitis or arthropathy, or severe hemorrhagic manifestations requiring frequent administrations of coagulation factors.

To evaluate efficacy and decide on the need to adjust the prophylaxis regimen, it is recommended to monitor the ongoing prophylactic therapy clinically and laboratory-wise. During clinical monitoring, the decision that prophylactic replacement therapy is insufficiently effective is made in cases of: more than 2 episodes of spontaneous hemarthrosis per year, the appearance of signs of chronic synovitis or progression of arthropathy, or the occurrence of life-threatening bleeding. Laboratory monitoring consists of determining the residual factor activity before the next administration (should be at least 1%), monitoring for the presence of an inhibitor, and, if possible, conducting a pharmacokinetic study.

For laboratory monitoring of therapy, the assay approved for the specific product used for treatment should be used. For plasma coagulation factors VIII**/IX**, recombinant coagulation factor concentrates (octocog alfa**, moroctocog alfa**, nonacog alfa**, eptacog alfa (activated)**, simoctocog alfa (human coagulation factor VIII recombinant)**, lonoctocog alfa, turoctocog alfa) and extended half-life recombinant coagulation factor concentrates (efmoroctocog alfa**, rurioctocog alfa pegol, albutrepenonacog alfa), a one-stage or chromogenic assay is recommended. For patients receiving emicizumab**, determining FVIII activity and FVIII inhibitor titer using a chromogenic assay with bovine blood factors is recommended. The results of the one-stage aPTT assay in patients receiving emicizumab** will be distorted because, unlike FVIII, emicizumab** does not require thrombin activation to bind to substrates. As a result, all aPTT-based tests, including the one-stage FVIII activity assay and the Bethesda inhibitor titer assay, will yield distorted results. This must be taken into account when prescribing and interpreting the results of laboratory tests in patients receiving emicizumab** and those who discontinued the drug less than 6 months ago [43,44].

Causes of insufficiently effective replacement prophylactic therapy may include: development of an inhibitor to the coagulation factor, prescription of an inadequate dose and/or administration frequency, non-compliance with the administration regimen and dosages by the patient and parents, and individual patient characteristics requiring higher doses or more frequent administration of the product.

The decision to increase the dose or administration frequency of the product during prophylactic therapy must be made if there are objective clinical or laboratory data indicating its ineffectiveness.

• All patients with severe hemophilia and/or a severe clinical phenotype of the disease are recommended to undergo primary prophylaxis to prevent the development of hemophilic arthropathy and patient disability [4,11].

GPP CLE 4Grading of Recommendations Assessment, Development and Evaluation (GRADE) level C (Level of Evidence – 4)

• Patients with frequent recurrent joint hemorrhages (especially patients with target joints) are recommended to undergo secondary or tertiary prophylaxis [20,27].

LoR BGoE 2Level of Recommendation B (Grade of Evidence – 2)

• The recommended prophylaxis regimen is [7,20,22,24,28–32]:

• for patients with hemophilia A – infusion of coagulation factor VIII** (plasma coagulation factor VIII) / moroctocog alfa**, simoctocog alfa (human coagulation factor VIII recombinant)**, turoctocog alfa at a dose of 25–40 IU/kg once every 2 days or 3 times a week; infusion of octocog alfa** in children under 6 years of age at a dose of 20–50 IU/kg 3–4 times a week, for patients 6 years and older 25–40 IU/kg once every 2 days or 3 times a week; infusion of lonoctocog alfa in children under 12 years of age at a dose of 30–50 IU/kg 2–3 times a week, for patients 12 years and older 20–50 IU/kg 2–3 times a week; infusion of efmoroctocog alfa** at a dose of 50 IU/kg with a 3–5 day interval; the dose and administration frequency may be adjusted based on the patient's response in the range of 25 to 65 IU/kg; infusion of rurioctocog alfa pegol in children under 12 years of age at a dose of 55 IU/kg twice a week, for patients 12 years and older 40–50 IU/kg twice a week.

• for patients with hemophilia B – infusion of coagulation factor IX** at a dose of 25–40 IU/kg once every 3 days or twice a week; infusion of nonacog alfa** 40–50 IU/kg once every 3–4 days (#nonacog alfa for children under 6 years – 2 infusions per week, 33–87 IU/kg [32]), infusion of albutrepenonacog alfa at a dose of 35–50 IU/kg once a week.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: for long-term prophylaxis with albutrepenonacog alfa some adult patients (over 18 years of age) with hemophilia B who have achieved bleeding control with once-weekly administration can be prescribed the drug at a dosage of up to 75 IU/kg at intervals of 10 or 14 days, with a possible further increase in administration intervals (maximum up to once every 21 days). In pediatric patients, the recommended dosing regimen ranges from 35 to 50 IU/kg once a week.

During prophylactic treatment with nonacog alfa** in children under 12 years of age, depending on individual pharmacokinetic characteristics, age, bleeding type, physical activity, higher doses or a shortened administration interval may be used in some cases [33]

Prophylactic administration of any drug is best performed in the morning so that the maximum factor activity in the blood coincides with the period of highest activity. The prophylactic therapy protocol should be as individualized as possible, depending on age, venous access, bleeding phenotype, factor activity, comorbidities, the patient's social activity, and the characteristics of the pharmacokinetic curve. In some cases (increased risk of injury, individual pharmacokinetic features in the absence of an inhibitor to FVIII), higher doses of blood coagulation factors (ATC code B02BD) may be used for prophylactic treatment.

• For patients with severe hemophilia A, it is recommended to initiate prophylactic treatment with emicizumab**: a loading dose of 3 mg/kg of body weight—4 administrations at 7-day intervals, followed by regular administration of the drug at a dose of 1.5 mg/kg once a week or 3 mg/kg of body weight once every 2 weeks [34].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: emicizumab** is a bispecific humanized monoclonal antibody that binds activated FIX with FX and replaces the function of activated FVIII. The action of emicizumab** is not affected by FVIII concentration or the presence of an inhibitor to it. The decision to use emicizumab** is made by the attending physician, taking into account additional factors (venous access, clinical course of the disease, presence of arthropathy, patient compliance and comorbidities). It can be used in patients of any age. Emicizumab** is administered subcutaneously; the injection site selection should be restricted to the recommended areas: the abdomen, the upper outer arm, and the thigh.  If bleeding occurs during emicizumab** prophylaxis, additional administration of blood coagulation factor VIII** (preferred)/octocog alfa**/moroctocog alfa**/simoctocog alfa (recombinant human blood coagulation factor VIII)**/turoctocog alfa in standard dosages is required.

3.4. Specifics of hemostatic therapy depending on the bleeding site

• For patients with hemophilia presenting with hemarthrosis and muscle hemorrhages, it is recommended to immediately initiate replacement therapy upon the onset of the first subjective symptoms (pain, sensation of fullness, discomfort, functional impairment) [3,23].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: joint hemorrhages manifest as discomfort, pain, functional impairment, and fluctuation. Hematomas, like hemarthroses, are accompanied by pain syndrome and impairment of organ and/or limb function. Hemorrhages are most dangerous in areas where they can damage the neurovascular system (iliac, gastrocnemius, and other muscles).

If severe pain develops, short-term immobilization may be performed, which should be removed immediately after the pain subsides.

In case of pain syndrome, local hypothermia is indicated for 15–20 minutes every 4–6 hours only during the first 24 hours.

Rehabilitation measures and exercise therapy (physiotherapy) should expediently be started after the cessation of the pain syndrome, taking into account the local status of the injury site.

If the patient is not receiving continuous prophylactic treatment, short-term prophylaxis is indicated after bleeding cessation, especially during the rehabilitation period.

Joint aspiration (puncture with content evacuation) is indicated for: hemarthrosis with pain syndrome, presence of a large volume of blood in the joint cavity, signs of developing purulent arthritis, and neuromuscular disorders developing against the background of hemarthrosis.

• For patients with hemophilia presenting with traumatic brain injury or in any other case of suspected CNS hemorrhage, it is recommended to immediately initiate replacement therapy prior to diagnostics [1,3,23].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: any traumatic brain injury in patients with hemophilia can lead to intracranial hemorrhage. Back trauma can lead to hemorrhage into the spinal canal. In addition, spontaneous CNS hemorrhages are possible. Signs of intracranial hemorrhage include: persistent and increasing headache, drowsiness, unmotivated anxiety or lethargy, repeated vomiting or regurgitation, and other focal or general neurological symptoms.

In infants during the first months of life, hemorrhages may occur with minimal symptoms or be asymptomatic. Even minimal CNS hemorrhages are life-threatening, require emergency hospitalization, intensive replacement therapy, and immediate brain CT or MRI.

The decision on surgical treatment for patients with intracranial hemorrhages is made by a medical board taking into concomitant diseases.

• For patients with hemophilia following CNS hemorrhage, it is recommended to administer prophylactic therapy for 3–6 months [1,3,23].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

• For patients with hemophilia presenting with gastrointestinal bleeding, it is recommended to immediately initiate replacement therapy, as well as therapy with antifibrinolytic agents (fibrinolysis inhibitors; ATC code B02A) and treatment of the local process that led to the bleeding [1,3,23].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: acute GI bleeding may manifest as hematemesis, "coffee-ground" emesis or emesis with streaks of blood, bloody stools, or melena. Sharp weakness, tachycardia, blood pressure drop, dry mouth, and skin pallor are characteristic.

GI bleeding typically develops against the background of concomitant GI pathology: peptic ulcer disease, erosions, polyps, inflammatory bowel diseases, etc. Such bleeding is life-threatening, requires emergency hospitalization, and immediate adequate replacement therapy.

Urgent diagnostics of the bleeding source are necessary, for which a set of required diagnostic measures using endoscopic, radiological, ultrasonic, and other methods is performed.

Complete blood count parameters should be regularly monitored and anemia treated if necessary.

• For patients with hemophilia presenting with renal hemorrhage, it is recommended to immediately initiate replacement therapy and observe strict bed rest for the first 48 hours [1–3,23].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: patients who have developed renal hemorrhage must be consulted by a urologist and undergo a urological examination.

• For patients with hemophilia presenting with renal hemorrhage, the use of antifibrinolytic agents (fibrinolysis inhibitors; ATC code B02A) is not recommended [3,11,23].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

To stop bleeding in patients with severe HA receiving emicizumab**, it is recommended to additionally administer blood coagulation factor VIII**/octocog alfa**, moroctocog alfa**, simoctocog alfa (human recombinant blood coagulation factor VIII)**, turoctocog alfa in standard dosages depending on the bleeding site. For patients with hemophilia A complicated by inhibitors who are receiving emicizumab**, the first-line drug for bleeding control is eptacog alfa (activated)** in standard doses. The initial dose of anti-inhibitor coagulant complex** should not exceed 50 U/kg, and the daily dose should not exceed 100 U/kg [45].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

3.5. Treatment of inhibitor hemophilia

The appearance of an FVIII/FIX inhibitor is considered the most severe complication associated with hemophilia treatment. Inhibitors are alloantibodies (IgG) that neutralize exogenous FVIII/FIX.

The appearance of an inhibitor is primarily manifested by the absence of a clinical response to standard blood coagulation factor therapy (ATC code B02BD) or the occurrence of bleeding while on prophylactic therapy.

Inhibitors most frequently appear in patients with severe hemophilia (up to 30% of patients with severe hemophilia A and up to 3–5% of patients with severe hemophilia B). The inhibitor most commonly develops within the first 20–50 (up to 100) exposure days (EDs) to the factor and following intensive therapy during surgical intervention.

Since the appearance of inhibitors renders standard replacement therapy with blood coagulation factor VIII**/octocog alfa**, moroctocog alfa**, simoctocog alfa (human recombinant blood coagulation factor VIII)**, turoctocog alfa, lonoctocog alfa, rurioctocog alfa pegol, or blood coagulation factor IX concentrate**/nonacog alfa**, albutrepenonacog alfa ineffective, these patients are at a higher risk of severe complications and even death from bleeding.

In moderate or mild hemophilia, the inhibitor can neutralize endogenous FVIII/FIX, thereby converting the clinical phenotype of the disease into a severe form.

Clinical features of inhibitor-complicated hemophilia. Up to 50% of patients with inhibitor-complicated hemophilia may experience severe allergic reactions, including anaphylaxis, upon administration of FIX**. Such reactions are often the first symptom of inhibitor development.

• In patients with hemophilia and a low inhibitor titer, it is recommended to manage bleeding by administering blood coagulation factors (B02BD according to the ATC classification) at doses 3 times higher than standard, or by administering bypassing agents [35].

CGR CLEL 5Level of Clinical Guidance Recommendation C (Level of Evidence – 5).

Comments: the choice of drug for treatment should be based on the inhibitor titer, clinical response to therapy, and the nature of the bleeding.

Comments: currently, bypassing agents include 2 drugs: anti-inhibitor coagulant complex** and eptacog alfa (activated)**. No significant difference in efficacy, safety, and treatment cost between these drugs has been established. However, there is data on individual patient response variations to each drug, which must be considered when choosing treatment in each specific case.

Doses of bypassing agents for bleeding management:

- #anti-inhibitor coagulant complex** is prescribed at a dose of 30–100 IU/kg every 12–24 hours. The maximum daily dose is 200 IU/kg (for patients receiving emicizumab** - no more than 100 IU/kg/day);

- #eptacog alfa (activated)** is prescribed at a dose of 90–120 mcg/kg every 2–4 hours until bleeding stops. A single daily administration of eptacog alfa (activated)** at a dose of 270 mcg/kg is possible.

Comments: the action of emicizumab** is not affected by FVIII concentration and the presence of its inhibitor.

• As first-line therapy in patients with inhibitor-complicated hemophilia A, it is recommended to perform immune tolerance induction (ITI) to eliminate the inhibitor [9,10,41,42].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: the optimal timing for initiating ITI is immediately after inhibitor detection. ITI efficacy is significantly increased if the inhibitor titer does not exceed 10 BU at the start of therapy. Nevertheless, a high inhibitor titer is not a contraindication to ITI. ITI can be performed using any FVIII product (blood coagulation factor VIII**, blood coagulation factor VIII + von Willebrand factor**, octocog alfa**, moroctocog alfa**, simoctocog alfa (human recombinant blood coagulation factor VII)**, lonoctocog alfa, turoctocog alfa, efmoroctocog alfa**, rurioctocog alfa pegol). It is preferable to perform ITI with blood coagulation factor VIII**. When conducting ITI, it is unacceptable to switch the blood coagulation factor VIII**, as this significantly worsens the prognosis of therapy. Before starting ITI, it is necessary to ensure an adequate supply of the drug is available.

There is no optimal ITI regimen. For patients with a high-responding inhibitor, regardless of the inhibitor titer at the start of ITI, the recommended initial regimen is 100–150 IU/kg of FVIII product every 12 hours. For patients with a low-responding inhibitor, starting ITI with a regimen of 50–100 IU/kg of the product daily or every other day is recommended.

Dose reduction and frequency tapering of the drug begin after achieving the following parameters: inhibitor titer less than 0.6 BU, normalization of recovery test (greater than 66%), and normalization of the half-life (greater than 7 hours). Dose reduction of the drug is carried out gradually according to a schedule with continuous laboratory monitoring. After reaching a dose of 30–50 IU/kg once every 2 days, therapy should be continued in a secondary/tertiary prophylaxis regimen at this dose long-term. An alternative option for prophylaxis after achieving tolerance is the use of emicizumab** in standard regimens. Discontinuation of prophylactic treatment may lead to inhibitor relapse. The maximum duration of ITI is 3 years. The criteria for ITI efficacy are presented in Table 3.

Table 3. Criteria for ITI efficacy

The choice of drug for ITI must be individualized.

During ITI, any influences and drugs that stimulate immune responses must be avoided, including vaccination, interferon therapy, and other types of immunotherapy.

• In patients with inhibitor-form HA during ITI, for the management of hemorrhagic syndrome during ITI, it is recommended to use bypassing agents: anti-inhibitor coagulant complex** or eptacog alfa (activated)** [3,9].

Level of Evidence CGrade of Recommendation 5Level of Evidence C (reliability of evidence – 5)

• In patients with inhibitor-form HA during ITI, for the prevention of hemorrhagic syndrome during ITI, it is recommended to use emicizumab** in standard regimens [43]

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: in case of using emicizumab** during ITI, the doses and administration regimens of #blood coagulation factor VIII concentrates**must be modified: 50–100 IU/kg administered 3 times a week, every other day, or daily depending on the inhibitor titer [44]. In case series of patients receiving ITI with ongoing emicizumab prophylaxis** no increased risk of adverse and/or thrombotic events has been reported.

Comments: re-administering ITI using a different drug or modifying the treatment regimen is possible.

Experience with ITI in patients with inhibitor-form HB is limited due to very low efficacy and allergic reactions.

3.6. Treatment of orthopedic complications of hemophilia

Management of patients with hemophilia presenting with chronic deforming arthropathy must be carried out in cooperation with orthopedic traumatologists experienced in treating patients with hemophilia [1,3,22,23].

Chronic deforming arthropathy develops as a result of the progressive course of chronic synovitis and recurrent hemarthroses. It manifests as osteoporosis, structural impairment, thinning and loss of articular cartilage, pain syndrome, contractures, muscle atrophy, and joint deformity.

The basis for preventing the development of chronic arthropathy is adequate and continuous prophylactic replacement therapy. Timely treatment of synovitis is also necessary to prevent the development of arthropathy. The diagnosis of arthropathy is based on the detection of clinical signs and the results of instrumental studies: ultrasound, CT, MRI.

The goal of treating already developed chronic arthropathy is to improve joint function and reduce pain syndrome. To combat pain in patients older than 18 years, it is optimal to use oxicams (COX-2 inhibitors, M01AC according to the ATC classification) (specific drugs from the NSAID group [M01A non-steroidal anti-inflammatory and antirheumatic products], namely ketorolac**, nimesulide, ibuprofen**, drugs from the "coxibs" group [M01AH according to the ATC classification]). In children with a body weight of more than 5 kg, the use of ibuprofen** is possible; in children older than 2 years, the use of nimesulide is possible; in children older than 16 years, the use of ketorolac** is possible [46]. To restore joint function and muscle condition, courses of exercise therapy (physical therapy) and physiotherapy are carried out. In some cases, the use of exercise equipment is effective. In the initial stages of rehabilitation treatment, courses of hyaluronic acid in combination with drugs from the S01KA51 group (hyaluronic acid in combination with other agents according to the ATC classification) are indicated. If conservative therapy is insufficiently effective, surgical treatment is indicated. Surgical treatment of patients with hemophilia should be performed by physicians experienced in treating patients with hemophilia.

• Patients with hemophilia and chronic synovitis are recommended to undergo prophylactic replacement therapy with blood coagulation factor (B02BD according to the ATC classification) in a regimen that will prevent the development of spontaneous hemarthrosis. An important point is also performing daily exercises (physical therapy) aimed at strengthening muscles and maintaining joint mobility [1, 3, 22, 23, 46].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: chronic synovitis develops after recurrent hemarthrosis. As a rule, it is a consequence of the absence or insufficient efficacy of replacement therapy. Manifestations include prolonged elevated temperature over the affected joint, an increase in the soft tissue volume of the joint area, recurrent hemorrhages, and limited mobility.

Diagnosis includes the detection of clinical signs, joint ultrasound and/or MRI. Therapy is carried out jointly with orthopedic traumatologists experienced in treating patients with hemophilia. If signs of inflammation persist, patients older than 18 years are indicated therapy with oxicams (COX-2 inhibitors) (specific drugs from the NSAID group, namely ketorolac**, nimesulide, ibuprofen**, drugs from the "coxibs" group [M01AH according to the ATC classification]). In children with a body weight of more than 5 kg, the use of ibuprofen** is possible; in children older than 2 years, the use of nimesulide is possible; in children older than 16 years, the use of ketorolac** is possible [46].

If replacement therapy is insufficiently effective, a course of joint punctures with the administration of steroidal anti-inflammatory drugs can be performed (at the first stage); further, the options of choice are chemical or endoscopic synovectomy, and if they are insufficiently effective, surgical correction.

• Patients with hemophilia and pseudotumors are recommended to undergo intensive replacement therapy for 6–8 weeks at the first stage, followed by MRI control. If the mass shows no tendency to regress, total tumor removal with capsule excision is recommended [47].

GCR CLOC 5 Grade of Recommendation C (Level of Evidence – 5)

Comments: pseudotumors areformed as a result of improper therapy for hemorrhages into soft tissues, usually into muscles located adjacent to the bone, which may be secondarily affected, or in subperiosteal hemorrhages. Manifestations of a pseudotumor are a stable tumor-like mass displacing surrounding tissues, which exists for many months or years and shows no tendency to regress during intensive factor replacement therapy.

The management of patients with hemophilia and pseudotumors should be carried out jointly by surgeons and hematologists.

In the absence of treatment, a pseudotumor can reach giant sizes, exerting pressure on neurovascular structures and causing pathological fractures.

The surgery must be performed by specialists with experience in the surgical and orthopedic treatment of patients with hemophilia.

• In patients with hemophilia who develop a fracture, it is recommended to immediately initiate replacement therapy with blood coagulation factors (ATC code B02BD). During the first 3–5 days, it is necessary to maintain a factor level in the blood of at least 50–100% (depending on the location and severity of the trauma). Continuous factor replacement therapy should be administered for 10–14 days [48].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5)

Comments: the risk of fractures in patients with hemophilia is associated with osteoporosis and hemophilic arthropathy. Rehabilitation therapy should be initiated immediately after fracture stabilization.

3.7. Surgical treatment

• In patients with hemophilia, it is recommended to perform any surgical intervention or invasive procedure under the cover of replacement therapy with blood coagulation factors (ATC code B02BD) [2,3,11,23].

Level of Evidence CGrade of Recommendation 5Level of Evidence C (reliability of evidence – 5)

Comments: in patients with hemophilia, surgical intervention may be required to treat both hemophilia complications and unrelated diseases. Consultation at a hemophilia treatment center is required before any surgical intervention. If possible, surgical treatment is best performed in a specialized inpatient facility. Surgical intervention in patients with inhibitor hemophilia must be performed exclusively in a specialized inpatient setting. The anesthesiologist-intensivist must have experience in treating patients with blood coagulation disorders.

Strict monitoring of the coagulogram, factor activity, and screening for the presence of an inhibitor is required. Doses and duration of blood coagulation factor therapy depend on the type of surgical intervention (Table 3).

If diagnostic procedures such as lumbar puncture, arterial puncture, or endoscopic examination with biopsy are necessary, patient management is the same as for surgical treatment.

Patients receiving prophylactic treatment with emicizumab** are recommended to undergo any surgical intervention or invasive procedure without discontinuing the drug, using standard doses of coagulation factor VIII**/coagulation factor VIII + von Willebrand factor**/octocog alfa**/moroctocog alfa**/simoctocog alfa (human recombinant coagulation factor VIII)**[49]/lonクトocog alfa/turoctocog alfa/efmoroctocog alfa**/rurioctocog alfa pegol. For patients with hemophilia A complicated by inhibitors and receiving emicizumab**, the drug of choice is eptacog alfa (activated)** in standard doses. If it is necessary to prescribe an anti-inhibitor coagulant complex**, the initial dose must not exceed 50 IU/kg, and the daily dose must not exceed 100 IU/kg [50].

3.8. Long-term vascular access in patients with hemophilia

• In patients with hemophilia, it is recommended to use peripheral venous access whenever possible [51,52].

LoR CQoE 4Level of Recommendation C (Level of Evidence – 4)

Comments: vascular access is a prerequisite for the treatment of patients with hemophilia, since blood coagulation factors are administered intravenously. Intravenous administration of coagulation factors allows for prophylactic treatment, on-demand treatment, home treatment, and immune tolerance induction. Subcutaneous drugs cannot replace intravenous coagulation factors, especially in emergency situations.

Peripheral venous puncture is the method of choice for vascular access in patients with hemophilia. Its use is not associated with a high rate of complications; small-gauge needles (23–25G) are required, and the short infusion time is sufficient for the administration of clotting factors. Arm veins are usually punctured using a butterfly needle. Repeated frequent venipunctures can be complicated by hematomas. Patient and caregiver training in performing venipunctures plays an important role when using this access. At the same time, in some patients, peripheral venous access is impossible due to small vein size, poor tolerance of repeated venipunctures in children, the need for frequent vascular access, or the inability of caregivers and patients to learn venipuncture. Factors influencing the rejection of peripheral access may include patient age and frequent bleeding.

• In patients with hemophilia, it is recommended to use port systems and peripherally inserted central venous catheters as long-term central access devices [53, 54].

CGR BLEL 2Level of Clinical Guidance Recommendation B (Level of Evidence – 2).

Comments: the use of long-term central venous access devices compared to peripheral venous access was more frequently associated with infection (29% vs. 17%, P = 0.01). Catheter-associated thrombotic complications are possible when using long-term central venous access devices.

Indications for the use of long-term central venous access devices are:

- the need for regular long-term vascular access in patients with hemophilia in whom peripheral venous access cannot be used due to small vein size;

- the need for daily intravenous administration of clotting factors, particularly during ITI;

- in children who poorly tolerate repeated venipunctures.

An absolute contraindication to the placement of a long-term central venous access device is the presence of signs of active infection in the patient.

Relative contraindications to the placement of a long-term central venous access device are a history of catheter-associated bloodstream infection and catheter-associated deep vein thrombosis.

• In patients with hemophilia without inhibitors, it is recommended to ensure FVIII/FIX activity during the placement of a long-term central venous access device via infusion of coagulation factor VIII**/coagulation factor IX** [55].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Table 4 shows the doses of coagulation factor VIII**/IX** and target FVIII/IX activity during the placement of a long-term central venous access device in patients with hemophilia without inhibitors.

Table 4. Hemostasis management regimen during port placement in patients with hemophilia

• In patients with hemophilia with an inhibitor, it is recommended to ensure hemostasis during the placement of a long-term central venous access device via infusion of bypassing agents – eptacog alfa (activated)** or anti-inhibitor coagulant complex** [55–58].

ACR CLEL 3Level of Clinical Recommendation C (Level of Evidence – 3)

Comments: during port placement in patients with hemophilia complicated by coagulation factor inhibitors, hemostasis is ensured by administering bypassing agents: anti-inhibitor coagulant complex** 80–100 IU/kg or #eptacog alfa (activated)** 120 mcg/kg. In patients with an inhibitor, #eptacog alfa (activated)** is used every 2–3 h at 90–120 mcg/kg for the first 24 h and then every 4–6 h up to day 7, or #anti-inhibitor coagulant complex** at 80–100 IU/kg every 8 h for the first 3 days, followed by every 12 h. Despite this regimen, port placement in patients with inhibitors is frequently complicated by hematomas.

Comments: patients and their caregivers must be informed about the nature of long-term central venous access devices, their care, potential complications, procedures to follow, and whom to contact in case of complications. Training parents in port management is a mandatory condition for providing effective care to this group of patients. Training is conducted from the first day of port implantation, individually, by the physicians and nurses of the center where the surgery is performed. Subsequently, training is continued at the center where the patient is followed up on an ongoing basis. Parents and patients must master the rules of asepsis and antisepsis, and skills for performing drug infusions using the port.

3.9. Other treatment

• Patients with hemophilia are recommended additional hemostatic therapy to stop bleeding: antifibrinolytic agents (ATC code B02A), local hemostatic agents (ATC code B02BC) [1, 59–62].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: the following medicinal products may be used as additional hemostatic therapy:

- Fibrinolysis inhibitors (antifibrinolytic agents). Used as an adjunct to specific replacement therapy. Most effective for bleeding from mucosal wounds. Can be used to treat bleeding of other localizations. Contraindicated in renal hemorrhage.

- Local hemostatic agents. During surgical interventions, especially on parenchymal organs, tooth extraction, and wound treatment, the use of local hemostatic agents is indicated. These agents are used in conjunction with replacement therapy and are intended to optimize the local hemostatic effect.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• In patients with hemophilia with musculoskeletal system involvement, it is recommended to provide long-term treatment of joint and muscle injuries, functional rehabilitation, as well as spa treatment to prevent the progression of musculoskeletal disorders and improve their orthopedic status [24].

Level of Evidence CGrade of Recommendation 5Level of Evidence C (reliability of evidence – 5)

Comments: the main clinical manifestation of hemophilia is recurrent hemarthrosis, which irreversibly leads to the development of deforming arthropathy and chronic synovitis in these patients. Musculoskeletal involvement significantly limits patients' social adaptation and impairs their quality of life. Treatment can be carried out in health resorts within the patient's climatic zone, as well as at balneological resorts. The development of rehabilitation measures should be carried out jointly by rehabilitation specialists, balneologists, and hematologists experienced in treating patients with blood clotting disorders.

Possible types of therapy include:

- psychological prevention school for patients and relatives;

- ultrasound therapy for joint diseases;

- medicinal ultraphonophoresis for joint diseases;

- drug electrophoresis for joint diseases;

- high-frequency electromagnetic field therapy (inductothermy);

- ultra-high-frequency electric field therapy (UHF therapy);

- alternating magnetic field therapy (AMF).

5. Prevention and Dispensary Observation

Patients with hemophilia must be monitored by a multidisciplinary team of specialists, including a hematologist, pediatrician, orthopedic traumatologist, dentist, physical therapist, exercise therapy physician, and medical psychologist with experience in working with hemophilia patients [1, 24].

Examinations of patients by a hematologist, orthopedic traumatologist, and dentist should be performed at least twice a year; by other specialists, as needed. It is advisable to conduct an annual health check-up (dispensary observation) of patients in a specialized hemostasis disorders center, provided the center has adequate clinical and laboratory facilities [1, 63].

Dispensary observation of patients with hemophilia includes:

Dynamic monitoring of the patient's condition with assessment for adverse events during replacement therapy: development of a coagulation factor inhibitor, individual drug intolerance, viral contamination, changes in the patient's psychological or social status, and assessment of the peripheral venous system.

Treatment of hemophilia complications: correction of iron deficiency and inhibitors.

Detection of comorbid conditions, especially dental, oral, gastrointestinal, and ENT disorders, cardiovascular diseases, etc., and referral to appropriate specialists.

• All patients with hemophilia should be registered and monitored at a specialized center (where possible) [1,3].

Level of Recommendations CLevel of Evidence 5Level of recommendations C (level of evidence – 5).

Comments: patients or the physicians they consult must have round-the-clock access to a hematologist experienced in treating patients with hemostatic disorders.

6. Organization of Medical Care

All patients with hemophilia should be registered and monitored at a specialized center (where possible). There must be round-the-clock access to contact a hematologist experienced in treating patients with hemostatic disorders.

Indications for planned hospitalization:

• planned surgical treatment.

Indications for emergency hospitalization:

• life-threatening bleeding;

• emergency surgical intervention.

Indications for patient discharge from the hospital:

• complete cessation of bleeding

7. Additional Information

7.1 Basic principles of organizing care for patients with hemophilia

Guaranteed uninterrupted supply of coagulation factor VIII** and FIX**, coagulation factor VIII + von Willebrand factor**, octocog alfa**, moroctocog alfa**, simoctocog alfa (recombinant human coagulation factor VIII)**, nonacog alfa**, lonoctocog alfa, turoctocog alfa, efmoroctocog alfa**, rurioctocog alfa pegol, albutrepenonacog alfa, emicizumab** in patients with non-inhibitor hemophilia, or bypassing agents and emicizumab** in patients with inhibitor hemophilia A, and training family members of hemophilia patients in the administration of these drugs are priorities in organizing care for hemophilia patients.

The following principles must be observed when treating bleeding:

1. To stop bleeding, replacement therapy with coagulation factors VIII** and FIX**, coagulation factor VIII in combination with von Willebrand factor**, octocog alfa**, moroctocog alfa**, simoctocog alfa (recombinant human coagulation factor VIII)**, nonacog alfa**, lonoctocog alfa, turoctocog alfa, efmoroctocog alfa**, rurioctocog alfa pegol, albutrepenonacog alfa, or bypassing agents in patients with inhibitor hemophilia must be used.

2. Effective doses of coagulation factors or bypassing agents must be administered immediately. Inadequate dosing will fail to stop bleeding, lead to wasted time, progression of the hemorrhagic syndrome, and unjustified consumption of expensive medication.

3. Hemostatic therapy (administration of coagulation factors) must be initiated as early as possible (as soon as possible, preferably within the first 2 hours after injury or the appearance of the first subjective or objective signs of hemorrhage). Therefore, the basis for initiating therapy can be the patient's subjective sensations or the fact of an injury. The administration of the drug must be carried out. Efforts should be made to stop the bleeding or hemorrhage before significant clinical manifestations develop. In the event of an injury, the patient must be examined by a hematologist without fail.

4. Treatment of mild and moderate bleeding should be carried out at home by the patient or their relatives in accordance with the hematologist's recommendations. In the event of severe bleeding, therapy must be initiated as soon as possible (at home) and continued under the supervision of a hematologist in an inpatient or outpatient setting.

5. Patients must not use drugs that impair platelet function and inhibit blood coagulation, especially acetylsalicylic acid** and other NSAIDs, with the exception of certain oxicams (cyclooxygenase-2 (COX-2) inhibitors) – ketorolac**, nimesulide, ibuprofen**, and drugs from the "coxibs" group (ATC code M01AH).

6. Intramuscular injections and arterial punctures should be avoided.

7. Regular exercise that promotes muscle development, joint protection, and physical fitness should be encouraged (e.g., therapeutic gymnastics, swimming, terrain cures).

8. Patients should avoid situations associated with a high risk of injuries, including contact combat sports, games with a heavy ball, exercising on sports apparatus, etc.

7.2. Dental care

Local anesthesia in patients with severe and moderate hemophilia may be performed only after the administration of a coagulation factor [60,62].

Good oral hygiene is important for hemophilia patients to help prevent the development of periodontal disease and caries. A soft toothbrush should be used for brushing teeth. Routine dental examinations should be performed at least twice a year. Routine dental examinations and tooth cleaning can be performed without factor replacement therapy. However, hemostatic agents (coagulation factors VIII**/IX**, antifibrinolytic agents) must be readily available.

When providing dental care, close cooperation between the dentist and the hematologist is essential. Tooth extraction or surgical procedures must be performed under strict hemostatic control and after consultation with a hematologist.

Tranexamic acid** (except for children under 1 year of age) or other antifibrinolytic agents may be used during dental procedures to reduce the need for coagulation factor replacement therapy. Topical hemostatic agents can be used after tooth extractions. For extensive dental procedures (suturing, multiple tooth extractions), hospitalization may be required.

The use of NSAIDs, especially acetylsalicylic acid**, should be avoided.

Special attention is required for prophylaxis during dental procedures in patients with inhibitors to factor VIII/IX.

7.3. Hemophilia in newborns.

When deciding on the mode of delivery (vaginal or surgical), if the birth of a child with hemophilia is expected, the most atraumatic method should be chosen. Vacuum extraction is hazardous and must not be performed on fetuses suspected of having hemophilia. After delivery, it is advisable to collect a cord blood sample into a tube with sodium citrate to determine coagulation factor activity. Age-related norms must be considered when evaluating results. Until diagnosis, venipunctures (performed solely for hemophilia diagnostics), capillary blood sampling, and other invasive procedures should preferably be avoided in newborns with suspected hemophilia.

7.4. Laboratory testing

Laboratory tests are the basis for diagnosis and monitoring in patients with hemophilia. Requirements for the conditions and techniques of sample collection and testing do not differ from standard ones. An important aspect of laboratory testing is participation in a quality control system. In diagnosing hemophilia, it is optimal to participate in both national and international quality control systems for laboratory tests covering the main coagulological parameters.

7.5. Vaccination.

Patients with hemophilia can be vaccinated. Hepatitis B vaccination is especially important. Oral or subcutaneous administration of the vaccine is preferred over intramuscular or intradermal routes. If only the intramuscular route is available for a given vaccine, replacement therapy is required to prevent hematoma formation. In this case, replacement therapy is administered the day before vaccination. Administration of the drug on the day of vaccination is not recommended. Vaccination must not be performed during bleeding.

7.6 Undesirable drug therapy.

The use of such drugs can lead to severe bleeding that cannot be controlled by the administration of coagulation factors. However, developed thrombosis may require the use of antithrombotic agents (anticoagulants, ATC code B01A). Short-acting drugs should be preferred. The risk-benefit ratio of using antithrombotic agents (anticoagulants and platelet aggregation inhibitors) must be analyzed each time.

7.7 Patient and family education.

Education of patients and their family members is a prerequisite for ensuring adequate care for such patients. Education begins immediately after diagnosis and is conducted on an ongoing basis by the doctors and nurses of the center where the patient is monitored.

Training is conducted individually during visits to the center and within the framework of the school for hemophilia patients.

Main areas of education for the patient and their family members:

- what hemophilia is;

- specific features of children with hemophilia;

- skills for assessing the child's condition;

- skills for assessing symptoms, nature, and severity of bleeding;

- storage and use of blood clotting factors;

- indications and doses of replacement therapy;

- home infusion skills;

- vein care;

- use of other hemostatic agents;

- physical activity;

- psychological and social adaptation;

- career guidance;

- legal aspects.

In addition to physicians and nurses, medical psychologists, lawyers, and members of public organizations representing the interests of hemophilia patients should be involved in educating patients and their family members.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Zozulya Nadezhda Ivanovna, MD, Association for the Promotion of the Development of Hematology, Transfusiology and Bone Marrow Transplantation "National Hematological Society", Moscow

2. Al-Radi Lyubov Sattarovna, PhD, Association for the Promotion of the Development of Hematology, Transfusiology and Bone Marrow Transplantation "National Hematological Society", Moscow

3. Andreeva Tatyana Andreevna, PhD, St. Petersburg

4. Galstyan Gennady Martinovich, MD, Association for the Promotion of the Development of Hematology, Transfusiology and Bone Marrow Transplantation "National Hematological Society", Moscow

5. Zharkov Pavel Alexandrovich, MD, National Society of Pediatric Hematologists and Oncologists, Moscow

6. Mamaev Andrey Nikolaevich, MD, Association for the Promotion of the Development of Hematology, Transfusiology and Bone Marrow Transplantation "National Hematological Society", Barnaul

7. Petrov Viktor Yuryevich, MD, National Society of Pediatric Hematologists and Oncologists, Moscow

8. Polyanskaya Tatyana Yuryevna, PhD, Association for the Promotion of the Development of Hematology, Transfusiology and Bone Marrow Transplantation "National Hematological Society", Moscow

Conflict of interest: none declared

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Hematologists

2. Pediatricians

3. Internists

4. Surgeons

5. Dentists

6. Otolaryngologists

7. Trauma and orthopedic surgeons

Methods used for evidence collection/selection:

Search for publications in specialized peer-reviewed periodicals with an impact factor > 0.3.

Search in electronic databases.

Databases used for evidence collection/selection:

The evidence base for the recommendations consists of publications included in the PUBMED, MEDLINE, and Cochrane Library databases. The search covered a depth of more than 20 years.

Methods used for evidence analysis:

- Reviews of meta-analyses, randomized prospective controlled crossover clinical trials.

- Reviews of published case-control or cohort studies.

- Systematic reviews with evidence tables.

Methods used for assessing the quality and strength of evidence:

- Expert consensus;

- Assessment of the significance of evidence in accordance with the evidence grading system (Appendix 1).

Methodology for developing recommendations:

Description of the methodology for evidence analysis and recommendation development

When selecting publications as potential sources of evidence, the methodology used in each study must be examined to ensure its compliance with the principles of evidence-based medicine. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations derived from it.

Methodological review focuses on the features of the study design that had a significant impact on the quality of results and conclusions.

To eliminate the influence of subjective factors, each study is evaluated by at least two independent members of the authoring team. Discrepancies in evaluation are discussed at meetings of the working group of the authoring team for these recommendations.

Based on the analysis of evidence, sections of clinical recommendations were developed with an assessment of strength in accordance with the grading system of recommendation evidence (Appendix 2).

Methods used to formulate the recommendations:

- Expert consensus.

- Assessment of the significance of recommendations in accordance with the grading system of recommendation evidence.

Methodology for validation of recommendations:

Methods of recommendation validation:

- External expert review.

- Internal expert review.

Description of the methodology for validating recommendations:

Draft recommendations are peer-reviewed by independent experts who are asked to comment on the quality of evidence interpretation and guideline development. An expert assessment of the presentation style and readability of the recommendations is also conducted.

Draft recommendations are submitted for discussion at scientific hematology conferences of the National Hematology Society, meetings of the Profile Commission for Hematology, the Working Group for the Development of Clinical Guidelines of the Hematological Research Center, as well as by leading specialists of relevant Federal Centers of the Russian Federation and practicing physicians.

Comments from outpatient and inpatient hematologists regarding the clarity and importance of the recommendations as a tool for daily practice are reviewed.

Remarks and comments received from experts are carefully systematized and discussed by the authoring group. If necessary, changes and additions are made to the text of the recommendations.

Final Version:

For the final version and quality control, the recommendations are re-analyzed by members of the authoring group to confirm that all significant remarks and comments from experts have been taken into account, and the risk of bias during development has been minimized.

The final version of the clinical guidelines is reviewed and approved at a meeting of the Profile Commission for Hematology, the Working Group for the Development of Clinical Guidelines of the Hematological Research Center, and ultimately at the congress (conference, plenum) of the National Hematology Society.

Table A2.1. Scale for grading the levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table A2.2. Scale for grading the levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table A2.3. Scale for grading the grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision — at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1. Recommended factor activity and duration of therapy for various types of bleeding

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Appendix B.1 Sample protocol for home-based replacement / hemostatic therapy with blood coagulation factors

PROTOCOL

for replacement / hemostatic therapy with blood coagulation factors

for ________________ 202__

Patient's Full Name _____________________________________________________ Weight _______ (kg)

Date of birth _______________ Tel. ________________ Diagnosis ________________

date patient's signature

Estimated doses required for administration:

hemarthrosis: 20-40 IU/kg body weight

soft tissue hematoma: 20-40 IU/kg body weight

hematuria (blood in urine): 10-15 IU/kg body weight

mucosal bleeding (epistaxis, gingival, tooth extraction socket): 20-30 IU/kg body weight

retroperitoneal hematoma: 40-50 IU/kg body weight (seek medical attention immediately)

gastrointestinal bleeding: 60-80 IU/kg body weight (seek medical attention immediately)

WARNING!

Blood coagulation factors must be administered at the very onset of hemorrhage!

For consultations, call tel. _____________________

Appendix B.2 Sample patient informed consent for home treatment

PATIENT INFORMED CONSENT FOR HOME TREATMENT

I, ____________________________________________________________________

I agree that my participation in the home treatment program imposes the following obligations on me:

undergo all necessary laboratory tests;

carry out treatment strictly according to the doctor's recommendation;

fill out and submit coagulation factor administration logs monthly;

in the event of complications or lack of clinical effect, immediately contact ______________________________________________________

In case of failure to fulfill my obligations, medical recommendations, or examinations, my participation in the home treatment program will be terminated.

date patient's signature

* name of the medical organization, its address and telephone number.

Appendix B.3 Sample informed consent of parents (legal representatives) of a child for home treatment

INFORMED CONSENT OF PARENTS (LEGAL REPRESENTATIVES) OF A CHILD FOR HOME TREATMENT

I, ____________________________________________________________________

(Full Name, degree of kinship or status)

consent to the participation of my child ________________________________________

in the home treatment program. I have been warned about potential adverse events and treatment outcomes. I have been warned about the need to follow the monitoring schedule and laboratory tests.

I have the opportunity to administer this drug at my place of residence and am familiar with the rules for its administration. I am informed of the need to:

timely carry out all necessary laboratory examinations for the child;

carry out treatment strictly according to the doctor's recommendation;

fill out and submit drug administration logs monthly;

in the event of complications or lack of clinical effect, immediately contact ______________________________________________________

In case of failure to fulfill my obligations, medical recommendations, or examinations, my child's participation in the home treatment program will be terminated.

date patient's signature

* name of the medical organization, its address and telephone number.

Appendix B.4 Hemophilia patient passport

HEMOPHILIA PATIENT PASSPORT

The holder of this document suffers from impaired blood clotting and receives intravenous injections of antihemophilic drugs. They may carry medications and supplies for intravenous administration.