How is hemophilia treated?

The main component of hemophilia treatment is timely adequate replacement action, replenishing the level of the deficient factor in the plasma. Currently, there are three methods of treating patients with hemophilia:

• prophylactic;
• home treatment;
• treatment upon occurrence of bleeding.

Preventive treatment method for hemophilia

This is the most progressive method. Its goal is to maintain the activity of the deficient factor at a level of about 5% of the norm in order to avoid hemorrhages in the joints. Preventive treatment begins at the age of 1-2 years before the first hemarthrosis or immediately after it. The treatment uses highly purified coagulation factor concentrates (CFC). The drugs are administered 3 times a week for hemophilia A and 2 times a week for hemophilia B (since the half-life of factor IX is longer) at a rate of 25-40 IU/kg. The duration of preventive treatment ranges from several months to lifelong. Patients do not have any musculoskeletal disorders, they are completely socially adapted and can play sports.

Coagulation factor VIII concentrates

Preparation	Method of obtaining	Virus inactivation	Application
Hemophilus M	Immunoaffinity chromatography with monoclonal antibodies to factor VIII	Solvent-detergent + immunoaffinity chromatography	Hemophilia A, Inhibitory hemophilia A
Immunate	Ion exchange chromatography	Double: solvent-detergent + thermal	Hemophilia A, Inhibitory hemophilia A, von Willebrand disease
Koeit-DVI	Chromatography	Double: solvent-detergent + thermal	Hemophilia A, inhibitory hemophilia A
Emoklot D.I.	Chromatography	Double: solvent-detergent + thermal	Hemophilia A, inhibitory hemophilia A

Coagulation factor IX concentrates

Preparation	Method of obtaining	Virus inactivation	Application
Immunin	Ion exchange chromatography	Double: solvent-detergent + thermal	Hemophilia B, inhibitory hemophilia B
Aimafix	Chromatography	Double: solvent-detergent + thermal	Hemophilia B
Octane F	Chromatography	Double: solvent-detergent + thermal	Hemophilia B, inhibitory hemophilia B

The approaches to prescribing these drugs are the same as for hemophilia A.

Treatment of hemophilia at home

It is recommended for patients with either less pronounced hemorrhagic syndrome or limited drug supply. The drug is administered immediately after injury or at the slightest sign of incipient hemorrhage. Immediate administration of the drug helps stop bleeding at an early stage, prevents tissue damage or the formation of massive hemarthrosis with less drug consumption. KFS is also used for home treatment.

Treatment of hemophilia after bleeding occurs

This treatment requires a small amount of drugs, but does not prevent massive intermuscular and retroperitoneal hematomas and hemorrhages in the central nervous system. Patients suffer from progressive arthropathy and are socially maladapted. They are prescribed unpurified drugs that have not undergone viral inactivation: blood coagulation factor VIII (cryoprecipitate), FFP, native plasma concentrate (NPC).

The choice of treatment method depends on the form and severity of hemophilia, as well as the location of the hemorrhage or bleeding.

For the treatment of mild hemophilia with a factor level of over 10% and female carriers of hemophilia A with a factor VIII level of under 50%, desmopressin is used, which ensures the release of factor VIII and von Willebrand factor from the endothelial cell depot. Desmopressin is administered intravenously by drip at a dose of 0.3 mcg/kg in 50 ml of isotonic sodium chloride solution over 15-30 minutes. Desmopressin is indicated for minor surgical interventions and for operations on female carriers. Severe hemophilia requires treatment with factor VIII/IX concentrates.

It is known that 1 IU of the factor, administered per 1 kg of the patient's weight, increases the activity of factor VIII in the blood plasma by 2% in hemophilia A and factor IX by 1% in hemophilia B. The dose of factors VIII/IX is determined by the formulas:

• Dose for a child under one year = body weight x desired factor level (%);
• Dose for a child after one year = body weight x desired factor level (%) x 0.5.

The recommended doses of factors VIII/IX vary in specific cases. All FSCs are administered intravenously by jet stream.

In the initial stage of acute hemarthrosis, KFS is administered at a rate of 10 IU/kg, in the late stage - 20 IU/kg with repeated administration every 12 hours. The desired factor level is 30-40%.

Joint puncture

Indications for joint puncture: primary hemarthrosis; pain syndrome due to massive hemarthrosis; recurrent hemarthrosis; exacerbation of chronic synovitis.

After blood aspiration, hydrocortisone (hydrocortisone hemisuccinate) 50-100 mg is injected into the joint cavity every other day, and for prolonged treatment - betamethasone (diprospan).

In the presence of signs of chronic synovitis in the acute stage and recurrent hemarthrosis, a series of punctures 1-3 times a week is recommended until the inflammation is completely relieved against the background of daily hemostatic treatment (4-6 punctures in total).

In the absence of sufficient effect or impossibility of adequate treatment, synovectomy (radioisotope, arthroscopic or open) is indicated. 1-2 days after surgery, patients are prescribed physiotherapy and a course of preventive hemostatic treatment for 3-6 months.

Treatment for hemorrhages in the iliopsoas muscle

KFS is administered at a dose of 30-40 IU/kg every 8-12 hours for 2-3 days, subject to bed rest and limited physical activity.

Treatment for nosebleeds

For nosebleeds, KFS is administered at a rate of 10-20 IU/kg every 8-12 hours with simultaneous irrigation of the nasal mucosa with carbazochrome (adroxone), transamine, etamsylate (dicinone), 5% aminocaproic acid and thrombin.

Treatment for bleeding of the oral mucosa

Such bleeding is prolonged. A loose clot often forms at the site of injury, which prevents the edges of the wound from joining. After the introduction of the CFS, at a rate of 20-40 IU/kg every 8-12 hours, the clot should be removed and the edges of the wound should be joined. Antifibrinolytic agents: aminocaproic acid, transamine. Fibrin glue and cooled mashed food promote local hemostasis.

Oral cavity sanitation

Before treating a carious tooth, a single intravenous injection of factor concentrates or, in case of hemophilia A, blood coagulation factor VIII (cryoprecipitate) is sufficient. Aminocaproic acid is prescribed for 72-96 hours before and after the procedure: for children, 5% aminocaproic acid intravenously by drip at a dose of 100 mg/kg per infusion, for adults - orally up to 4-6 g/day of aminocaproic acid in 4 doses. Hemostatic treatment begins before the operation and continues for 2-3 days after it. The drug is administered at a rate of 10-15 IU/kg for incisor extraction and 20 IU/kg for removal of large molars. Additionally, local and systemic antifibrinolytic agents and fibrin glue are used. A strictly gentle diet and cold drinks are recommended.

Treatment for renal bleeding

Hemostatic action is carried out until macrohematuria is relieved at a dose of 40 IU/kg per administration. The desired factor level is 40%. In addition, a short course of prednisolone is prescribed orally at a dose of 1 mg/kg per day with subsequent rapid withdrawal.

The use of aminocaproic acid in patients with renal bleeding is contraindicated due to the risk of renal glomerular thrombosis.

Gastrointestinal bleeding

In case of gastrointestinal bleeding, endoscopic examination is indicated to clarify the cause and source of bleeding. The desired factor level is 60-80%. Active use of fibrinolysis inhibitors is necessary, as well as treatment generally accepted for erosive and ulcerative diseases of the stomach and intestines.

Life-threatening bleeding, including cerebral hemorrhage, and extensive surgical interventions require the administration of CFS at a rate of 50-100 IU/kg 1-2 times a day until the signs of bleeding are stopped and subsequent maintenance treatment with smaller doses until the wound heals. Continuous infusion of CFS at a dose of 2 IU/kg per hour ensures their constant level of at least 50% of the norm. In addition, the use of fibrinolysis inhibitors is indicated. Subsequently, hemostatic action is carried out according to the preventive treatment regimen for 6 months.

In the absence of CFS, blood coagulation factor VIII (cryoprecipitate), FFP and KNP (contain factor IX) are used.

The average activity of 1 dose of blood coagulation factor VIII (cryoprecipitate) is 75 IU. The drug maintains the level of factor VIII within 20-40%, which is sufficient for surgical interventions. It is administered slowly, intravenously by jet stream, at a dose of 30-40 units/kg after 8, 12, 24 hours, depending on the desired level and type of bleeding. 1 unit/kg of the drug increases the factor level by 1%.

If it is impossible to treat patients with hemophilia B with factor IX concentrate, KNP is used at a rate of 20-30 ml/kg per day in 2 doses until the condition stabilizes, and if this is not possible, FFP is used. 1 dose of FFP/KNP contains, on average, 50-100 IU of factor IX. FFP/KNP is administered at a rate of 1 dose per 10 kg of the patient's weight.

Objective limitations of the use of blood coagulation factor VIII (cryoprecipitate), FFP and KNP:

• non-standardization and insignificant hemostatic effect (lead to arthropathy with limited movement from childhood, and later to early disability);
• low purification of drugs and lack of antiviral inactivation (therefore, 50-60% of patients with hemophilia have positive markers for hepatitis C, 7% are permanent carriers of the hepatitis B virus;
• high frequency of allergic and transfusion reactions;
• the risk of circulatory overload due to the introduction of large volumes of these agents with a minimal concentration of coagulation factors in them;
• immunosuppression;
• low quality of life of patients.

Inhibitory form of hemophilia

The occurrence of circulating anticoagulant inhibitors belonging to the immunoglobulin G class in patients with hemophilia complicates the course of the disease. The frequency of the inhibitor form of hemophilia ranges from 7 to 12%, and in very severe hemophilia - up to 35%. The inhibitor most often appears in children aged 7-10 years, but can be detected at any age. The appearance of an inhibitor to factors VIII/IX aggravates the prognosis of the disease: bleeding becomes profuse, combined, severe arthropathy develops, leading to early disability. The duration of inhibitor circulation ranges from several months to several years. Determination of a possible inhibitor is mandatory for each patient, both before the start of treatment and during it, especially in the absence of an effect from the replacement effect.

The presence of the inhibitor in the blood is confirmed by the Bethesda test. The measurement value is the Bethesda unit (BE). The higher the concentration of the inhibitor in the blood, the greater the number of Bethesda units (or the higher the Bethesda titer). A low inhibitor titer is considered to be less than 10 U/ml, average - from 10 to 50 U/ml, high - more than 50 U/ml.

Treatment of patients with inhibitor forms of hemophilia I

Increased treatment efficacy in patients with low inhibitor titers is achieved by using high doses of factor concentrates. The dose is selected empirically to completely neutralize the inhibitor, and then the concentration of factor VIII in the patient's blood is maintained at a given level for the required period.

In life-threatening bleeding or when surgical intervention is required, porcine factor VIII (Hyate-O), activated prothrombin complex preparations: anti-inhibitor coagulant complex (Feiba Team 4 Immuno) and (Autoplex), eptacog alpha [activated] (NovoSeven) are usually used. Porcine coagulation factor is used when the titer of inhibitors in the blood is high (from 10 to 50 BE and higher). In 40% of patients, an inhibitor to porcine factor VIII appears after 1-2 weeks of treatment. Treatment is started with a dose of 100 IU/kg (2-3 times a day for 5-7 days), which is increased if necessary. Premedication with hydrocortisone is mandatory to prevent allergic reactions and thrombocytopenia.

Prothrombin complex concentrates (PCC) and activated prothrombin complex concentrates (aPCC) provide hemostasis bypassing factor VIII/IX. They contain activated factors VII and X, which significantly increases the effectiveness of treatment. Anti-inhibitory coagulant complex (Feiba Tim 4 Immuno) is administered at a dose of 40-50 IU/kg (maximum single dose - 100 units/kg) every 8-12 hours.

Eptacog alfa [activated] (NovoSeven) forms a complex with tissue factor and activates factors IX or X. The drug is administered every 2 hours. Doses from 50 mcg/kg (for an inhibitor titer of less than 10 VE/ml) and 100 mcg/kg (for a titer of 10-50 VE/ml) to 200 mcg/kg (for a titer of more than 100 VE/ml). Antifibrinolytic agents are prescribed in combination with it, as well as with the anti-inhibitor coagulant complex (Feiba Team 4 Immuno). Exceeding the doses of the anti-inhibitor coagulant complex (Feiba Team 4 Immuno) and eptacog alfa [activated] (NovoSeven) leads to thrombotic side effects.

In the complex treatment of inhibitor forms of hemophilia, plasmapheresis may be used. After the inhibitor is removed, the patient is administered 10,000-15,000 IU of coagulation factor VIII concentrate. Various types of immunosuppression are used: corticosteroids, immunosuppressants.

Development of immunological tolerance According to the Bonn Protocol

In the first period, blood coagulation factor VIII is administered at 100 IU/kg and an anti-inhibitor coagulant complex (Feiba Tim 4 Immuno) at 40-60 IU/kg 2 times a day daily until the inhibitor is reduced to 1 IU/ml.

In the second period, blood coagulation factor VIII is administered at 150 IU/kg 2 times a day until the inhibitor completely disappears. Subsequently, most patients return to prophylactic treatment.

High-dose treatment according to the Malmö protocol

Treatment is prescribed to patients with an inhibitor titer of more than 10 VE/kg. Extracorporeal absorption of antibodies is performed with simultaneous administration of cyclophosphamide (cyclophosphamide) (12-15 mg/kg intravenously during the first two days, and then 2-3 mg/kg is administered orally from the 3rd to the 10th day). The initial dose of coagulation factor VIII is calculated so as to completely neutralize the inhibitor remaining in the circulation and increase the level of coagulation factor VIII by more than 40%. Then, coagulation factor VIII is administered again 2-3 times a day so that its level in the blood remains within 30-80%. In addition, immediately after the first use of coagulation factor VIII, the patient is administered normal human immunoglobulin G intravenously at a dose of 2.5-5 g during the first day or 0.4 g/kg per day for 5 days.

Treatment with intermediate doses of factor VIII preparations involves their daily administration at a dose of 50 IU/kg.

The use of low doses of blood coagulation factor VIII involves its initial administration in a high dose to neutralize the inhibitor. Subsequently, the factor is administered at 25 IU/kg every 12 hours for 1-2 weeks daily, then every other day. The protocol is used for life-threatening bleeding and surgical interventions.

Complications of substitution treatment

The appearance of an inhibitor to deficiency factors in the blood, the development of thrombocytopenia, hemolytic anemia and secondary rheumatoid syndrome. Complications also include infection with hepatitis B and C viruses, HIV, parvavirus B 19 and cytomegalovirus.

Practical recommendations for patients with hemophilia

• Patients and their family members should receive specialized medical care in hemophilia treatment centers, where they are trained in intravenous injection skills and the basics of replacement therapy.
• The upbringing of children is normal, the only difference is that from early childhood it is necessary to avoid injuries (put pillows around the crib, do not give toys with sharp corners, etc.).
• Only non-contact sports, such as swimming, are allowed.
• Preventive dental sanitation is carried out regularly.
• Patients are vaccinated against viral hepatitis B and A.
• Surgical interventions, tooth extractions, prophylactic vaccinations and any intramuscular injections are carried out only after adequate replacement treatment.
• NSAIDs can be used only under strict indications, only in the presence of hemophilic arthropathy and exacerbation of chronic synovitis. It is necessary to avoid taking antiplatelet agents and anticoagulants.
• Before surgical interventions and if treatment is ineffective, patients are screened for the presence of an inhibitor to factors VIII or IX.
• Twice a year, patients are tested for markers of viral hepatitis B and C and HIV, and a biochemical blood test with liver function tests is performed.
• Once a year, patients undergo a medical examination.
• They are registering childhood disability.

The estimated annual requirement of one patient with hemophilia for the deficient blood clotting factor is considered to be 30,000 IU. It is also possible to calculate the requirement for antihemophilic drugs depending on the population size: 2 IU of factor per inhabitant per year or 8,500 doses of blood clotting factor VIII (cryoprecipitate) per 1 million inhabitants per year.

Complications of hemostatic therapy and their prevention of hemophilia. In patients with severe hemophilia, with multiple infusions of factor VIII concentrates, neutralizing antibodies can be produced against it (detected in 10-20% of cases), which is manifested by low activity of factor VIII in the blood, despite its replacement with large doses. Similar inhibitory factors can be produced against coagulation factor IX in severe hemophilia B.

The presence of inhibitors should be suspected in patients in whom replacement therapy does not produce a hemostatic effect, and the level of the administered factor in the blood continues to remain low. The titer of the inhibitor in the blood is indirectly determined based on the calculation that 1 unit/kg of the inhibitor neutralizes 1% of the coagulation factor. The diagnosis of the inhibitor form of hemophilia is confirmed in the absence of a shortening of the recalcification time of the patient's plasma, to which the plasma of a healthy person was added.

To prevent inhibitory forms of hemophilia, various treatment regimens are used: high-dose therapy with factor VIII concentrates in combination with immune suppression, the use of medium or low doses.

Risk of infection of the patient with hepatitis B or HIV. The safest are purified monoclonal recombinant concentrates of factor VIII; the most dangerous is cryoprecipitate, which is prepared from a mixture of plasmas of hundreds (up to 2000) donors. The following symptoms are typical of AIDS in children: hepatosplenomegaly, lymphadenopathy, weight loss, fever; unexplained interstitial pneumonia; persistent bacterial infections (otitis, meningitis, sepsis); pneumocystis, less often cytomegalovirus infection, toxoplasmosis, candidiasis; unexplained progressive neurological symptoms; autoimmune thrombocytopenia, neutropenia, anemia.

Immune complex and autoimmune complications. With long-term replacement therapy with antihemophilic drugs in large doses, the development of rheumatoid arthritis, glomerulonephritis, amyloidosis and other pathoimmune diseases is possible.

Isoimmune complications. The risk of hemolysis occurs when patients with hemophilia with A(II), B(III), AB(IV) blood groups are administered cryoprecipitate obtained from the plasma of hundreds of donors.

Indications for urgent hospitalization: bleeding from the oral cavity (biting the tongue, tearing the frenulum, tooth extraction); hematomas in the head, neck, oral cavity; headache associated with trauma and increasing over time; large hematomas of the knee and other large joints; suspected retroperitoneal hematomas; gastrointestinal bleeding.

Prevention of bleeding in patients with hemophilia: timely administration of adequate replacement hemostatic therapy; prevention of injuries while ensuring sufficient physical activity; prevention of infectious diseases; administration of drugs orally or intravenously; intramuscular injections are excluded (subcutaneous injections of up to 2 ml are acceptable); administration of gamma globulin under the protection of antihemophilic globulin; exclusion of acetylsalicylic acid; replacement with paracetamol; dental sanitation and strengthening of gums.

The prognosis for hemophilia is unfavorable in the case of spinal or renal bleeding with blockage of the urinary tract and the development of acute renal failure, and questionable in the case of cerebral hemorrhage.

The scope of rehabilitation: a complete diet, enriched with vitamins; a regimen with reasonable restrictions on physical activity; injury prevention; exemption from physical education and work lessons; sanitation of foci of chronic infection and timely sanitation of teeth; exclusion of vaccinations and intake of acetylsalicylic acid; in case of hemarthrosis - surgical and physiotherapeutic treatment; therapeutic exercise, massage and all types of hardware rehabilitation; training parents in the technique of emergency intravenous administration of hemostatic drugs in case of injuries and the onset of hemorrhagic syndrome; spa treatment; optimization of quality of life, family psychotherapy and career guidance.

Outpatient observation. Carried out jointly by a hematologist of a specialized center and a local pediatrician. The child is exempt from vaccinations and physical education classes at school due to the risk of injury. At the same time, physical activity is indicated for a patient with hemophilia, as it increases the level of factor VIII. The nutrition of a sick child does not differ from the nutrition of healthy children. Of the medicinal herbs, decoctions of oregano and intoxicating harelip (lagochilus) are indicated. In case of colds, aspirin or indomethacin should not be prescribed (acetaminophen is preferred). Cupping is contraindicated, as they can provoke the occurrence of pulmonary hemorrhages.

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