How is hemophilia treated?

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

• prophylactic;
• home treatment;
• treatment for the occurrence of bleeding.

Preventative method of treatment of hemophilia

This is the most progressive method. Its goal is to maintain the activity of the deficit factor at about 5% of the norm in order to avoid joint hemorrhage. Preventative treatment begins at the age of 1-2 years before the onset of the first hemarthrosis or immediately after it. The treatment uses concentrates of coagulation factors (CFS) of high purity. The drugs are administered 3 times a week for haemophilia A and 2 times a week for hemophilia B (since the half-life of factor IX is longer) from a calculation of 25-40 IU / kg. Duration of preventive treatment - from several months to life. Patients have no injuries to the musculoskeletal system, they are fully socially adapted and can play sports.

Concentrates of the coagulation factor VIII

A drug	Method of obtaining	Inactivation of the virus	Application
Hemofil 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, Willebrand disease
Coate-DWI	Chromatography	Double: solvent-detergent + thermal	Hemophilia A, inhibitory haemophilia A
Emoklot D.I.	Chromatography	Double: solvent-detergent + thermal	Hemophilia A, inhibitory haemophilia A

Concentrates of the coagulation factor IX

A drug	Method of obtaining	Inactivation of the virus	Application
Immunin	Ion-exchange chromatography	Double: solvent-detergent + thermal	Hemophilia B, inhibitory haemophilia B
Amifix	Chromatography	Double: solvent-detergent + thermal	Hemophilia B
Octaneine F	Chromatography	Double: solvent-detergent + thermal	Hemophilia B, inhibitory haemophilia B

Approaches in the appointment of these drugs are the same as in the case of hemophilia A.

Treatment of hemophilia at home

It is recommended for patients with a less severe hemorrhagic syndrome, or with limited possibilities of drug provision. The drug is administered immediately after the injury or at the slightest signs of a hemorrhage that begins. Immediate administration of the drug helps to stop bleeding at an early stage, prevents tissue damage or the formation of massive hemarthrosis with less drug consumption. For treatment at home, also apply CFS.

Treatment of hemophilia after bleeding

Such treatment requires a small amount of drugs, but does not allow to avoid massive intermuscular and retroperitoneal hematomas and hemorrhages in the central nervous system. Patients suffer from progressive arthropathy and are socially maladjusted. They are prescribed untreated, non-viral inactivation drugs: blood coagulation factor VIII (cryoprecipitate), FFP, native plasma concentrate (CNR).

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

For the treatment of a mild form of hemophilia with a factor level of more than 10% and female carriers of hemophilia A with a factor VIII level of less than 50%, desmopressin is used, which ensures the release of factor VIII and vWF from the endothelial cell depot. Desmopressin is administered intravenously drip in a dose of 0.3 μg / kg in 50 ml of isotonic sodium chloride solution for 15-30 minutes. Desmopressin is indicated for non-extensive surgical interventions and for carrying out operations in female carriers. In severe hemophilia, treatment with factor VIII / IX concentrates is required.

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

• Dose to child up to a year = body weight x desired factor level (%);
• The dose to the child after the year = body weight x the desired level of the factor (%) x0.5.

The recommended doses of factors VIII / IX in specific cases are different. All CFS is injected intravenously.

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

Joint puncture

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

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

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

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

Treatment for hemorrhages in the ilio-lumbar muscle

CFS is administered in a dose of 30-40 IU / kg every 8-12 hours for 2-3 days under the condition of bed rest and restriction of physical activity.

Treatment for nasal bleeding

With nasal bleeding, CFS 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, etamzilate (dicinone), 5% aminocaproic acid and thrombin.

Treatment for bleeding mucous membranes of the mouth

Such bleeding is of a lasting nature. At the site of the lesion, a loose clot is often formed, which prevents the edges of the wound from joining up. After the administration of CFS, from the calculation of 20-40 IU / kg every 8-12 hours, you should remove the clot and ensure the connection of the edges of the wound. Antifibrinolytic agents: aminocaproic acid, transamin. Fibrin glue and chilled, frozen food contribute to local hemostasis.

Oral sanitation

Before the treatment of the carious tooth, a single intravenous injection of factor concentrates or, in hemophilia A, the coagulation factor VIII (cryoprecipitate) is sufficient. Within 72-96 hours before and after the procedure, aminocaproic acid is prescribed: to children 5% aminocarbon acid is intravenously dripped intravenously at a dose of 100 mg / kg per infusion, adults - inside to 4-6 g / day aminocaproic acid for 4 doses. Hemostatic treatment is started before the operation and lasts 2-3 days after it. The drug is administered at a rate of 10-15 IU / kg for extraction of incisors and 20 IU / kg when large molars are removed. Additionally, local and systemic antifibrinolytic agents, fibrin glue, are used. Recommend rigorous sparing diet and cold drink.

Treatment for Renal Bleeding

Hemostatic exposure is carried out before the arrest of macrohematuria in a dose of 40 IU / kg per administration. The desired level of the factor is 40%. In addition, a short course of prednisolone is given orally at a dose of 1 mg / kg per day followed by a rapid cancellation.

The use of aminocaproic acid in patients with renal bleeding is contraindicated in connection with the risk of thrombosis of the renal glomeruli.

Gastrointestinal bleeding

Gastrointestinal bleeding shows endoscopic examination to determine the cause and source of bleeding. The desired level of the factor is 60-80%. It is necessary to actively use fibrinolysis inhibitors, as well as treatment, common in erosive and ulcerative diseases of the stomach and intestines.

Life-threatening hemorrhages, including cerebral hemorrhages, and extensive surgical interventions require CFS administration at a rate of 50-100 IU / kg 1-2 times a day until the symptoms of bleeding stop and subsequent maintenance treatment with smaller doses until the wound is healed. Continuous infusion of CFS in a dose of 2 IU / kg per hour ensures their constant level is not lower than 50% of the norm. In addition, the use of fibrinolysis inhibitors is indicated. Further haemostatic effects are carried out according to the scheme of preventive treatment for 6 months.

In the absence of CFS, the blood clotting factor VIII (cryoprecipitate), FFP and CNR (contain factor IX) is used.

The average activity of 1 dose of the coagulation factor VIII (cryoprecipitate) is 75 IU. The drug maintains the level of factor VIII in the range of 20-40%, which is enough for surgical interventions. Enter slowly, intravenously, in 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 not possible to treat patients with hemophilia In factor IX concentrate, use KNP at a rate of 20-30 ml / kg per day in 2 doses to stabilize the condition, and in its absence - FFP. The B1 dose of FFP / CNR on average contains 50-100 IU of factor IX. Enter FFP / CNR from the calculation of 1 dose per 10 kg of patient weight.

Objective restrictions on the use of the coagulation factor VIII (cryoprecipitate), FFP and CNR:

• non-standardization and minor hemostatic effect (lead from childhood to arthropathy with limited movements, and later ~ to early disability);
• low purification of preparations and absence of antiviral inactivation (therefore 50-60% of patients with hemophilia have positive markers of hepatitis C, 7% - permanent carriers of hepatitis B virus;
• high frequency of allergic and transfusion reactions;
• the threat of the overload of blood circulation due to the introduction of large volumes of these funds with the minimum concentration of coagulation factors in them;
• immunosuppression;
• poor quality of life of patients.

Inhibitory form of hemophilia

The appearance of circulating anticoagulant inhibitors in patients with hemophilia, belonging to the class of immunoglobulins G, complicates the course of the disease. The frequency of the inhibitory form of hemophilia varies from 7 to 12%, and in very severe hemophilia - up to 35%. The inhibitor often appears in children 7-10 years old, 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, leading to early disability. The duration of the inhibitor circulation ranges from several months to several years. Determination of a possible inhibitor is mandatory for every patient, both before the start of treatment and in its process, especially in the absence of the effect of the substitution effect.

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

Treatment of patients with inhibitory forms of hemophilia I

Increasing the effectiveness of treatment of patients with low inhibitor titer achieves high doses of factor concentrates. The dose is selected empirically to completely neutralize the inhibitor, and then maintain the concentration of factor VIII in the patient's blood at a given level for the required period.

For life-threatening hemorrhages, or for surgical intervention, a pork factor of blood coagulation VIII (Hyate-O), activated preparations of prothrombin complex: anti-inhibitory coagulant complex (Feiba Tim 4 Immuno) and (Autoplex), eptacog alpha [activated] ( NovoSeven). The pork factor of blood coagulation is used at high titer of inhibitors in the blood (from 10 to 50 BE and above). In 40% of patients after 1-2 weeks of treatment, an inhibitor appears to the porcine factor VIII. Treatment begins with a dose of 100 IU / kg (2-3 times a day for 5-7 days), which if necessary increase. For the prevention of allergic reactions and thrombocytopenia, premedication with hydrocortisone is mandatory.

Concentrates of prothrombin complex (CPC) and activated concentrates of prothrombin complex (aKPK) provide hemostasis bypassing the action of factor VIII / IX. They include Factors VII and X in an activated form, 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 (the maximum single dose is 100 units / kg) every 8-12 hours.

Eptakog alpha [activated] (NovoSeven) forms a complex with a tissue factor and activates factors IX or X. The drug is injected every 2 hours. Doses from 50 μg / kg (at an inhibitor titer of less than 10 VE / ml) and 100 μg / kg (at a titer 10-50 VE / ml) to 200 mcg / kg (at a titer of more than 100 VE / ml). In combination with it, as with the anti-inhibitory coagulant complex (Feiba Tim 4 Immuno), antifibrinolytic agents are prescribed. Excess doses of the anti-inhibitory coagulant complex (Feiba Tim 4 Immuno) and eptactagogue alpha [activated] (NovoSeven) lead to thrombotic side reactions.

In the complex treatment of inhibitory forms of hemophilia, the use of plasmapheresis is possible. After removal of the inhibitor, the patient is administered 10 000-15 000 ME of the coagulation factor VIII concentrate. Apply different types of immunosuppression: corticosteroids, immunosuppressants.

Development of immunological tolerance According to the Bonn Protocol

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

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

High-dose treatment according to the Malmö protocol

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

Treatment with the use of intermediate doses of preparations of factor VIII includes their daily administration in a dose of 50 IU / kg.

The use of low doses of the coagulation factor VIII factor presupposes the primary administration of it at a high dose to neutralize the inhibitor. Further, 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 hemorrhages and for surgical interventions.

Complications of substitution treatment

The appearance of an inhibitor to deficient factors in the blood, the development of thrombocytopenia, hemolytic anemia and secondary rheumatoid syndrome. Also, complications include infection with hepatitis B and C. Virus HIV, parvavirus B 19 and cytomegalovirus.

Practical recommendations for hemophilia patients

• Patients and their family members should receive specialized medical care in the centers for the treatment of hemophilia, where they are taught the skills of intravenous injections and the basics of substitution treatment.
• The upbringing of children is ordinary, different only in that from an early age you must avoid injuries (cover the bed with cushions, do not give toys with sharp angles, etc.).
• It is possible to practice only non-contact sports, for example, swimming.
• Regularly conduct preventive sanitation of teeth.
• Patients are vaccinated against viral hepatitis B and A.
• Operative interventions, tooth extraction, preventive vaccinations and any intramuscular injections are performed only after adequate substitution treatment.
• NSAIDs can be used according to strict indications, only in the presence of hemophilic arthropathy and exacerbation of chronic synovitis. It is necessary to avoid the use of disaggregants and anticoagulants.
• Before surgery and when treatment is ineffective, patients are screened for the presence of an inhibitor for VIII or IX factors.
• Twice a year, patients are identified by markers of viral hepatitis B and C and HIV and also make a biochemical blood test with a study of liver samples.
• Once a year, patients underwent a medical examination.
• The disability of childhood is formalized.

The estimated need of one patient with hemophilia in the deficit factor of blood coagulation per year is considered equal to 30 000 ME. It is also possible to calculate the need for antihemophilic preparations depending on the population: 2 ME factors per inhabitant per year or 8,500 doses of factor VIII (cryoprecipitate) per million inhabitants per year.

Complications of haemostatic therapy and their prevention of hemophilia. In patients with severe hemophilia with multiple infusions of factor VIII concentrates, neutralizing antibodies can be produced (it is 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 IX coagulation factor in severe hemophilia B.

The presence of inhibitors should be assumed in those patients in whom substitution therapy does not produce a haemostatic effect, and the level of the injected factor in the blood continues to be low. The inhibitor titer in blood is indirectly determined on the basis that 1 unit / kg inhibitor neutralizes 1% clotting factor. The diagnosis of the inhibitory form of hemophilia is confirmed in the absence of a shortening of the recalcification time of the patient's plasma into which a healthy person's plasma was added.

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

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

Immunocomplex and autoimmune complications. With long-term high-dose replacement therapy with anti-hemophilic drugs, rheumatoid arthritis, glomerulonephritis, amyloid-dose and other pathogens can develop.

Isoimmune complications. The risk of hemolysis occurs when hemophilia with A (P), B (III), AB (IV) patients is injected with blood clots of cryoprecipitate obtained from the plasma of hundreds of donors.

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

Prevention of bleeding in patients with hemophilia: timely conduct of adequate replacement hemostatic therapy; prevention of injuries while providing sufficient physical exertion; prevention of infectious diseases; administration of drugs orally or intravenously; intramuscular injections are excluded (subcutaneous injections up to 2 ml are permissible); introduction of gamma globulin under the protection of antihemophilic globulin; exclusion of acetylsalicylic acid; replacing it with paracetamol; sanitization of teeth and strengthening of gums.

The prognosis for hemophilia is unfavorable in the case of spinal or renal bleeding with blockade of the urinary tract and the development of acute renal failure and doubtful - with a hemorrhage in the brain.

The volume of rehabilitation: a full-fledged diet, vitaminized; a regime with a justified restriction of physical exertion; prevention of injuries; exemption from the lessons of physical education and work; sanation of foci of chronic infection and timely sanitation of teeth; the exclusion of vaccinations and the intake of acetylsalicylic acid; with hemarthrosis - surgical and physiotherapeutic treatment; therapeutic physical training, massage and all kinds of hardware rehabilitation; teaching parents methods of emergency intravenous administration of haemostatic drugs in trauma and early hemorrhagic syndrome; Spa treatment; optimization of quality of life, family psychotherapy and career guidance.

Dispensary observation. It is carried out jointly by the hematologist of the specialized center and the district pediatrician. The child is released from vaccinations and physical education at school because of the danger of injury. At the same time, physical exertion to a patient with hemophilia is shown, as this increases the level of factor VIII. The nutrition of a sick child does not differ from that of healthy children. From medicinal herbs broths of oregano and hare-lings of intoxicating (lagohilus) are shown. For colds, you should not prescribe aspirin or indomethacin (acetomifene is preferred). The banks are contraindicated, since they can provoke the onset of pulmonary hemorrhage.

[1], [2], [3], [4]