Reduced factor 8. Pyrogenicity or bacterial endotoxins

Factor VIII could not be isolated for a long time pure form due to low concentration (10 µg/l) and susceptibility to proteolysis. However, gene mapping factor VIII on the X chromosome, cloning and determination of the nucleotide sequence of cDNA made it possible to establish the structure of this protein and improve both the prenatal diagnosis of hemophilia A and the identification of carriers. f.VIII is a high-molecular glycoprotein; it is present in the blood as an inactive cofactor. Coagulation factor VIII (antihemophilic globulin) is a single-chain protein with a molecular weight of 265,000, which is necessary for the activation of factor X by proteases formed by the internal coagulation mechanism (Fig. 60.5 and Fig. 60.6). It is synthesized by hepatocytes and circulates in combination with von Willebrand factor. F.VIII is sensitive to proteolysis, resulting in the appearance of lower molecular forms of molecules. with masses of 200 and 80 kDa. They are formed as a result of proteolysis of the Arg-1313-Ala and Arg-1648-Glu bonds. F.V and F.VIII are divided into a number of domains (Fig. 4.2). The amino acid sequences are identical in three A domains (approximately 350 amino acid residues) and two C domains (approximately 150 amino acid residues). The large regions connecting the N-terminal residues of the heavy chains to the C-terminal residues of the light chains are rich in carbohydrate components and have no amino acid homology.

Factor VIII deficiency occurs in 1 in 10,000 male births. The corresponding disease (hemophilia A) is manifested by hemorrhages in the muscles, other soft tissues and supporting joints.

Although for normal hemostasis the factor VIII level must be at least 25%, symptoms usually appear when it decreases to 5% or below. The severity of the disease is directly related to the level of the factor.

Factor VIII - antihemophilic globulin A, or plasma thromboplastic factor A, is a complex glycoprotein. The synthesis of factor VIII in the liver, spleen, endothelial cells, leukocytes, and kidneys has been proven. Antihemophilic globulin A is quickly inactivated at 200 and 370C. It is stable for several hours at +40C and several weeks at -200C. Disappears quickly from preserved blood. Factor VIII is active longer in the presence of sodium citrate at pH 6.2-6.9, but quickly loses activity in EDTA. It does not adsorb on barium sulfate and aluminum hydroxide. This is used to separate factor VIII from factors II, VII, IX and X. In the blood, this factor circulates in the form of a complex of three subunits, designated VIIIk (coagulating unit), VIII-AG (the main antigenic marker) and VIII-vWF (von Willebrand factor , associated with VIII-AG). VIII-vWF regulates the synthesis of the coagulant part of antihemophilic globulin - VIIIk.

During blood clotting, factor VIII remains inactive.

Why is it important to do clotting factor VIII?

One of the most common severe hereditary diseases is hemophilia, the frequency of which in our country is 1 per 8-10 thousand male population. The disease is characterized by spontaneous, often fatal bleeding, hemorrhages in the joints, leading to early disability. These patients throughout their lives need replacement therapy plasma preparations. The main thing in the pathogenesis of hemophilia is a violation of the 1st phase of blood coagulation, associated with a deficiency of f.VIII (hemophilia A), f.IX (hemophilia B), f.XI (hemophilia C). Already when the deficiency factor is reduced to 30% (the norm is 50-150%), the disease manifests itself in hidden form and is detected after surgical interventions in the form of profuse bleeding. It is obvious that for a reliable diagnosis of hemophilia and in the treatment of patients it is extremely great importance acquires a method for determining the activity of a deficient factor in the patient’s blood plasma.

Severe hemophilia. The level of f.VIII or IX is less than 1%. Hemorrhages in joints, muscles and other organs occur with minimal or even unnoticeable damage.

Hemophilia medium degree. The level of f.VIII or IX is between 1-5%. Bleeding occurs due to obvious minor damage, also after various operations and tooth extractions.

Hemophilia mild degree. The level of f.VIII or IX is between 6-30%. Hemorrhages usually follow only major damage, surgical operations or tooth extraction. Diagnosis of this form may not be made until adulthood or until bleeding occurs after these situations.

Carried out mainly by proteins called plasma clotting factors. Plasma coagulation factors are procoagulants, the activation and interaction of which leads to the formation of a fibrin clot.

According to the International Nomenclature, plasma coagulation factors are designated by Roman numerals, with the exception of von Willebrand, Fletcher and Fitzgerald factors. To indicate the activated factor, the letter “a” is added to these numbers. In addition to the digital designation, other names of coagulation factors are also used - according to their function (for example, factor VIII - antihemophilic globulin), according to the names of patients with a newly discovered deficiency of one or another factor (factor XII - Hageman factor, factor X - Stewart-Prower factor) , less often - by the names of the authors (for example, von Willebrand factor).

Below are the main blood clotting factors and their synonyms according to the international nomenclature and their main properties in accordance with literature data and special studies.

Fibrinogen (factor I)

Fibrinogen is synthesized in the liver and cells of the reticuloendothelial system (in bone marrow, spleen, lymph nodes etc.). In the lungs, under the influence of a special enzyme - fibrinogenase or fibrin destructase - fibrinogen is destroyed. The fibrinogen content in plasma is 2–4 g/l, half-life is 72–120 hours. The minimum level required for hemostasis is 0.8 g/l.

Under the influence of thrombin, fibrinogen is converted into fibrin, which forms the mesh basis of a blood clot that clogs a damaged vessel.

Prothrombin (factor II)

Prothrombin is synthesized in the liver with the participation of vitamin K. The content of prothrombin in plasma is about 0.1 g/l, the half-life is 48 - 96 hours.

The level of prothrombin, or its functional usefulness, decreases with endogenous or exogenous vitamin K deficiency, when defective prothrombin is formed. The rate of blood clotting is impaired only when the prothrombin concentration is below 40% of normal

IN natural conditions during blood clotting under the influence of and, as well as with the participation of factors V and Xa (activated factor X), combined general term“prothrombinase”, prothrombin is converted into thrombin. The process of converting prothrombin into thrombin is quite complex, since during the reaction a number of prothrombin derivatives, autoprothrombins and, finally, various types thrombin (thrombin C, thrombin E), which have procoagulant, anticoagulant and fibrinolytic activity. The resulting thrombin C, the main product of the reaction, promotes the coagulation of fibrinogen.

Tissue thromboplastin (factor III)

Tissue thromboplastin is a thermostable lipoprotein, found in various organs– in the lungs, brain, kidneys, heart, liver, skeletal muscles. It is not found in tissues in an active state, but in the form of a precursor - prothromboplastin. Tissue thromboplastin, when interacting with plasma factors (VII, IV), is capable of activating factor X and is involved in external path formation of prothrombinase - a complex of factors that convert thrombin.

Calcium ions (factor IV)

Calcium ions are involved in all three phases of blood coagulation: in the activation of prothrombinase (phase I), the conversion of prothrombin into thrombin (phase II) and fibrinogen into fibrin ( III phase). Calcium is able to bind heparin, which speeds up blood clotting. In the absence of calcium, platelet aggregation and retraction are impaired blood clot. Calcium ions inhibit fibrinolysis.

Proaccelerin (factor V)

Proaccelerin (factor V, plasma AC globulin or labile factor) is formed in the liver, but, unlike other hepatic factors of the prothrombin complex (II, VII, and X), it is not dependent on vitamin K. It is easily destroyed. The content of factor V in plasma is 12–17 units/ml (about 0.01 g/l), half-life is 15–18 hours. The minimum level required for hemostasis is 10 – 15%.

Proaccelerin is necessary for the formation of internal (blood) prothrombinase (activates factor X) and for the conversion of prothrombin to thrombin.

Accelerin (factor VI)

Accelerin (factor VI or serum AC-globulin) is the active form of factor V. It is excluded from the nomenclature of coagulation factors; only the inactive form of the enzyme is recognized - factor V (proaccelerin), which, when traces of thrombin appear, turns into active form.

Proconvertin, convertin (factor VII)

Proconvertin is synthesized in the liver with the participation of vitamin K. It remains in stabilized blood for a long time and is activated by a wetted surface. The content of factor VII in plasma is about 0.005 g/l, the half-life is 4 – 6 hours. The minimum level required for hemostasis is 5 – 10%.

Convertin, the active form of the factor, plays a major role in the formation of tissue prothrombinase and in the conversion of prothrombin to thrombin. Activation of factor VII occurs at the very beginning chain reaction upon contact with a foreign surface. During the coagulation process, proconvertin is not consumed and remains in the serum.

Antihemophilic globulin A (factor VIII)

Antihemophilic globulin A is produced in the liver, spleen, endothelial cells, leukocytes, and kidneys. The content of factor VIII in plasma is 0.01 – 0.02 g/l, half-life is 7 – 8 hours. The minimum level required for hemostasis is 30 – 35%.

Antihemophilic globulin A participates in the “intrinsic” pathway of prothrombinase formation, enhancing the activating effect of factor IXa (activated factor IX) on factor X. Factor VIII circulates in the blood, being associated with.

Antihemophilic globulin B (Christmas factor, factor IX)

Antihemophilic globulin B (Christmas factor, factor IX) is formed in the liver with the participation of vitamin K, is thermostable, and persists for a long time in plasma and serum. The content of factor IX in plasma is about 0.003 g/l. Half-life is 7 – 8 hours. The minimum level required for hemostasis is 20 – 30%.

Antihemophilic globulin B participates in the “intrinsic” pathway of prothrombinase formation, activating factor X in combination with factor VIII, calcium ions and platelet factor 3.

Stewart-Prower factor (X factor)

Stewart-Prower factor is produced in the liver in an inactive state and is activated by trypsin and an enzyme from viper venom. K-vitamin dependent, relatively stable, half-life - 30 - 70 hours. The content of factor X in plasma is about 0.01 g/l. The minimum level required for hemostasis is 10 – 20%.

Stewart-Prower factor (factor X) is involved in the formation of prothrombinase. IN modern scheme Blood coagulation active factor X (Xa) is the central factor of prothrombinase, which converts prothrombin into thrombin. Factor X is converted into its active form by factors VII and III (external, tissue, prothrombinase formation pathway) or factor IXa together with VIIIa and phospholipid with the participation of calcium ions (internal, blood, prothrombinase formation pathway).

Plasma precursor of thromboplastin (factor XI)

The plasma precursor of thromboplastin (factor XI, Rosenthal factor, antihemophilic factor C) is synthesized in the liver and is thermolabile. The content of factor XI in plasma is about 0.005 g/l, the half-life is 30 – 70 hours.

The active form of this factor (XIa) is formed with the participation of factors XIIa, and. Form XIa activates factor IX, which is converted to factor IXa.

Hageman factor (factor XII, contact factor)

Hageman factor (factor XII, contact factor) is synthesized in the liver, produced in an inactive state, half-life is 50 - 70 hours. The factor content in plasma is about 0.03 g/l. Bleeding does not occur even with very deep factor deficiency (less than 1%).

Activated upon contact with the surface of quartz, glass, cellite, asbestos, barium carbonate, and in the body - upon contact with skin, collagen fibers, chondroitinsulfuric acid, micelles of saturated fatty acids. Activators of factor XII are also Fletcher factor, kallikrein, factor XIa, plasmin.

Hageman factor participates in the “intrinsic” pathway of prothrombinase formation, activating factor XI.

Fibrin stabilizing factor (factor XIII, fibrinase, plasma transglutaminase)

Fibrin stabilizing factor (factor XIII, fibrinase, plasma transglutaminase) is determined in vascular wall, platelets, red blood cells, kidneys, lungs, muscles, placenta. In plasma it is found in the form of a proenzyme combined with fibrinogen. It is converted to its active form under the influence of thrombin. Contains in plasma in the amount of 0.01 - 0.02 g/l, half-life - 72 hours. The minimum level required for hemostasis is 2 – 5%.

Fibrin stabilizing factor is involved in the formation of a dense clot. It also affects the adhesiveness and aggregation of blood platelets.

Von Willebrand factor (antihemorrhagic vascular factor)

von Willebrand factor (antihemorrhagic) vascular factor) is synthesized by vascular endothelium and megakaryocytes, found in plasma and platelets.

Von Willebrand factor serves as an intravascular carrier protein for factor VIII. The binding of von Willebrand factor to factor VIII stabilizes the latter molecule, increases its half-life inside the vessel and promotes its transport to the site of damage. Other physiological role The relationship between factor VIII and von Willebrand factor is the ability of von Willebrand factor to increase the concentration of factor VIII at the site of vascular damage. Because circulating von Willebrand factor binds to both exposed subendothelial tissue and stimulated platelets, it directs factor VIII to the affected area, where the latter is required to activate factor X with the participation of factor IXa.

Fletcher's factor (plasma prekallikrein)

Fletcher factor (plasma prekallikrein) is synthesized in the liver. The factor content in plasma is about 0.05 g/l. Bleeding does not occur even with very deep factor deficiency (less than 1%).

Participates in the activation of factors XII and IX, plasminogen, converts kininogen into kinin.

Fitzgerald factor (plasma kininogen, Flozhek factor, Williams factor)

Fitzgerald factor (plasma kininogen, Flozhek factor, Williams factor) is synthesized in the liver. The factor content in plasma is about 0.06 g/l. Bleeding does not occur even with very deep factor deficiency (less than 1%).

Participates in the activation of factor XII and plasminogen.

Literature:

Handbook of Clinical Laboratory Methods. Ed. E. A. Kost. Moscow, "Medicine", 1975
Barkagan Z.S. Hemorrhagic diseases and syndromes. – Moscow: Medicine, 1988
Gritsyuk A. I., Amosova E. N., Gritsyuk I. A. Practical hemostasiology. – Kyiv: Health, 1994.
Shiffman F. J. Pathophysiology of blood. Translation from English - Moscow - St. Petersburg: BINOM Publishing House - Nevsky Dialect, 2000.
Directory " Laboratory methods research in the clinic" edited by Prof. V.V. Menshikov. Moscow, "Medicine", 1987.
Study of the blood system in clinical practice. Ed. G. I. Kozints and V. A. Makarov. - Moscow: Triad-X, 1997

Introduced for the first time

PHARMACOPOEIAL ARTICLE

This pharmacopoeial monograph applies to preparations of human blood coagulation factor VIII obtained from human blood plasma for fractionation.

Human blood coagulation factor VIII is a preparation of the protein fraction of human blood containing the glycoprotein complex of blood coagulation factor VIII and, depending on the method of preparation, various quantities von Willebrand factor.

The activity of the drug after reconstitution under the conditions specified on the label must be at least 20 IU of factor VIII per 1 ml.

PRODUCTION

For the production of human blood coagulation factor VIII preparations, blood plasma from healthy donors is used, which meets the requirements of the Federal Law “Human Plasma for Fractionation”. The production technology includes stages of removal or inactivation of infectious agents. If used to inactivate viruses in production chemical compounds, their concentration should be reduced to a level that does not affect the safety of the drug for patients. No antimicrobial preservatives are used in the production process. The drug may contain stabilizers (albumin, polysorbate, sodium chloride, sodium citrate, calcium chloride, glycine, lysine, etc.). The drug solution is aseptically packaged in primary packaging using sterilizing filtration, lyophilized and sealed under vacuum or in an inert gas atmosphere.

TESTS

Description

White or pale yellow powder or friable solid. The determination is carried out visually.

Authenticity

Species specificity

Confirmed by the presence of only human serum proteins. The test is carried out by immunoelectrophoresis in a gel using sera against serum proteins of human blood, large cattle, horses and pigs in accordance with . It is acceptable to carry out the gel immunodiffusion test in accordance with. The test should detect precipitation lines only with serum against human serum proteins.

FactorVIII

Confirmed by the presence of factor VIII activity. The test is carried out using the chromogenic or coagulometer method. The determination is carried out in accordance with.

Time to receive reconstituted drug

No more than 10 minutes (unless there are other instructions in the regulatory documentation). A description of the method is provided, indicating the solvent used, its volume and dissolution conditions (temperature of the solvent, the need for stirring, etc.).

Water

No more than 2%. The determination is carried out by K. Fisher's method in accordance with (unless there are other instructions in the regulatory documentation). The method of determination and the amount of sample required for testing are indicated in the regulatory documentation.

Mechanical inclusions

There should be no visible mechanical inclusions. The determination is carried out in accordance with. The regulatory documentation indicates the name of the solvent, describes the method of recovery and (if necessary) preparation of the drug.

pH

From 6.5 to 7.5. The determination is carried out by the potentiometric method in accordance with.

Osmolality

Not less than 240 mOsm/kg. The determination is carried out in accordance with.

Protein

The quantitative protein content per bottle or ml of reconstituted solution is indicated in the regulatory documentation. The determination is carried out in accordance with.

Clotting factor activityVIII

The activity of blood coagulation factor VIII per bottle or ml of reconstituted solution is indicated in the regulatory documentation. The determination is carried out using the coagulometer method in accordance with.

von Willebrand factor

The activity of von Willebrand coagulation factor per bottle or ml of reconstituted solution is indicated in the regulatory documentation. Determination is carried out by agglutination method or enzyme immunoassay method in accordance with .

Stabilizer(s)

Quantitative determination of the stabilizer(s) added to the drug is carried out in accordance with and/or, if there are no other instructions in the regulatory documentation.

The permissible limit for the content of stabilizer(s) must be specified in the regulatory documentation.

Virus-activating agents

Quantitative determination of the residual content of the virus inactivating agent(s) in the preparation is carried out in accordance with and/or, if there are no other instructions in the regulatory documentation. The permissible limit for the content of virus inactivating agent(s) must be specified in the regulatory documentation.

Sterility

The drug must be sterile. The test is carried out in accordance with.

Pyrogenicity or bacterial endotoxins

Must be pyrogen-free or contain bacterial endotoxins in an amount of no more than 0.03 EU per 1 IU of blood coagulation factor VIII activity.

The test is carried out in accordance with (test dose - at least 50 IU of blood coagulation factor VIII per 1 kg of animal weight) or in accordance with the method specified in the regulatory documentation.

Virus safety

Hepatitis B virus surface antigen (HBsAg)

The drug should not contain the surface antigen of the hepatitis B virus. Determination is carried out by the enzyme immunoassay method using test systems approved for use in Russian healthcare practice and having a sensitivity of at least 0.1 IU/ml in accordance with the instructions for use.

Antibodies to hepatitis C virus

Antibodies to the hepatitis C virus must be absent. The determination is carried out by the enzyme immunoassay method using test systems approved for use in Russian healthcare practice and having 100% sensitivity and specificity in accordance with the instructions for use.

Antibodies to human immunodeficiency virus (HIV-1 and HIV-2)and HIV-1 p24 antigen

The drug should not contain antibodies to the human immunodeficiency virus (HIV-1 and HIV-2) and HIV-1 p24 antigen. The determination is carried out by the enzyme immunoassay method using test systems approved for use in Russian healthcare practice and having 100% sensitivity and specificity in accordance with the instructions for use.

Packageand labeling

X wound

Store in a place protected from light at a temperature of 2 to 8 ° C, unless otherwise indicated in the regulatory documentation.

Formula, chemical name: no data.
Pharmacological group: hematotropic agents / Coagulants (including blood clotting factors), hemostatic agents.
Pharmachologic effect: hemostatic, replenishing the deficiency of coagulation factor VIII.

Pharmacological properties

Blood clotting factor VIII is a hemostatic drug that is used in hemophilia A. Blood clotting factor VIII accelerates the conversion of prothrombin to thrombin and thus promotes fibrin clot formation. When administered to patients with hemophilia, coagulation factor VIII binds to von Willebrand factor in the blood vessels. Activated coagulation factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X, in turn, converts prothrombin to thrombin. Thrombin then converts fibrinogen into fibrin, and a clot can form. Hemophilia A is an inherited, sex-linked bleeding disorder that is caused by decreased levels of clotting factor VIII, leading to profuse bleeding into muscles, joints, internal organs and can be either spontaneous or as a result of surgical interventions or accidental injuries. When conducting replacement treatment the level of blood coagulation factor VIII in the blood serum increases, which makes it possible to temporarily compensate for the deficiency of blood coagulation factor VIII and reduce the tendency to bleeding. Specific activity blood clotting factor VIII is at least 100 IU/mg total protein.
Blood coagulation factor VIII is a common component of human serum and has the same effect as endogenous blood coagulation factor VIII. After administration of blood clotting factor VIII, approximately 2/3 to 3/4 of the drug remains in the bloodstream. The level of factor VIII activity achieved in the blood serum should be 80 - 120% of the expected factor VIII activity. The activity of coagulation factor VIII in the blood serum decreases according to a biphasic exponential decay pattern. In the first phase, blood coagulation factor VIII is distributed between intravascular and other body fluids with a half-life of 3–6 hours. In the second, more slow phase, which most likely reflects the consumption of coagulation factor VIII, the half-life averages 12 hours (range 8 to 20 hours). Which corresponds to the true biological half-life of coagulation factor VIII. In patients with hemophilia A, the average values of the pharmacokinetic parameters of blood coagulation factor VIII are: recovery - 2.4% × IU-1 × kg; area under the pharmacokinetic curve concentration - time curve - from 33.4 to 45.5% × h × IU-1 × kg; the average time spent in the blood is from 16.6 to 19.6 hours; half-life - from 12.6 to 14.3 hours; clearance - from 2.6 to 3.2 ml × h^-1 × kg.

Indications

Therapy and prevention of bleeding in patients with congenital hemophilia A or acquired coagulation factor VIII deficiency, including inhibitor forms (using the induction method immune tolerance).

Method of administration of blood coagulation factor VIII and dose

Blood clotting factor VIII is administered intravenously after dilution in water for injection. The dose and duration of replacement treatment depends on the severity of factor VIII deficiency, the location and duration of bleeding, and the patient’s objective condition. Treatment should begin under the supervision of a physician who has experience treating patients with hemophilia.
The number of units of clotting factor VIII is expressed in international units (IU), which are established by current standards World Organization Health care for clotting factor VIII. The activity of coagulation factor VIII in blood serum is expressed as a percentage (relative to normal level coagulation factor VIII in human serum) or in IU (relative to international standard for blood clotting factor VIII). 1 IU of coagulation factor VIII activity is equivalent to the content of coagulation factor VIII in 1 ml of normal human serum. Calculation of the required dose of the drug is based on empirical data, according to which 1 IU of blood coagulation factor VIII per kg of body weight increases the activity of blood coagulation factor VIII in the blood serum by 1.5 - 2% of normal activity. To calculate the required dose of the drug, the initial level of activity of blood coagulation factor VIII is determined and how much this activity needs to be increased. The required dose of the drug is calculated using the following formula: required dose= body weight (kg) × desired increase in factor VIII level (%) (IU/dL) × 0.5. The frequency of use and dosage of the drug should always be aimed at achieving clinical effect in each specific case. In case of bleeding after the start of treatment, the activity of coagulation factor VIII should not decrease below the initial serum level (% of normal concentration) in the appropriate period of time.
For early hemarthrosis, intramuscular bleeding, bleeding oral cavity the required level of blood clotting factor VIII is 20 - 40%, necessary repeated administrations the drug every 12 to 24 hours for at least one day until the pain subsides or the source of bleeding heals. For more intense bleeding, intramuscular bleeding or hematomas, the required level of blood coagulation factor VIII is 30 - 60%; repeated administration of the drug is necessary every 12 - 24 hours for 3 - 4 days until the pain subsides and the ability to work is restored. At life-threatening bleeding, the required level of blood coagulation factor VIII is 60 - 100%; repeated administration of the drug is necessary every 8 - 24 hours until the threat completely disappears. At small surgical interventions, including tooth extraction, the required level of blood clotting factor VIII is 30 - 60%, it is necessary to administer the drug every 24 hours for at least one day until healing is achieved. For major surgical interventions, the required level of blood coagulation factor VIII is 80 - 100% (preoperative and postoperative), repeated administration of the drug is necessary every 8 - 24 hours until adequate wound healing, then at least one week to maintain the activity of blood coagulation factor VIII at the level 30 - 60%. The required frequency of use and dose of the drug is determined by the attending physician.
During treatment, the level of blood coagulation factor VIII should be assessed to adjust the dose and frequency of repeated injections of the drug. It is necessary to carefully monitor the activity of coagulation factor VIII in the blood serum, especially during major surgical procedures. Response to treatment may vary among individual patients, as indicated by differences in the half-life and degree of recovery of coagulation factor VIII activity.
For long-term prevention bleeding in patients with severe hemophilia A average dose blood clotting factor VIII is 20 - 40 IU/kg body weight at intervals of 2 - 3 days. In some patients, especially in patients young, it may be necessary to shorten the interval between administrations of coagulation factor VIII or increase its dose.
In some patients, after drug therapy, the formation of inhibitors of blood coagulation factor VIII is possible, which may affect the effectiveness of further therapy. If, against the background of the therapy, the expected increase in the activity of blood coagulation factor VIII is not observed or there is no required hemostatic effect, then consultation with a specialized specialist is recommended. treatment center using the Bethesda test. To eliminate the inhibitor of blood coagulation factor VIII, induction of immune tolerance can be used, which consists of daily administration of blood coagulation factor VIII in a concentration that exceeds the blocking ability of the inhibitor (100 - 200 IU/kg/day depending on the titer of the inhibitor). Blood coagulation factor VIII acts as an antigen and provokes an increase in the titer of the coagulation factor VIII inhibitor until tolerance develops, that is, a decrease and further disappearance of the inhibitor. Induction of immune tolerance is carried out continuously and lasts on average from 10 to 18 months. Immune tolerance induction should only be performed by physicians who are specialists in antihemophilic treatment.
Clinical data on the use of coagulation factor VIII in previously untreated patients are limited.
A clinical study involving 15 patients under 6 years of age did not reveal special requirements for dosing the drug in children.
It is necessary to monitor the presence of factor VIII inhibitors in patients. If, against the background of the therapy, the expected increase in the activity of blood coagulation factor VIII is not observed or there is no necessary hemostatic effect, then it is necessary to conduct an analysis for the presence of inhibitors of blood coagulation factor VIII. If patients with high level coagulation factor VIII inhibitors, treatment with the drug is ineffective, then it is necessary to consider alternative therapy. These patients should be treated by doctors who have experience in treating hemophilia.
Interim data are available from an ongoing study in patients undergoing factor VIII immune tolerance induction. The dosage regimen is established in the medical institution individually for each patient. Patients with a weak response usually receive coagulation factor VIII at a dose of 50 - 100 IU/kg body weight every day or every other day, patients with a strong response usually receive coagulation factor VIII at a dose of 100 - 150 IU/kg body weight every 12 hours. Factor VIII inhibitor titers are determined twice every 7 days for the first three months, then factor VIII inhibitor titers are determined every three months during routine visits. medical institutions to continue treatment. The result of immune tolerance induction is determined after three years according to three consecutive criteria, including a negative titer of factor VIII inhibitors, restoration of factor VIII activity, and normalization of the half-life of blood coagulation factor VIII. An interim analysis found that of the 69 patients who received factor VIII for immune tolerance induction, 49 patients completed the study. In patients with successful elimination of the coagulation factor VIII inhibitor, the monthly frequency of bleeding decreased significantly.
Before intravenous administration, the reconstituted drug must be examined for discoloration and the presence of mechanical inclusions. The reconstituted factor VIII solution should be clear or slightly opalescent. Do not use a factor VIII solution that is cloudy or has clots in it. Reconstituted factor VIII solution must be used immediately after preparation and only once.
As a precaution, heart rate should be monitored before and during administration of clotting factor VIII. If the heart rate increases significantly, the administration of blood coagulation factor VIII should be slowed down or stopped.
Any unused factor VIII solution must be disposed of according to existing regulations.
As with any medicine protein origin, For intravenous administration reactions may develop hypersensitivity allergic type. In addition to blood clotting factor VIII, the medicinal product contains trace amounts of other human plasma proteins. Patients need to be informed about early signs hypersensitivity reactions, including generalized and local urticaria, wheezing, squeezing sensation chest, hypotension, anaphylaxis. If these symptoms develop, you should immediately stop using the drug and consult your doctor. If shock develops, it is necessary to carry out standard anti-shock treatment.
When using blood clotting factor VIII in in rare cases hypersensitivity reactions or allergic reactions which may include a burning sensation at the injection site, a tingling sensation at the injection site, angioedema, flushing of the face, chills, generalized urticaria, local urticaria, headache, hypotension, lethargy, nausea, tachycardia, anxiety, a feeling of chest compression, vomiting, ringing in the ears, wheezing, in some cases these symptoms may progress, in including before the development of severe anaphylaxis, including shock.
In patients with hemophilia A, when using blood coagulation factor VIII, inhibitors (antibodies) of blood coagulation factor VIII may appear, which is manifested by an insufficient clinical response to the drug. In this situation, it is necessary to contact a specialized hematology center. The formation of neutralizing inhibitors (antibodies) of coagulation factor VIII is known complication treatment of patients with hemophilia A. Typically, these factor VIII inhibitors are immunoglobulins G, which act against the procoagulant activity of factor VIII, their level is determined in Bethesda units per ml of blood serum using a modified method. The risk of forming factor VIII inhibitors correlates with drug use and is highest in the first 20 days of treatment. In rare cases, clotting factor VIII inhibitors may be detected after the first 100 days of using the drug. All patients receiving treatment with coagulation factor VIII drugs should be carefully monitored for the development of anti-coagulation factor VIII antibodies by appropriate testing. laboratory tests And clinical observations. In ongoing clinical trial in previously untreated patients, 3 of 39 people who received factor VIII on an as-needed basis developed factor VIII inhibitors. Two cases were clinically significant; in two other patients, factor VIII inhibitors spontaneously disappeared without changing the drug dose. All cases of the formation of factor VIII inhibitors were observed during therapy as needed for no more than 50 days. There was an initial level of factor VIII activity of less than 1% in 35 previously untreated patients and less than 2% in 4 previously untreated patients. At the time of the interim analysis, factor VIII had been used for at least 20 days in 34 patients and for at least 50 days in 30 patients. In previously untreated patients who used factor VIII prophylaxis, factor VIII inhibitors were not determined. During the study, 12 previously untreated patients underwent 14 surgical interventions. Average age of the patient at the time of the first use of blood coagulation factor VIII was 7 months (from 3 days to 67 months), and average duration use of blood coagulation factor VIII in a clinical study was 100 days (range 1 to 553 days).
There is information about a connection between the formation of coagulation factor VIII inhibitors and allergic reactions, therefore, if allergic reactions develop, the patient should be examined for the presence of coagulation factor VIII inhibitors. Patients with coagulation factor VIII inhibitors may be at increased risk of anaphylaxis with subsequent use of coagulation factor VIII. Therefore, the first administration of blood coagulation factor VIII must be carried out as prescribed by the attending physician under medical supervision in conditions that allow us to provide the necessary medical care with the development of allergic reactions.
Standard measures to prevent infectious diseases that may be caused by the use of medicinal products prepared from human blood or serum include the selection of donors, screening of individual donations and blood serum pools for specific markers of infectious diseases, and the introduction of effective stages of inactivation and removal of microorganisms into the production of medicinal products. But when using medicinal products that are prepared from human blood or serum, the risk of transmitting microorganisms that cause infectious diseases cannot be completely excluded. This also applies to new or unknown microorganisms. These infectious disease prevention measures are considered effective against enveloped viruses (human immunodeficiency virus, hepatitis B virus, hepatitis C virus) and non-enveloped hepatitis A virus. These infectious disease prevention measures may have limited effectiveness against non-enveloped viruses, such as parvovirus B19. Infection which is caused by parvovirus B19 may have serious consequences for women during pregnancy (fetal infection) and patients with immunodeficiency or increased erythropoiesis (for example, with hemolytic anemia). In patients who regularly and repeatedly receive medications clotting factor VIII derived from human serum, appropriate vaccination against hepatitis A and B should be considered.
To establish a connection between the patient and the batch of the drug, it is recommended that the name and batch number of the drug be recorded each time clotting factor VIII is used.

When using coagulation factor VIII, care must be taken when performing potential dangerous species activities that require increased concentration and speed of psychomotor reactions (including control vehicles, mechanisms), since the development of headache, tinnitus, hypotension and others is possible adverse reactions, which can have Negative influence to carry out these types of activities. If such adverse reactions develop, it is necessary to refrain from performing potentially hazardous activities that require increased concentration and speed of psychomotor reactions (including driving vehicles and machinery).

Contraindications for use

Hypersensitivity (including to auxiliary components medicinal product).

Restrictions on use

Pregnancy, breastfeeding.

Use during pregnancy and breastfeeding

Since hemophilia A is rare in women, experience with the use of blood clotting factor VIII in women during pregnancy and during breastfeeding absent. Blood clotting factor VIII in women during pregnancy and breastfeeding should be used only if absolute readings when the expected benefit to the mother is higher possible risk for the fetus or child.

Side effects of clotting factor VIII

Nervous system, psyche and sensory organs: headache, anxiety, ringing in the ears.
Cardiovascular system, blood (hemostasis, hematopoiesis) and lymphatic system: hypotension, flushing, tachycardia.
Digestive system: nausea, vomiting.
Respiratory system: feeling of chest compression, wheezing.
The immune system: hypersensitivity reactions, anaphylactic shock, allergic reactions, severe anaphylaxis, angioedema, generalized urticaria, local urticaria.
General disorders and reactions at the injection site: burning sensation at the injection site, tingling sensation at the injection site, chills, apathy, increased body temperature.
Laboratory indicators: formation of antibodies to blood coagulation factor VIII in blood serum.

Interaction of blood coagulation factor VIII with other substances

There is no data on the interaction of blood coagulation factor VIII with other drugs.
Others should not be used medicines with the introduction of blood coagulation factor VIII.

Overdose

There have been no cases of overdose of blood coagulation factor VIII. It is recommended not to exceed the prescribed dose of clotting factor VIII.

Trade names of drugs with the active substance blood clotting factor VIII

Agemfil A
Antihemophilic human factor-M(AHF-M)
Beriat
Hemoctine
Hemophilus M
Immunat
Koate-DVI
Coate-HP
Cryobulin TIM 3
Cryoprecipitate
LongEight
Octavi
Octanate
Fundy
Hemate P
Emoklot D.I.

Combined drugs:
Blood coagulation factor VIII + von Willebrand factor: Vilate, Hemate® P.