FS.3.2.0003.15 Human blood coagulation factor VIII. Plasma coagulation factors

Approximately 20-30% of patients with hemophilia A develop antibodies to clotting factor 8

Vegetarian capsules prevent complication of hemophilia treatment in mice. September 4, 2014 American scientists have developed a strategy to prevent one of the most serious complications treatment of hemophilia. An approach that uses vegetable capsules to train the immune system to tolerate rather than attack the clotting factor 8 protein. This is encouraging research for preventing one of the most serious complications of hemophilia treatment.

Blood coagulation factor - a target for the treatment of hemophilia

Healthy people have proteins in their blood - clotting factors that help stop bleeding quickly. In patients with hemophilia, these proteins are not enough, so even small bleeding is difficult to stop. The main treatment option for people with severe hemophilia is to receive continuous injections of a blood clotting factor. However, 20 to 30% of people who receive these injections develop antibodies that are inhibitors of the blood clotting factor. Once these inhibitors are formed in patients, it becomes very difficult to treat or prevent future episodes of bleeding.

In the new study, the scientists tried to develop a strategy to prevent the formation of these antibodies. Their approach uses plant cells to teach the immune system to tolerate rather than attack the clotting factor protein. This study offers hope for preventing one of the most serious complications of hemophilia treatment.

The only modern methods treatments to form an inhibitor cost $1 million and are risky for patients. The new technique uses capsules on plant-based and has the potential to be a cost effective and safe alternative. This could potentially be a way to prevent the formation of antibodies.

Hemophilia A - blood clotting deficiency 8

The study of scientists was focused on, in which there is a deficiency of blood coagulation factor 8, resulting in a defect in the clotting process. Worldwide, approximately one in 7,500 men is born with this condition. After receiving an injection of factor 8, some patients develop antibodies against it. The immune system reacts to this foreign protein as an invader and attacks it.

These antibodies are known as inhibitors in hemophilia. It is due to the formation of antibodies that standard therapy is ineffective in some patients. To prevent an attack immune system coagulation factors, researchers have focused on previous studies that have shown that by exposing the immune system to individual components of a coagulation factor protein, tolerance to the entire protein can be induced. clotting factor 8 consists of a heavy chain and a light chain, each containing three regions. The scientists used the entire heavy chain and the C2 domain of the light chain.

Modified plant material prevents the formation of inhibitors

Scientists have developed a drug and biological delivery platform therapeutic agent based on genetic modification of plants. They then applied the same method to the components of the clotting factor 8 molecule. The scientists first fused the heavy strand of DNA with the coding subunit of the cholera toxin DNA (a protein that can cross the intestinal wall and enter the bloodstream), and then did the same with the C2 DNA. They introduced fusion genes into tobacco chloroplasts such that some plants expressed heavy chain and cholera toxin proteins, while others expressed C2 and cholera toxin proteins. They then crushed the leaves of the plant and suspended them in the solution, mixed with the heavy chain and the C2 domain of the light chain.

Explorers fed mixed preparation mice with hemophilia A twice a week for two months and compared with mice fed unmodified plant material. Then they injected mice with an injection of blood clotting factor 8, which people with hemophilia get. As expected, in the control group of mice, high level inhibitors. In contrast, mice that received experimental plant material developed much more low levels inhibitors - an average of 7 times less!

What mechanism?

Scientists have studied certain types signaling molecules - cytokines that send messages to T-cells of the immune system. They found that mice fed the experimental plant had several cytokines associated with the suppression or regulation of immune responses. At the same time, mice in the control group showed more cytokines associated with triggering the immune response. By transferring subsets of regulatory T cells taken from mice fed the experimental plant to normal mice, the scientists were able to suppress the production of inhibitors. It is assumed that T cells are able to provide tolerance in a new population of animals.

Finally, the researchers tried to reverse the formation of the inhibitor. They fed the experimental plant material to mice that had already developed the inhibitors. Compared with the control group of mice, clotting factor 8 was formed more slowly in the group of mice that were fed plant material. In two to three months of feeding, the levels of inhibitors decreased three to seven times.

This new treatment strategy holds promise for preventing and even reversing inhibitor formation in hemophilia A patients who receive injections of blood coagulation factor 8. However, the scientists note that levels of blood coagulation factor 8 inhibitor can re-form (after a period of time if stop giving plant material to animals). With financial support from global pharmaceutical companies, scientists plan to study the effectiveness of capsules containing this plant material in clinical settings.

Factor VIII Test material: blood plasma Determination of factor VIII activity in blood plasma. Factor VIII The analysis detects the activity of factor VIII in blood plasma (in%) Factor ...

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Study Description

Preparation for the study: Blood is taken on an empty stomach Material under study: Taking blood

Factor VIII

Test material: blood plasma

Determination of factor VIII activity in blood plasma.

The assay detects factor VIII activity in blood plasma (in %)

clotting factor Blood VIII(Antihemophilic globulin) - plays important role in the process of blood coagulation. Factor VIII is synthesized in the liver, spleen, endothelial cells, leukocytes, and kidneys.

Coagulation factor VIII deficiency is found in one of the most severe hereditary diseases- hemophilia A. The disease is transmitted through the female line, but only men suffer from it. The frequency of the disease is 1 per 8-10 thousand of the male population. The disease is characterized by spontaneous, sometimes fatal bleeding, bleeding into the joints, which leads to irreversible damage to the musculoskeletal system and, as a result, to early disability. Patients with hemophilia throughout their lives need replacement therapy concentrates of antihemophilic globulin. The sooner a diagnosis is made and treatment initiated, the more likely that the patient can lead full image life.

Method

The simplest and most widely used method for determining factor VIII activity is a one-step method based on a linear relationship between factor VIII and clotting time in the APTT test (activated partial thromboplastin time).

Reference values ​​- norm
(Blood coagulation factor 8 (antihemophilic globulin), blood)

Information regarding the reference values ​​of the indicators, as well as the very composition of the indicators included in the analysis, may differ slightly depending on the laboratory!

Norm:

Factor VIII activity in blood plasma healthy person is 50-150%.

Indications

• Diagnosis of hemophilia.
• Control of replacement therapy in patients with hemophilia A with factor VIII concentrates.
• Diagnosis of thrombophilia due to an increase in the level of factor VIII.

Increasing values ​​(positive result)

• Increased Risk development of thrombosis

Decreasing values ​​(negative result)

• Factor VIII level less than 1% - a severe form of hemophilia A. With this form of hemorrhage into the joints, muscles and other organs occur with minimal or even imperceptible damage
• Factor VIII level 1-5% - hemophilia medium degree. In this form of hemophilia, bleeding occurs due to obvious minor injuries, also after various operations and tooth extractions
• Factor VIII level 5-30% - hemophilia mild degree. With this form of hemorrhage usually follow only major damage, surgical operations or extraction of teeth. Diagnosis of this form may not be made until adulthood or bleeding after these situations.

Chromatographically purified lyophilized human plasma fraction containing coagulation factor VIII. Antihemophilic globulin, compensates for the deficiency of coagulation factor VIII, temporarily compensates for the coagulation defect in patients with hemophilia A. It is found in natural combination with protein C of factor VIII, von Willebrand factor. It is involved in the processes of blood coagulation, promotes the transition of prothrombin to thrombin and the formation of a fibrin clot. Immediately after administration, it increases the coagulation potential of the blood. The decrease in the activity of the antihemophilic factor has a two-phase character: early phase — rapid decline activity, characterizes the equilibration time with the extravascular space, the second phase is slow, reflects the biological half-life of the introduced antihemophilic factor and is 9-14 hours. Specific activity (after adding human albumin) is 9-22 IU of protein. 1 IU (as defined by the WHO blood coagulation factor VIII standard) is approximately equal to the level of antihemophilic factor present in 1 ml of fresh human donor plasma.
The time to reach the maximum plasma concentration after intravenous administration is from 10 minutes to 2 hours. The half-life is 8.4-19.3 hours. The activity of coagulation factor VIII decreases gradually - by 15% within 12 hours. With hyperthermia, the period the half-life of coagulation factor VIII may decrease.

Indications for use of the drug Coagulation Factor VIII

Hemophilia A, von Willebrand's disease (treatment and prevention of bleeding, including during surgical interventions); acquired deficiency of factor VIII, diseases accompanied by the formation of antibodies to factor VIII.

How to use Coagulation Factor VIII

In / in. To prevent spontaneous bleeding or light bleeding- 10 IU / kg (the content of factor VIII, necessary to prevent spontaneous bleeding - 5% normal level); with moderate bleeding and a small surgical intervention (for example, tooth extraction) - 15-25 IU / kg (factor VIII content - 30-80% of the norm) followed by a maintenance dose of 10-15 IU / kg every 12-24 hours for 3 days or until a sufficient clinical effect is obtained; at acute bleeding life-threatening - 40-50 IU / kg (factor VIII content - 60-100% of the norm) followed by a maintenance dose of 20-25 IU / kg every 8-24 hours; with extensive surgical interventions - 40-50 IU / kg 1 hour before the procedure and 20-25 IU / kg - 5 hours after the first dose (that is, 80-100% of the norm before and after surgery), then repeat every 8-24 h until a sufficient clinical effect is obtained. For long-term prevention bleeding in severe hemophilia A - 12-25 IU / kg every 2-3 days.
Cryoprecipitate is used taking into account compatibility for AB0 blood groups. A container with frozen cryoprecipitate is placed for thawing and complete dissolution on water bath at a temperature not exceeding 35-37 ° C and kept for no more than 7 minutes. The resulting transparent yellowish colors rr, which should not contain flakes, is used immediately after preparation. Administered intravenously with a syringe or transfusion system with a disposable filter. The dose depends on the initial content of factor VIII in the blood of a patient with hemophilia, the nature and location of bleeding, the degree of risk of surgical intervention, the presence of specific inhibitor, capable of neutralizing the activity of factor VIII (expressed in units of factor VIII activity). To ensure effective hemostasis at the most frequent complications hemophilia (hemarthrosis, renal, gingival and nasal bleeding), as well as the removal of teeth, the content of factor VIII in plasma should be at least 20%; with intermuscular hematomas, gastrointestinal bleeding, fractures and other injuries - not less than 40%; in most surgical interventions - at least 70%. With the introduction of factor VIII at the rate of 1 unit per 1 kg of body weight, its content in the blood increases by an average of 1%. Based on this, the number of doses required to increase the concentration of factor VIII in the blood to a given level is calculated by the formula: the patient's body weight (in kg) multiplied by the required content of factor VIII in the patient's blood and divided by 200 (the minimum content of factor VIII in units of activity in 1 dose of cryoprecipitate). After a complete stop of bleeding, the introduction of factor VIII to patients with hemophilia is carried out at intervals of 12-24 hours at a dose that provides an increase in the content of factor VIII by at least 20%. Treatment is continued for several days - until a visible decrease in the size of the hematoma. In surgical interventions, a hemostatic dose is administered 30 minutes before surgery. In case of massive bleeding, blood loss is replenished, at the end of the operation, cryoprecipitate is re-introduced (1/2 dose from the original). 3-5 days after the operation, it is necessary to maintain the concentration of factor VIII in the patient's blood within the same limits as during the operation. AT postoperative period in the future, to maintain hemostasis, it is sufficient to increase the content of factor VIII to 20%. The duration of hemostatic therapy is 7-14 days and depends on the nature, location of bleeding, reparative tissue characteristics. It is advisable to combine the treatment of a patient with hemophilia with cryoprecipitate with the simultaneous administration of antifibrinolytic agents and corticosteroids in prophylactic and medium therapeutic doses.

Contraindications to the use of the drug Coagulation Factor VIII

Increased sensitivity.

Side effects of clotting factor VIII

Allergic and transfusion reactions (urticaria, rash, stridor breathing, decreased blood pressure, chills, hyperthermia, anaphylaxis), transient paresthesia of the oral mucosa, nausea, vomiting, headache.

Special instructions for the use of the drug Coagulation Factor VIII

Use with caution during pregnancy and lactation.
It is necessary to control the heart rate before and during therapy: with a significant increase in heart rate, the infusion rate is slowed down or the administration is stopped. During and after the end of the course of therapy, it is necessary to control the content of factor VIII in the blood. To detect signs of progressive hemolytic anemia it is necessary to monitor hematocrit and direct Coombs reaction. Changes immune status in patients with asymptomatic hemophilia are caused by repeated exposure to viral pathogens and / or possible presence impurities in factor VIII preparations (eg IgG). To achieve satisfactory clinical results in addition to the initially calculated dose, an additional dose may be administered. In the absence of a clinical effect, it is necessary to conduct a test to identify the inhibitor and determine its amount in neutralized antihemophilic units per 1 ml or total plasma volume. To reduce the risk of developing side effects it is recommended to use no later than 1 hour after dilution, enter only in / in, for at least 3 hours (at a rate of 10 ml / min), do not freeze the solution and do not reuse. It is possible to develop antibodies to coagulation factor VIII, in such cases the effectiveness of therapy is usually reduced, which may require an increase in the dose of coagulation factor VIII. It is possible to increase the rate of decline in CD4 cell counts in HIV-seropositive patients with hemophilia.

Factor VIII (antihemophilic factor A) is a plasma protein essential for proper blood clotting. It is present in plasma in combination with von Willebrand factor (VWF). Factor VIII is a non-enzymatic cofactor in the internal machinery of the blood coagulation system that, in the presence of phospholipids and calcium ions, accelerates the activation of factor X by factor IXa. Hemophilia A, which is a recessively inherited, sex-linked disease, is characterized by congenital factor VIII deficiency. T1 / 2 factor VIII is 8-12 hours. Von Willebrand factor, on the one hand, protects factor VIII from proteolytic degradation, on the other hand, is involved in platelet adhesion, forming a bridge between the subendothelial layer blood vessels and platelets. Deficiency of this factor is the cause of von Willebrand disease. After the use of factor VIII, there is an increase in the procoagulant activity of factor VIII in plasma, which can temporarily correct blood clotting disorders in patients with hemophilia A. Factor VIII is obtained from the blood plasma pool of several donors after a preliminary study for the carriage of HBsAg, the presence of antibodies to HCV and to HIV. Factor VIII concentrate is made using various methods(for example, thermal inactivation, chemical methods) in order to inactivate viruses and reduce the risk of transmission infectious diseases. Factor VIII is also produced using genetic engineering techniques.

Indications

Prevention and treatment of blood clotting disorders due to congenital (hemophilia A) or acquired deficiency of factor VIII. Von Willebrand disease (drugs containing factor VIII and von Willebrand factor) with factor VIII deficiency.

Contraindications

Hypersensitivity to any of the components of the drug or to animal proteins, for example, mice, large cattle, or hamsters (depending on the drug). If an allergic or anaphylactic reaction use must be stopped immediately. In patients on a diet with low content sodium, it is necessary to take into account the sodium content in the preparations. When using therapy using products based on human blood or plasma, the possibility of transmission of infectious agents cannot be completely excluded. This also applies to unknown or newly discovered viruses and other pathogens. Patients with von Willebrand's disease are at risk of developing thrombotic complications; patients with risk factors should be monitored to identify early signs thrombosis.

drug interaction

No data available. The preparations should not be mixed with other pharmaceuticals.

Unwanted Effects

Often: chills. Less common: nausea sharp redness facial skin, slight fatigue, rash, bruising, sweating, tremors, tremors, fever, leg pain, cold extremities, sore throat and larynx, ear inflammation, abnormal hearing test results, nosebleeds, pallor, allergic reactions(urticaria, rash, shortness of breath, cough, chest tightness, shortness of breath, hypotension, anaphylaxis). In addition: cyanosis, tachycardia, vomiting, discomfort in abdominal cavity, fainting, peeling of the skin. In 15-30% of patients with severe hemophilia A, a factor VIII inhibitor is produced, especially in the first 20 days of therapy.

Pregnancy and lactation

Dosage and administration

Intravenously. The individual dose depends on the severity of the disease, the location and extent of bleeding, as well as on clinical condition patient. It is recommended to control the heart rate before and during the administration of the drug - in case of an increase in the heart rate, it is necessary to reduce the rate of administration of the drug or stop it for a moment. Hemophilia A. Dose calculation (IU): body weight (kg) x desired factor VIII concentration (% of normal) x 0.5. In case of early hemorrhages in the joints and muscles or bleeding from the mouth, it is necessary to maintain the activity of factor VIII at the level of 20-40% of the usual (IU / dl), inject the drug for 1-3 days every 12-24 hours until the pain stops or healing wounds. In more severe hemorrhages in the joint, muscles, or in the case of a hematoma, it is necessary to maintain the activity of factor VIII at the level of 30-60% of the norm (IU / dl), inject the drug for 3 days or longer every 12-24 hours, until the pain stops and troubleshooting. With severe life threatening bleeding, it is necessary to maintain the activity of factor VIII at the level of 60-100% of the norm, to inject the drug every 8-24 hours until the threat is eliminated. Small surgical interventions, including tooth extraction - maintain factor VIII activity at the level of 30-60% of the norm (IU / dl), enter every 24 hours until the wound heals, according to at least, in one day. Major surgery - maintain factor VIII activity at 80-100% of normal (IU/dl) before and after surgery, inject until the wound heals every 8-24 hours, and then continue therapy for at least 7 days, maintaining factor VIII activity at the level of 30-60% of the norm (IU / dl). Preventive maintenance therapy - usually 20-40 IU / kg of body weight every 2-3 days; in some patients, especially children, it may be necessary to use higher doses or shorter intervals between injections. It is necessary to monitor the condition of patients for the appearance of factor VIII inhibitors in them, it is recommended to perform appropriate laboratory tests, including to determine the activity of antihemophilic factor (AHF). If the expected plasma AHF activity is not achieved, or if bleeding has not stopped despite the application of the required dose, an analysis for the presence of a factor VIII inhibitor should be performed. If the inhibitor titer is > 10 BU/mL, factor VIII therapy may not be effective and other therapies should be considered. Von Willebrand disease. Typically, 1 IU/kg von Willebrand factor (vWf) increases the plasma concentration of von Willebrand factor by 0.02 IU/mL (2%). The recommended concentration of von Willebrand factor to achieve is > 0.6 IU/ml (60%) and factor VIII > 0.4 IU/ml (40%). As a rule, the recommended concentration for obtaining hemostasis is 40-80 IU von Willebrand factor/kg body weight and 20-40 IU factor VIII/kg body weight. It may be necessary to administer an initial dose of 80 IU/kg b.w. von Willebrand factor, especially in patients with type 3 von Willebrand disease, which may require higher doses than other types of VWD to achieve adequate levels. For prevention heavy bleeding during or after surgery, the administration of the drug should be started 1-2 hours before surgery, and then re-administer a certain dose every 12-24 hours. The dose and duration of treatment depends on the clinical condition of the patient, the type and intensity of bleeding, and also on the concentration von Willebrand factor and factor VIII. In the case of the use of drugs with von Willebrand factor containing factor VIII, long-term treatment may lead to an excessive increase in the concentration of factor VIII. After 24-48 hours of therapy, to prevent an uncontrolled increase in the concentration of factor VIII, the need to reduce the dose and / or increase the interval between doses of the drug should be considered. In the case of von Willebrand disease with factor VIII deficiency, the prevention and treatment of bleeding is based on recommendations for use in hemophilia A.

Study Information

special instructions: Do not conduct research during acute periods diseases and while taking anticoagulant drugs (after cancellation, at least 30 days must pass). Biomaterial for research must be taken on an empty stomach. At least 8 hours should elapse between the last meal and blood sampling.

GENERAL RULES OF PREPARATION FOR RESEARCH:

1. For most studies, it is recommended to donate blood in the morning, from 8 to 11 am, on an empty stomach (at least 8 hours should elapse between the last meal and blood sampling, you can drink water as usual), the day before research easy restricted dinner fatty foods. For infection tests and emergency investigations, it is acceptable to donate blood 4-6 hours after the last meal.

2. ATTENTION! Special rules for preparing for a number of tests: strictly on an empty stomach, after 12-14 hours of fasting, you should donate blood for gastrin-17, lipid profile(total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, triglycerides, lipoprotein (a), apolipo-proten A1, apolipoprotein B); a glucose tolerance test is performed in the morning on an empty stomach after 12-16 hours of fasting.

3. On the eve of the study (within 24 hours), exclude alcohol, intense physical exercise, reception medicines(by agreement with the doctor).

4. 1-2 hours before donating blood, refrain from smoking, do not drink juice, tea, coffee, you can drink non-carbonated water. Exclude physical stress(running, fast climbing stairs), emotional arousal. It is recommended to rest and calm down 15 minutes before donating blood.

5. You should not donate blood for laboratory research immediately after physiotherapy procedures, instrumental examination, X-ray and ultrasound research, massage and other medical procedures.

6. Under control laboratory indicators in dynamics, it is recommended to conduct repeated studies in same conditions- in the same laboratory, donate blood at the same time of day, etc.

7. Blood for research should be donated before the start of taking medications or no earlier than 10-14 days after they are discontinued. To evaluate the control of the effectiveness of treatment with any drugs, it is necessary to conduct a study 7-14 days after the last dose of the drug.

If you are taking medication, be sure to tell your doctor about it.