Plasma coagulation factors. Association of plasma factor VIII levels with the severity of the bleeding disorder

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

Pharmacological properties

Coagulation factor VIII is a hemostatic drug that is used in hemophilia A. Coagulation 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 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 to fibrin, and a clot may already form. Hemophilia A is a hereditary, sex-related bleeding disorder that is caused by a decrease in blood clotting factor VIII, leading to profuse bleeding into the muscles, joints, internal organs and can be both spontaneous and as a result of surgical interventions or accidental injuries. When conducting substitution treatment the level of blood coagulation factor VIII in the blood serum increases, which makes it possible to temporarily compensate for the insufficiency of blood coagulation factor VIII and reduce the tendency to bleed. Specific activity coagulation factor VIII is at least 100 IU/mg total protein.
Coagulation factor VIII is a common component of human serum and has the same effect as endogenous factor blood clotting VIII. After administration of coagulation factor VIII, approximately 2/3 to 3/4 of the drug remains in the bloodstream. The level of activity of blood coagulation factor VIII, which is achieved in the blood serum, should be 80 - 120% of the expected activity of blood coagulation factor VIII. The activity of blood coagulation factor VIII in the blood serum decreases according to the model of biphasic exponential decay. In the first phase, the distribution of blood coagulation factor VIII between intravascular and other body fluids occurs with a half-life of 3-6 hours. In the second, more slow phase, which most likely reflects consumption of coagulation factor VIII, the half-life is 12 hours on average (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 - curve time - from 33.4 to 45.5% × h × IU ^-1 × kg; the average time spent in the blood - 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 deficiency of blood coagulation factor VIII, including inhibitory forms (using the method of induction of immune tolerance).

Route of administration of coagulation factor VIII and doses

Coagulation 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 objective condition of the patient. Treatment should be initiated under the supervision of a physician experienced in the treatment of patients with hemophilia.
The number of blood coagulation factor VIII units is expressed in international units (IU), which are set by the current World Health Organization standards for blood coagulation factor VIII. The activity of blood 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 the international standard for coagulation factor VIII). 1 IU of blood coagulation factor VIII activity is equivalent to the content of blood coagulation factor VIII in 1 ml of normal human blood serum. The 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, determine First level coagulation factor VIII activity 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 blood clotting factor VIII (%) (IU/dl) × 0.5. The frequency of use and doses of the drug should always be directed to achieve the clinical effect in each case. In case of bleeding after the start of treatment, the activity of blood coagulation factor VIII should not decrease below the initial level in the blood serum (% of normal concentration) in the appropriate period of time.
With early hemarthrosis, intramuscular bleeding, bleeding oral cavity the required level of blood coagulation factor VIII is 20 - 40%, necessary repeated injections drug every 12-24 hours for at least one day until the pain subsides or the source of bleeding heals. With more intense bleeding, intramuscular bleeding or hematomas, the required level of blood coagulation factor VIII is 30-60%, repeated injections of the drug are necessary every 12-24 hours for 3-4 days until the pain subsides and the ability to work is restored. With life-threatening bleeding, the required level of coagulation factor VIII is 60-100%, repeated injections of the drug are necessary every 8-24 hours until the threat disappears completely. At small surgical interventions, including extraction of teeth, the required level of blood coagulation 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 injections of the drug are necessary every 8-24 hours until the wound heals adequately, 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 blood coagulation factor VIII in the blood serum, especially during major surgical interventions. The response to treatment in individual patients may differ, as indicated by differences in the half-life and the degree of recovery of the activity of blood coagulation factor VIII.
For long-term prevention of bleeding in patients with severe hemophilia A, the average dose of coagulation factor VIII is 20-40 IU/kg body weight at intervals of 2-3 days. In some patients, especially in patients young age, it may be necessary to reduce the interval between injections of 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 ongoing therapy there is no expected increase in the activity of blood coagulation factor VIII or there is no required hemostatic effect, it is recommended to consult in a specialized treatment center using the Bethesda test. To eliminate the inhibitor of blood coagulation factor VIII, the induction of immune tolerance can be used, which consists in the daily administration of blood coagulation factor VIII at a concentration that exceeds the blocking ability of the inhibitor (100–200 IU/kg/day, depending on the inhibitor titer). Coagulation factor VIII performs the function of an antigen and provokes an increase in the titer of an inhibitor of blood coagulation factor VIII until tolerance develops, that is, a decrease and further disappearance of the inhibitor. The induction of immune tolerance is carried out continuously and lasts an average of 10 to 18 months. Immune tolerance induction should only be carried out by doctors who are experts in the field of 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 any special requirements for dosing the drug in children.
It is necessary to monitor the presence of inhibitors of blood coagulation factor VIII in patients. If against the background of ongoing therapy there is no expected increase in the activity of blood coagulation factor VIII or there is no necessary hemostatic effect, then it is necessary to analyze for the presence of inhibitors of blood coagulation factor VIII. If drug treatment is not effective in patients with high levels of factor VIII inhibitors, then alternative therapy should be considered. The treatment of these patients should be carried out by doctors who have experience in the treatment of hemophilia.
Interim data are available from an ongoing study in patients undergoing immune tolerance induction with coagulation factor VIII. The dosage regimen is set in a medical institution individually for each patient. Patients with a poor response usually receive factor VIII at a dose of 50-100 IU/kg of body weight every day or every other day, patients with a strong response usually receive 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 scheduled visits medical institutions to continue treatment. The result of the induction of immune tolerance is determined after three years according to three consecutive criteria, including a negative titer of blood coagulation factor VIII inhibitors, restoration of blood coagulation factor VIII activity, normalization of the half-life of blood coagulation factor VIII. An interim analysis found that of the 69 patients who received coagulation factor VIII as immune tolerance induction, 49 patients completed the study. In patients with successful elimination of the factor VIII inhibitor, the monthly bleeding rate was significantly reduced.
Before intravenous administration, the reconstituted medicinal product should be examined for discoloration and the presence of mechanical impurities. The reconstituted clotting factor VIII solution should be clear or slightly opalescent. Do not use a cloudy clotting factor VIII solution or if there are clots in it. The reconstituted solution of coagulation factor VIII must be used immediately after preparation and only once.
As a precautionary measure, heart rate should be monitored before and during administration of coagulation factor VIII. With a pronounced increase in heart rate, the introduction of blood coagulation factor VIII must be slowed down or stopped.
Any unused clotting factor VIII solution should be disposed of in accordance with current regulations.
As with any drug protein origin, for intravenous administration possible development of reactions hypersensitivity allergic type. In addition to coagulation factor VIII, the medicinal product contains trace amounts of other human plasma proteins. Patients should be informed of the early signs of hypersensitivity reactions, including generalized and local urticaria, wheezing, chest tightness, hypotension, and anaphylaxis. With the development of these symptoms, you should immediately stop using the drug and consult your doctor. With the development of shock, standard anti-shock treatment should be carried out.
With the use of clotting factor VIII in rare cases hypersensitivity reactions or allergic reactions have been noted, which may include a burning sensation at the injection site, a tingling sensation at the injection site, angioedema, flushing, chills, generalized urticaria, local urticaria, headache, hypotension, lethargy, nausea, tachycardia, restlessness, chest pressure, 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, the use of blood coagulation factor VIII may cause inhibitors (antibodies) of blood coagulation factor VIII, which is manifested by an insufficient clinical response to the administration of the drug. In this situation, it is necessary to contact a specialized hematology center. The formation of neutralizing inhibitors (antibodies) of factor VIII is a known complication of the 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 measured in units of Bethesda per ml of serum blood 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, factor VIII inhibitors may appear after the first 100 days of drug use. All patients treated with factor VIII medicinal products should be carefully monitored for the presence of antibodies to factor VIII by conducting appropriate laboratory tests and clinical observations. In the ongoing clinical trial in previously untreated patients, 3 of 39 people who received coagulation factor VIII as needed developed factor VIII inhibitors. Two cases were clinically significant, in two other patients, factor VIII inhibitors spontaneously disappeared without changing the dose of the drug. All cases of the formation of inhibitors of blood coagulation factor VIII were observed during therapy as needed for no more than 50 days. There was an initial level of activity of blood coagulation factor VIII less than 1% in 35 previously untreated patients and less than 2% in 4 previously untreated patients. At the time of the interim analysis, coagulation 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 coagulation factor VIII for prophylaxis, inhibitors of blood coagulation factor VIII were not detected. 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 coagulation factor VIII use in a clinical study was 100 days (range 1 to 553 days).
There is information about the existence of a relationship between the formation of inhibitors of blood coagulation factor VIII and allergic reactions, therefore, with the development of allergic reactions, the patient should be examined for the presence of inhibitors of blood coagulation factor VIII. In patients with inhibitors of blood coagulation factor VIII, the risk of anaphylaxis may be increased with subsequent use of blood coagulation factor VIII. Therefore, the first injection of blood coagulation factor VIII must be carried out according to the prescription of the attending physician under medical supervision in conditions that allow you to provide the necessary medical care with the development of allergic reactions.
Standard measures for the prevention of infectious diseases that may be caused by the use of medicinal products prepared from human blood or serum include the selection of donors, the screening of individual donations and blood serum pools for specific markers of infectious diseases, the introduction of effective stages of inactivation and removal of microorganisms into the production of medicinal products. But when using drugs that are prepared from human blood or serum, the risk of transmission of 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 (infection of the fetus) and patients with immunodeficiency or increased erythropoiesis (for example, with hemolytic anemia). In patients who regularly and repeatedly receive medications coagulation factor VIII derived from human serum, appropriate vaccination against hepatitis A and B should be considered.
To establish a link between the patient and the drug lot, it is recommended that each time coagulation factor VIII is used, the name and lot number of the drug be recorded.

When using coagulation factor VIII, care must be taken when performing potentially dangerous species activities that require increased concentration attention and speed of psychomotor reactions (including control vehicles, mechanisms), as it is possible to develop headache, tinnitus, hypotension and other adverse reactions which can provide Negative influence to carry out these activities. With the development of such adverse reactions, it is necessary to abandon the performance of potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions (including driving vehicles, mechanisms).

Contraindications for use

Hypersensitivity (including to the auxiliary components of the drug).

Application restrictions

Pregnancy, breastfeeding.

Use during pregnancy and lactation

Because hemophilia A is rare in women, experience with the use of factor VIII in women during and during pregnancy breastfeeding missing. Coagulation factor VIII in women during pregnancy and during 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 sense organs: headache, anxiety, ringing in the ears.
Cardiovascular system, blood (hemostasis, hematopoiesis) and lymphatic system: hypotension, flushing, tachycardia.
Digestive system: nausea, vomiting.
Respiratory system: chest tightness, 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, fever.
Laboratory indicators: the formation of antibodies to blood coagulation factor VIII in the blood serum.

Interaction of blood coagulation factor VIII with other substances

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

Overdose

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

Trade names of drugs with the active substance clotting factor VIII

Agemfil A
Antihemophilic human factor-M(AHF-M)
beriate
Gemoctin
Hemophilus M
Immunat
Coate-DWI
Coate-HP
Cryobulin TIM 3
cryoprecipitate
LongAit
Octavi
Octanate
fandi
Hemate P
Emoklot D.I.

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

Russian name

Latin name of substances Blood coagulation factor VIII + Willebrand factor

Pharmacological group of substances Blood coagulation factor VIII + Willebrand factor

Model clinical and pharmacological article 1

Characteristic. The effectiveness of clotting factor VIII is determined on the basis of the International Standard for concentrate (FVIII:C), the effectiveness of von Willebrand factor is determined on the basis of the determination of the effectiveness of ristocetin cofactor (VW:RK), based on the International Standard for concentrate in accordance with the European Pharmacopoeia. The specific activity of the drug is not less than 60 IU FVIII:C/mg and not less than 53 IU FV:RK/mg of total protein. The number of units of blood coagulation factor VIII is expressed in IU, corresponding to the WHO standards for these drugs. Activity is expressed either as a percentage (relative to the normal level of the factor in plasma), or in International Units (relative to International Standard for clotting factor VIII in plasma). 1 IU of coagulation factor VIII is equivalent to the amount of coagulation factor VIII in 1 ml of normal human plasma.

Pharma action. Blood coagulation factor VSH binds to von Willebrand factor; activated factor VSH is a cofactor for activated factor IX, accelerating the conversion of clotting factor X into active form; activated factor X activates the conversion of prothrombin to thrombin, thrombin, in turn, activates the conversion of fibrinogen to fibrin, followed by the formation of a thrombus. The drug contains von Willebrand factor, which is a normal component of human plasma and acts in the same way as endogenous, and corrects hemostasis disorders in patients with von Willebrand disease: restores platelet adhesion to the vascular subendothelium at the site of vessel damage (attached to the vascular subendothelium and to the platelet membrane, provides primary hemostasis, reduces clotting time, while the effect is immediate and depends on the degree of protein polymerization); normalizes the concomitant deficiency of factor VIII (when administered intravenously, it binds endogenous factor VSH and stabilizes it, slowing down its rapid degradation), restores the level of factor VIII:C to normal. Replacement therapy with the drug in patients with hemophilia A increases the level of blood coagulation factor VIII, providing a temporary correction of factor deficiency and reducing the risk of bleeding. In addition, the von Willebrand factor promotes platelet adhesion in the area of ​​vascular injury and plays a significant role in the process of platelet aggregation.

Pharmacokinetics. von Willebrand disease type 3: the average recovery of VW:RK and VW:Ag - 68-99%, respectively, which corresponds to an average increase in plasma concentration of 1.5 and 2.1% per substituted IU / kg of body weight. T 1/2 FV: RK - 17.5 h, clearance - 3.9 ml / h / kg. Hemophilia A: the concentration of factor VIII: C is 80-120% of the expected value. T 1/2 VIII: C - 14.8 hours, which corresponds to the biological T 1/2, clearance - 2.9 ml / h / kg.

Indications. Treatment and prevention of bleeding in patients with von Willebrand disease (with quantitative and / or qualitative deficiency of von Willebrand factor), congenital hemophilia A or acquired deficiency of blood coagulation factor VIII.

Contraindications. Hypersensitivity, age up to 6 years (efficacy and safety not established).

Carefully. Pregnancy, lactation.

Dosing. In / in, after dissolution with the attached solvent; the resulting solution contains 90 IU of coagulation factor VIII and 80 IU of von Willebrand factor in 1 ml.

von Willebrand disease: dose and duration replacement therapy depends on clinical condition patient, type and severity of bleeding, level of FVIII:C and VW:RK.

The ratio between FVIII:C and FV:RK is 1:1, on average 1 IU/kg. FVIII:C and VW:RK increase the plasma level by 1.5-2% of the normal activity of the corresponding protein. Usual dose drug 20-50 IU/kg, which increases the level of FVIII:C and VW:RK up to 30-100%. The initial dose may be increased to 50-80 IU/kg, especially in patients with von Willebrand disease type 3, with gastrointestinal bleeding.

To prevent bleeding, it is necessary to start the administration of the drug 30 minutes before the start of the surgical intervention. In the case of a planned surgical intervention, the drug is administered 12-24 hours and 1 hour before the start of the surgical intervention, while the expected concentration of VW: RK is 60 IU / dl or more (60% or more) and FVIII: C is 50 IU / dl or more (50% or more). The dose is administered every 12-24 hours. Long term treatment may cause an excessive increase in the level of FVIII:C. After 24-48 hours of treatment, in order to avoid an excessive increase in the level of FVIII:C, it is necessary to reduce the dose, or increase the interval between injections.

Hemophilia A: 1 IU of coagulation factor VIII:C/kg increases the factor in plasma by 1.5-2% of the normal content. Determination of the required dose: body weight (kg) × desired increase in the level of clotting factor VIII (%) × 0.5 IU / kg.

In the case of the bleeding events described below, the FVIII:C activity level should not fall below baseline plasma levels (% of normal) in the appropriate time period.

Moderate bleeding (early hemarthrosis, intramuscular bleeding, nosebleeds, oral bleeding and other minor injuries) - the required concentration of clotting factor VIII is 20-40 IU / dl (20-40%), the introduction is repeated every 12-24 hours, on at least, within 1 day, until the pain subsides or the source of bleeding heals.

More extensive bleeding (IM bleeding or hematoma) - the required concentration of coagulation factor VIII is 30-60 IU / dL (30-60%) every 12-24 hours for 3-4 days, until pain subsides and recovery is restored.

Life-threatening bleeding (intracranial, intraperitoneal, neck, blunt trauma, without a visible source of bleeding) - the required concentration of clotting factor VIII is 60-100 IU / dl (60-100%) every 8-24 hours, until the threat disappears completely.

Minor surgical interventions (including extraction of teeth) - the required concentration of clotting factor VIII is 30-60 IU / dL (30-60%) every 24 hours, for at least 1 day, until healing.

Major surgery - Required factor VIII levels (before and after surgery) - 80-100 IU/dl (80-100%) every 8-24 hours until wound heals adequately, then at least 7 days to maintain factor VIII activity at the level of 30-60%.

For long-term prevention of bleeding in patients with severe hemophilia A, it is necessary to administer 20-40 IU / kg every 2-3 days. In some cases, especially in young patients, it may be necessary to reduce the interval between injections or increase the dose.

If there is no effect from an adequate dose, or if it is impossible to achieve the desired plasma concentration of clotting factor VIII with adequate administration, it is necessary to conduct a Bethesda test for the presence of inhibitory antibodies to clotting factor VIII. In patients with high levels of inhibitors, treatment with factor VIII may be ineffective, and other therapeutic measures may be required.

Side effect. allergic reactions(hives, skin rash, chills, feeling of pressure in chest, shortness of breath, decreased blood pressure, rarely - anaphylactic shock), burning at the injection site, hyperthermia, hot flashes, headache, drowsiness, apathy, nausea, vomiting, anxiety. The development of inhibitory antibodies to von Willebrand factor - in von Willebrand disease, in hemophilia A - to blood coagulation factor VIII (usually IgG), which leads to an inadequate clinical response to the drug; inhibitory antibodies can cause precipitation and promote the development anaphylactic reactions.

In patients receiving von Willebrand factor preparations containing coagulation factor VIII, a prolonged increase in plasma levels of factor VIII: C increases the risk of thrombosis (control of patients at risk is necessary).

Patients with hemophilia A may develop inhibitory antibodies, while there is an inadequate clinical response to the administration of the drug.

Interaction. Do not mix with other drugs or administer at the same time using the same infusion set.

special instructions. With the introduction of the drug, it is necessary to carefully monitor the condition of patients. Early signs hypersensitivity reactions are urticaria, generalized rash, chest tightness, dyspnoea, hypotension and anaphylaxis. If these symptoms occur, the administration of the drug should be stopped immediately. With the development of anaphylactic reactions, patients should be examined for the presence of inhibitory antibodies.

When using drugs derived from human blood or plasma, the possibility of transmission of infectious agents cannot be completely ruled out, therefore it is recommended preventive vaccination against hepatitis A and B.

Long-term treatment of patients with von Willebrand disease with a drug containing von Willebrand factor and coagulation factor VIII can cause an excessive increase in coagulation factor VIII:C, which increases the risk of thrombosis (control of the concentration of coagulation factor VIII:C is necessary).

The risk of developing inhibitory antibodies in hemophilia A reaches a maximum during the first 20 days after the appointment, less often after the first 100 days of the drug. The possibility of using the drug in the presence of inhibitory antibodies to coagulation factor VIII has not been established.

To administer the drug, only the kit for dissolution and intravenous administration provided in the kit should be used. Other devices are capable of adsorbing clotting factors on their inner surface leading to a decrease in the effectiveness of treatment.

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.

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% of the 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 identify 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.