Coagulation factor VIII (antihemophilic factor): general information. Plasma clotting factors
Factor VIII could not be isolated in its pure form for a long time due to its low concentration (10 µg/l) and susceptibility to proteolysis. However, gene mapping factor VIII on the X chromosome, cloning and sequencing of the cDNA made it possible to establish the structure of this protein and improve both the prenatal diagnosis of hemophilia A and the detection of carriers. f.VIII is a high molecular weight glycoprotein, it is present in the blood as an inactive cofactor. Coagulation factor VIII (antihemophilic globulin) is a single-chain protein with molecular weight 265000, which is needed for the activation of factor X by proteases formed by the internal mechanism of coagulation (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 more low molecular weight forms from molecules. masses of 200 and 80 kDa. They are formed as a result of proteolysis of Arg-1313-Ala and Arg-1648-Glu bonds. F.V and F.VIII are divided into a number of domains (Fig. 4.2). Amino acid sequences are identical in three A domains (about 350 amino acid residues) and two C domains (about 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 lack amino acid homology.
Factor VIII deficiency occurs at a rate of 1 in 10,000 newborn boys. The corresponding disease (hemophilia A) is manifested by hemorrhages in the muscles, other soft tissues and supporting joints.
Although factor VIII levels must be at least 25% for normal hemostasis, symptoms usually appear when levels fall to 5% or less. 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 rapidly inactivated at 200 and 370C. It is stable for several hours at +40C and for several weeks at -200C. Disappears quickly from stored blood. Factor VIII is active longer in the presence of sodium citrate at pH 6.2-6.9, but quickly loses activity in the EDTA medium. 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 as a complex of three subunits, designated VIIIk (coagulant unit), VIII-AG (primary antigenic marker) and VIII-vB (von Willebrand factor associated with VIII-AG). VIII-vB regulates the synthesis of the coagulant part of antihemophilic globulin - VIIIk.
During blood clotting, factor VIII remains in an inactive state.
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 of the male population. The disease is characterized by spontaneous, often fatal bleeding, bleeding into the joints, leading to early disability. These patients throughout their lives need replacement therapy plasma preparations. The main 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 with a decrease in the deficient factor to 30% (the norm is 50-150%), the disease manifests itself in a latent form and is detected after surgical interventions in the form of profuse bleeding. Obviously, 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 blood plasma by a patient.
Severe hemophilia. The level of f.VIII or IX is less than 1%. Bleeding into joints, muscles and other organs occurs with minimal or even imperceptible damage.
Hemophilia moderate. The level of f.VIII or IX is between 1-5%. Bleeding occurs due to obvious minor injuries, also after various operations and tooth extractions.
Hemophilia mild degree. Level VIII or IX between 6-30%. Hemorrhage usually follows major damage, surgery or tooth extraction. Diagnosis of this form may not be made until adulthood or until bleeding occurs after these situations.
The level of coagulation factor VIII from 0 to 1% causes an extremely severe form of the disease, from 1 to 2% - severe, from 2 to 5% - moderate, above 5% - light form, but with the danger of severe and even fatal bleeding from injuries and surgical interventions.
Among all the possible manifestations of hemophilia, hemorrhages in the large joints of the extremities (hip, knee, ankle, shoulder and elbow), deep subcutaneous, intermuscular and intramuscular hemorrhages, profuse and prolonged bleeding with injuries, the appearance of blood in the urine. Other bleeding is somewhat less common, including such severe and dangerous ones as retroperitoneal hemorrhages, hemorrhages in organs abdominal cavity, gastrointestinal bleeding, intracranial hemorrhages(stroke).
With hemophilia, one can quite clearly trace the progression of all manifestations of the disease as the child grows, and later on as an adult. At birth, more or less extensive hemorrhages under the periosteum of the skull bones, subcutaneous and intradermal hemorrhages, late bleeding from the umbilical cord can be observed. Sometimes the disease is detected at the first intramuscular injection, which can cause a large, life-threatening intramuscular hematoma. Teething is often accompanied by not very heavy bleeding. In the first years of life, there are often bleeding from the oral mucosa associated with trauma to various sharp objects. When a child learns to walk, falls and bruises are often accompanied by profuse nosebleeds and hematomas on the head. Hemorrhages in the orbit, as well as postorbital hematomas, can lead to loss of vision. In a child who has begun to crawl, hemorrhages in the buttocks are typical. Then, hemorrhages in the large joints of the limbs come to the fore. They appear the earlier, the more severe the hemophilia is. The first hemorrhages predispose to repeated outpourings of blood in the same joints. Everyone has it individual person, suffering from hemophilia, with particular persistence and frequency of hemorrhages, 1-3 joints are affected. Most commonly affected knee joints, followed by ankle, elbow and hip. Hemorrhages in the small joints of the hands and feet (less than 1% of all lesions) and joints between the vertebrae are relatively rare. In each person, depending on the age and severity of the disease, from 1-2 to 8-12 joints are affected.
It is necessary to distinguish between acute hemarthrosis (primary and recurrent), chronic hemorrhagic-destructive osteoarthritis (arthropathy), secondary immune rheumatoid syndrome as a complication of the underlying process.
Acute hemarthrosis is manifested as sudden appearance(often after a minor injury) or a sharp increase in joint pain. The joint is often enlarged, the skin over it is red, hot to the touch. After the first transfusion of blood components, the pain quickly (within a few hours) decreases, and with the simultaneous removal of blood from the joint, it disappears almost immediately.
IV stages of joint damage are distinguished. In I, or early, stage, the volume of the joint may be increased as a result of hemorrhage. In the "cold" period, the function of the joint is not impaired, but X-ray examination determines characteristics defeat. In stage II, the progression of the process is noted, which is revealed according to x-ray data. AT Stage III the joint sharply increases in size, deforms, often uneven and bumpy to the touch, pronounced hypotrophy of the muscles of the affected leg is determined. The mobility of the affected joints is more or less limited, which is associated both with damage to the joint itself and with changes in muscles and tendons. At this stage, the formation severe osteoporosis fractures easily occur within the joints. In the femur, there is a crater- or tunnel-like destruction of the bone substance typical of hemophilia. The patella is partially destroyed. Intra-articular cartilages are destroyed, mobile fragments of these cartilages are found in the joint cavity. Various kinds of subluxations and displacements of bones are possible. In stage IV, the function of the joint is almost completely lost. Joint fractures are possible. With age, the severity and prevalence of damage to the articular apparatus progresses and becomes more severe when hematomas occur around pathologically altered joints.
Secondary rheumatoid syndrome (Barkagan-Egorova syndrome) is a common form of joint damage in patients with hemophilia. First this syndrome was described in 1969. In many cases, it is viewed by doctors, since it occurs against the background of already existing hemarthrosis and destructive processes characteristic of hemophilia in the joints. Secondary rheumatoid syndrome is accompanied by a chronic inflammatory process (often symmetrical) in the small joints of the hands and feet, which were not previously affected by hemorrhages. Subsequently, as the process progresses, these joints undergo a typical deformation. In large joints periodically appears strong pain, one can note the pronounced morning stiffness in the joints. Regardless of the appearance of new hemorrhages, the articular process is steadily progressing. At this moment, a blood test reveals the appearance or a sharp increase in the existing laboratory signs inflammatory process, including immunological ones.
In most people with hemophilia, the syndrome appears over the age of 10-14 years. By the age of 20, its frequency reaches 5.9%, and by 30 - up to 13% of all cases of the disease. With age, the prevalence and severity of all joint lesions are steadily progressing, which leads to disability, forces the use of crutches, wheelchairs and other devices. The progression of joint damage depends on the frequency acute hemorrhages, the timeliness and usefulness of their treatment (it is very important to conduct an early transfusion of blood and its components), the quality of orthopedic care, correct application physical therapy, physiotherapeutic and balneological effects, choice of profession and a number of other circumstances. All of these issues are currently extremely relevant, as life expectancy in hemophilia has increased dramatically due to the success of corrective treatment.
Extensive and intense subcutaneous, intermuscular, subfascial and retroperitoneal hematomas are very difficult and dangerous. Gradually increasing, they can reach a huge size, contain from 0.5 to 3 liters of blood or more, lead to the development of anemia, cause compression and destruction of the surrounding tissues and the vessels that feed them, necrosis. So, for example, retroperitoneal hematomas often completely destroy large areas of the pelvic bones (the diameter of the destruction zone can reach 15 cm or more), hematomas on the legs and arms destroy tubular bones and the calcaneus. Doom bone tissue leads to the formation of hemorrhages under the periosteum. The process of such bone destruction on radiographs is often mistaken for a tumor process. Often, calcium salts are deposited in hematomas, which sometimes leads to the formation of new bones, which can close the joints and completely immobilize them.
Many hematomas, putting pressure on the nerve trunks or muscles, cause paralysis, sensory disturbances, and rapidly progressive muscle atrophy. Especially dangerous are extensive hemorrhages in soft tissues submandibular region, neck, pharynx and pharynx. These hemorrhages cause narrowing of the upper respiratory tract and suffocation.
A serious problem in hemophilia is profuse and persistent renal bleeding, observed in 14-30% of individuals with this blood disease. These bleedings can occur both spontaneously and in connection with injuries. lumbar region associated with pyelonephritis. In addition, renal bleeding may occur due to increased excretion calcium in the urine due to bone destruction in hemophilia. The appearance or intensification of such bleeding can be facilitated by the use of analgesics (acetylsalicylic acid, etc.), massive blood and plasma transfusions, which leads to additional damage to the kidneys. Renal bleeding is often preceded by prolonged release in the urine of blood particles, which can only be detected when laboratory research.
The appearance of blood in the urine is often accompanied by severe urination disorders, as well as a change in the amount of urine excreted (there may be both an increase in its daily volume and a decrease), attacks of renal colic due to the formation of blood clots in urinary tract. These phenomena are especially intense and pronounced during treatment, when normal condition blood. The cessation of excretion of blood in the urine is often preceded by renal colic, and often by a temporary absence of urine excretion with the appearance of signs of intoxication of the body with toxic metabolic products.
Renal bleeding periodically recurs, which over the years can lead to severe dystrophic-destructive changes in this organ, secondary infection and death from development kidney failure.
Gastrointestinal bleeding in hemophilia may be spontaneous, but more often they are caused by taking acetylsalicylic acid(aspirin), butadione and other drugs. The second source of bleeding are obvious or hidden ulcers of the stomach or duodenum, as well as erosive gastritis of various origins. However, sometimes there are diffuse capillary bleeding without any destructive changes in the mucous membrane. These bleedings are called diapedetic. When they appear, the intestinal wall is saturated with blood for a long time, which quickly leads to coma as a result of severe anemia, fainting state in connection with sharp decline blood pressure and death. The mechanism of development of such bleeding remains unclear to date.
Hemorrhages in the abdominal organs mimic various acute surgical diseases- acute appendicitis, intestinal obstruction, etc.
Hemorrhages in the brain and spinal cord and their membranes in hemophilia are almost always associated either with injuries or with the use of drugs that disrupt the function of platelets, which are directly involved in blood clotting. Between the moment of injury and the development of hemorrhage there may be a light interval lasting from 1-2 hours to a day.
characteristic feature hemophilia are prolonged bleeding during injuries and operations. lacerations much more dangerous than linear breaks. Bleeding often does not occur immediately after injury, but after 1-5 hours.
Removal of the tonsils in hemophilia is much more dangerous than abdominal surgery.
Extraction of teeth, especially molars, is often accompanied by many days of bleeding not only from dental sockets, but also from hematomas formed at the site of tissue infiltration with novocaine, which leads to the development of anemia. These hematomas cause destruction of the jaw. With hemophilia, teeth are removed against the background of the action of antihemophilic drugs under general anesthesia. Extraction of several teeth is best done at once.
Part of the complications in hemophilia is due to blood loss, compression and destruction of tissues by hematomas, infection of hematomas. large group complications are also associated with immune disorders. The most dangerous of them is the appearance in the blood in in large numbers immune inhibitors ("blockers") of blood coagulation factor VIII (or IX), transforming hemophilia into the so-called inhibitory form, in which the main method of treatment - transfusion therapy (transfusion of blood or its components) - almost completely loses its effectiveness. Moreover, repeated administration of antihemophilic drugs often causes a rapid increase in the amount of inhibitor in the blood, as a result of which the transfusion of blood and its components, which initially had some effect, soon becomes useless. The frequency of the inhibitory form of hemophilia, according to different authors, ranges from 1 to 20%, more often from 5 to 15%. With inhibitory forms, platelet function is noticeably impaired, hemorrhages in the joints and excretion of blood in the urine become more frequent, joint damage is significantly higher.
The main method of treatment and prevention of bleeding and hemorrhage of any localization and any origin in hemophilia is the intravenous administration of sufficient doses of blood products containing factor VIII. Factor VIII is variable and practically not preserved in canned blood, natural and dry plasma. For substitution treatment only direct blood transfusions from a donor and blood products with preserved coagulation factor VIII are suitable. Direct blood transfusions from a donor are resorted to only when the doctor does not have any other antihemophilic drugs. It is a grave mistake to transfuse blood from the mother, as she is a carrier of the disease, and the level of factor VIII in her blood is sharply reduced. In view of short period life of factor VIII in the blood of the recipient (about 6-8 hours), blood transfusions, as well as transfusions of antihemophilic plasma, should be repeated at least 3 times a day. Such blood and plasma transfusions are unsuitable for stopping massive bleeding and reliable cover for various surgical interventions.
An equal volume of antihemophilic plasma is approximately 3-4 times more effective than fresh banked blood. Daily dose 30-50 ml/kg of body weight of antihemophilic plasma allows for some time to maintain a 10-15% level of factor VIII. The main danger such treatment is circulatory volume overload, which can lead to the development pulmonary edema. The use of antihemophilic plasma in a concentrated form does not change the situation, since a high concentration of the injected protein causes an intensive movement of fluid from the tissues into the blood, as a result of which the volume of circulating blood increases in the same way as when plasma is infused in a normal dilution. Concentrated dry antihemophilic plasma has only the advantage that it contains more concentrated factor VIII of blood coagulation, and in a small volume it is more quickly introduced into the bloodstream. Dry antihemophilic plasma is diluted with distilled water before use. Treatment with antihemophilic plasma is sufficient to stop most acute hemorrhages in the joints (except the most severe ones), as well as for the prevention and treatment minor bleeding.
The most reliable and effective in hemophilia concentrates of factor VIII of blood coagulation. The most accessible of them is cryoprecipitate. It is a protein concentrate released from plasma by cooling (cryoprecipitation), which contains enough coagulation factors, but few proteins. Low maintenance proteins allows you to enter the drug into the bloodstream in a very large quantities and increase the concentration of factor VIII to 100% or more without fear of circulatory overload and pulmonary edema. Cryoprecipitate must be stored at -20°C, which makes it difficult to transport. When thawed, the drug quickly loses its activity. Dry cryoprecipitate and modern concentrates of factor VIII of blood coagulation are deprived of these shortcomings. They can be stored in a regular refrigerator. Excessive administration of cryoprecipitate is undesirable, as it creates high concentration coagulation factors in the blood, as a result of which the microcirculation in the organs is disturbed and there is a danger of the formation of blood clots and the development of DIC.
All antihemophilic drugs are administered intravenously only by stream, in the most concentrated form and as soon as possible after they are reopened without mixing with other solutions for intravenous administration. One of the main reasons for the failure of replacement therapy is the drip of blood products, which does not lead to an increase in the level of factor VIII in plasma. Until a stable stop of bleeding, you can not use any blood substitutes and blood products that do not contain antihemophilic factors, as this leads to a dilution of factor VIII and a decrease in its concentration in serum.
In case of acute hemorrhages in the joints, temporary (no more than 3-5 days) immobilization (immobilization) of the affected limb in a physiological position, heating of the affected joint (compresses), but not cooling is necessary. early removal the blood poured into the joint not only immediately eliminates pain syndrome, prevents further blood clotting in the joint, but also reduces the risk of development and rapid progression of osteoarthritis. For the prevention and treatment of secondary inflammatory changes after removal of blood, 40-60 mg of hydrocortisone is injected into the joint cavity. Supportive transfusion therapy, which is carried out during the first 3-6 days, prevents further bleeding and allows you to start exercise therapy early, which contributes to a faster and more complete recovery of the function of the affected limb, and prevents muscle atrophy. It is better to develop movements in the affected joint in stages. In the first 5-7 days after removing the bandage, active movements both in the affected joint and in other joints of the limb, gradually increasing the frequency and duration of exercises. From the 6-9th day, they switch to "load" exercises, using bicycle ergometers, pedal gates for hands, elastic traction. From the 11-13th day, in order to eliminate residual stiffness and limit maximum flexion or extension, passive load exercises are performed with caution. Simultaneously with the 5-7th day, physiotherapy is prescribed - hydrocortisone electrophoresis, anodic galvanization.
With hemorrhages in soft tissues, more intensive treatment with antihemophilic drugs is carried out than with hemorrhages in the joints. With the development of anemia, intravenous infusions of erythrocyte mass are additionally prescribed. If there are signs of infection of the hematoma, then antibiotics are immediately prescribed. a wide range actions. Any intramuscular injections with hemophilia are contraindicated, as they can cause extensive hematomas and pseudotumors. Penicillin and its semi-synthetic analogues are also undesirable, since in large doses they increase bleeding.
Early and intensive treatment antihemophilic drugs contributes to the rapid regression of hematomas. Encapsulated hematomas are removed, if possible, surgically along with the capsule.
External bleeding from damaged skin, nosebleeds and bleeding from wounds in the oral cavity are stopped both by transfusion therapy and by local influences - by treating the bleeding area with drugs that promote blood clotting. In addition, these drugs can be taken orally. Pressure bandages or sutures are applied to the wounds. Similarly, stop bleeding after tooth extraction. When removed chewing teeth a slightly more intensive transfusion therapy is carried out, and the simultaneous removal of several teeth (3-5 or more) requires the introduction of antihemophilic drugs in the first 3 days.
In case of nosebleeds, tight packing should be avoided, since after the removal of the tampons, bleeding often resumes with even greater force. A quick stop of nosebleeds is usually provided by antihemophilic plasma and antihemophilic drugs and simultaneous irrigation of the nasal mucosa with solutions that promote blood clotting.
Serious danger represent renal bleeding, in which intravenous infusions of antihemophilic plasma and cryoprecipitate are ineffective.
Gastrointestinal bleeding is controlled with large doses of clotting factor concentrates. It should be remembered that gastric bleeding is often provoked by taking aspirin, brufen, indomethacin in connection with pain in the joints, toothache or headache. In patients with hemophilia, even a single dose of aspirin can cause stomach bleeding.
In the prevention and treatment of chronic osteoarthritis and other lesions of the musculoskeletal system, it is necessary to provide various ways joint protection and prevention of limb injuries. To do this, foam pads are sewn into clothes around the knee, ankle and elbow joints, and those sports that are associated with jumps, falls and bruises (including cycling and motorcycle riding) are avoided. Importance given as early as possible and full treatment acute hemorrhages in the joints and muscles, intensive year-round physiotherapy exercises. For this, there are special complexes of atraumatic exercises in water, on soft mats and load devices - bicycle ergometers, manual gates. Classes should start in preschool or junior school age, i.e. before they developed severe violations musculoskeletal system. Complex therapy is supplemented with physiotherapy (high frequency currents, electrophoresis of glucocorticosteroids) and balneological methods of treatment, primarily mud therapy, brine and radon baths. With frequent and stubbornly recurring hemorrhages in the same joints, X-ray therapy is performed and surgery.
Minimizing the risk of injury and cuts from early childhood is important in the prevention of hemorrhage. Easily breaking toys (including metal and plastic ones), as well as unstable and heavy objects, are excluded from everyday life. Furniture should be with rounded edges, the protruding edges are wrapped with cotton wool or foam rubber, the floor is covered with a pile carpet. Communication and games of patients with girls are preferable, but not with boys. important for the patient right choice professions and places of work.
Prevention of hemophilia has not yet been developed. Determination of the sex of the unborn child by genetic research cells obtained from amniotic fluid, allows you to terminate the pregnancy in a timely manner, but does not show whether the fetus is a carrier of the hemophilia gene. Pregnancy is preserved if the fetus is male, since all the sons of the sick are born healthy. Terminate pregnancy if the fetus is female, since all daughters of hemophilia patients are carriers of the disease.
In female conductors of hemophilia who have a 50% chance of giving birth to an affected child (if the fetus is male), or who are transmitters of hemophilia (if the fetus is female), the birth of only girls transfers the risk of having hemophilia patients in the family from the first generation to the second, at the same time increasing total number disease transmitters.
Formula, chemical name: no data.
Pharmacological group: hematotropic agents / coagulants (including blood coagulation factors), hemostatics.
Pharmachologic effect: hemostatic, replenishing the deficiency of coagulation factor 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. During replacement 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 of 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, slower phase, which most likely reflects consumption of coagulation factor VIII, the elimination 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 - 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 IU (relative to 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 of the oral cavity, the required level of blood coagulation factor VIII is 20-40%, 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. At 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. For minor surgical interventions, including tooth extraction, 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 prophylaxis bleeding in patients with severe hemophilia A, the average dose of coagulation factor VIII is 20 - 40 IU / kg of 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 of protein origin, reactions may develop for intravenous administration. hypersensitivity allergic type. In addition to coagulation factor VIII, the medicinal product contains trace amounts of other human plasma proteins. Patients should be informed about early signs hypersensitivity reactions, including generalized and local urticaria, wheezing, pressure sensation chest, hypotension, 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 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 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. The mean age of the patient at the time of first use of factor VIII was 7 months (range 3 days to 67 months), and the mean duration of use of factor VIII in the 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. Infectious disease 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). Appropriate vaccination against hepatitis A and B should be considered in patients who regularly and repeatedly receive coagulation factor VIII medicinal products derived from human blood serum.
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 hazardous 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 that may have a negative impact on the performance of 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, there is no experience with the use of factor VIII in women during pregnancy and while breastfeeding. 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.
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 disease. 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 therapeutic delivery platform based on plant genetic modification. 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.
The researchers fed the mixed preparation to hemophilia A mice twice a week for two months and compared them to mice fed unmodified plant material. Then they injected mice with an injection of blood clotting factor 8, which people with hemophilia get. As expected, a high level of inhibitors was formed in the control group of mice. 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 of signaling molecules - cytokines, which 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.
