Pharmacological properties of the drug Coagulation Factor VIII
Chromatographically purified lyophilized fraction of human blood plasma containing blood coagulation factor VIII. Antihemophilic globulin, replenishes the deficiency of coagulation factor VIII, temporarily compensates for the coagulation defect in patients with hemophilia A. It is found in a natural combination with protein C factor VIII, von Willebrand factor. Involved in blood coagulation processes, 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 is two-phase: the early phase is a rapid decrease in activity, characterizes the time of equilibration with the extravascular space, the second phase is slow, reflects the biological half-life of the administered antihemophilic factor and is 9–14 hours. Specific activity (after adding human albumin) - 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 donor human plasma. The time to reach the maximum concentration in the blood plasma 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.
References
- Hematology. National leadership. Ed. O. A. Rukavitsyna. "GEOTAR-Media". 2021.
- Clinical guidelines for the diagnosis and treatment of hemophilia. The recommendations were approved at the IV Congress of Russian Hematologists (April 2018). A team of authors led by Academician V.G. Savchenko. Authors: Zozulya N.I., Kumskova M.A., Polyanskaya T.Yu., Svirin P.V.
- Sheyda Khalilian, Majid Motovali-Bashi, Halimeh Rezaie. "Factor VIII: Perspectives on Immunogenicity and Tolerogenic Strategies for Hemophilia A Patients". Int J Mol Cell Med. 2021 Winter; 9(1): 33–50. doi: 10.22088/IJMCM.BUMS.9.1.33
- Sebastien Lacroix-Desmazes, Jan Voorberg, David Lillicrap, David W. Scott, Kathleen P. Pratt. "Tolerating Factor VIII: Recent Progress. Front Immunol" 2019; 10: 2991.doi: 10.3389/fimmu.2019.02991
- João A. Abrantes, Alexander Solms, Dirk Garmann, Elisabet I. Nielsen, Siv Jönsson, Mats O. Karlsson. “Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patients” Haematologica. May 2021; 105(5): 1443–1453.doi: 10.3324/haematol.2019.217133
Use of the drug Coagulation Factor VIII
IV. To prevent spontaneous bleeding or for mild bleeding - 10 IU/kg (the content of factor VIII, necessary to prevent spontaneous bleeding, is 5% of the normal level); for moderate bleeding and minor surgical intervention (for example, tooth extraction) - 15-25 IU/kg (factor VIII content - 30-80% of normal) followed by a maintenance dose of 10-15 IU/kg every 12-24 hours for 3 days or until sufficient clinical effect is obtained; for acute life-threatening bleeding - 40-50 IU/kg (factor VIII content - 60-100% of normal) followed by a maintenance dose of 20-25 IU/kg every 8-24 hours; for 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 sufficient clinical effect is obtained. For long-term prevention of bleeding in severe hemophilia A - 12–25 IU/kg every 2–3 days. Cryoprecipitate is used taking into account ABO blood group compatibility. The container with frozen cryoprecipitate is placed in a water bath at a temperature of no higher than 35–37 °C for thawing and complete dissolution and kept for no more than 7 minutes. The resulting transparent yellowish solution, which should not contain flakes, is used immediately after preparation. Administer intravenously using 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 in the patient’s blood of a specific inhibitor that can neutralize the activity of factor VIII (expressed in units of factor VIII activity). To ensure effective hemostasis during the most common complications of hemophilia (hemarthrosis, renal, gingival and nasal bleeding), as well as tooth extraction, the content of factor VIII in plasma should be at least 20%; for intermuscular hematomas, gastrointestinal bleeding, fractures and other injuries - not less than 40%; for most surgical interventions - at least 70%. When factor VIII is administered 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 using 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 activity units in 1 dose of cryoprecipitate). After complete cessation of bleeding, factor VIII is administered to patients with hemophilia at intervals of 12–24 hours at a dose that ensures an increase in the level of factor VIII by at least 20%. Treatment is continued for several days until a visible reduction in the size of the hematoma. During surgical interventions, a hemostatic dose is administered 30 minutes before surgery. In case of massive bleeding, blood loss is compensated; at the end of the operation, cryoprecipitate is reintroduced (1/2 dose of the original). 3–5 days after surgery, it is necessary to maintain the concentration of factor VIII in the patient’s blood within the same limits as during the operation. In the postoperative period, in order 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, and reparative characteristics of the tissue. It is advisable to combine treatment of a hemophilia patient with cryoprecipitate with the simultaneous administration of antifibrinolytic drugs and corticosteroids in prophylactic and medium therapeutic doses.
How to study coagulation?
To study coagulation, various models are created - experimental and mathematical. What exactly do they allow you to get?
On the one hand, it seems that the best approximation for studying an object is the object itself. In this case, a person or an animal. This allows you to take into account all factors, including blood flow through the vessels, interactions with the walls of blood vessels and much more. However, in this case the complexity of the problem exceeds reasonable limits. Convolution models make it possible to simplify the object of study without losing its essential features.
Let's try to get an idea of what requirements these models must meet in order to correctly reflect the coagulation process in vivo.
The experimental model must contain the same biochemical reactions as in the body. Not only proteins of the coagulation system must be present, but also other participants in the coagulation process - blood cells, endothelial and subendothelial cells. The system must take into account the spatial heterogeneity of coagulation in vivo: activation from a damaged area of the endothelium, the spread of active factors, the presence of blood flow.
It is natural to begin the consideration of coagulation models with methods for studying coagulation in vivo. The basis of almost all of these approaches used is to inflict controlled injury on the experimental animal in order to induce a hemostatic or thrombotic response. This reaction is studied by various methods:
- monitoring bleeding time;
- analysis of plasma taken from an animal;
- autopsy of a euthanized animal and histological examination;
- Real-time thrombus monitoring using microscopy or nuclear magnetic resonance (Figure 4).
Figure 4. In vivo thrombus formation in a laser-induced thrombosis model. This picture is reproduced from a historical work where scientists were able to observe the development of a blood clot “live” for the first time. To do this, a concentrate of fluorescently labeled antibodies to coagulation proteins and platelets was injected into the mouse’s blood, and, placing the animal under the lens of a confocal microscope (allowing for three-dimensional scanning), they selected an arteriole under the skin accessible for optical observation and damaged the endothelium with a laser. Antibodies began to attach to the growing clot, making it possible to observe it.
[7]
The classic setup of an in vitro coagulation experiment is that blood plasma (or whole blood) is mixed in a container with an activator, after which the coagulation process is observed. According to the observation method, experimental techniques can be divided into the following types:
- monitoring the coagulation process itself;
- monitoring changes in concentrations of coagulation factors over time.
The second approach provides incomparably more information. Theoretically, knowing the concentrations of all factors at an arbitrary point in time, one can obtain complete information about the system. In practice, studying even two proteins simultaneously is expensive and involves great technical difficulties.
Finally, coagulation in the body is heterogeneous. The formation of a clot starts on the damaged wall, spreads with the participation of activated platelets in the plasma volume, and is stopped with the help of the vascular endothelium. It is impossible to adequately study these processes using classical methods. The second important factor is the presence of blood flow in the vessels.
Awareness of these problems has led to the development of a variety of in vitro flow experimental systems since the 1970s. It took a little more time to understand the spatial aspects of the problem. Only in the 1990s did methods begin to appear that take into account spatial heterogeneity and diffusion of coagulation factors, and only in the last decade have they begun to be actively used in scientific laboratories (Fig. 5).
Figure 5. Spatial growth of a fibrin clot in normal and pathological conditions. Coagulation in a thin layer of blood plasma was activated by tissue factor immobilized on the wall. In the photographs the activator is located on the left. The gray expanding stripe is a growing fibrin clot.
Along with experimental approaches, mathematical models are also used to study hemostasis and thrombosis (this research method is often called in silico [8]). Mathematical modeling in biology makes it possible to establish deep and complex relationships between biological theory and experience. Conducting an experiment has certain boundaries and is associated with a number of difficulties. In addition, some theoretically possible experiments are infeasible or prohibitively expensive due to limitations in experimental technology. Modeling simplifies experiments, since it is possible to select in advance the necessary conditions for in vitro and in vivo experiments under which the effect of interest will be observed.
Special instructions for the use of the drug Coagulation Factor VIII
Use with caution during pregnancy and breastfeeding. It is necessary to monitor the heart rate before and during therapy: if the heart rate increases significantly, slow down the infusion rate or stop the administration. During and after completion of the course of therapy, it is necessary to monitor the level of factor VIII in the blood. To identify signs of progressive hemolytic anemia, it is necessary to monitor hematocrit and the direct Coombs reaction. Changes in the immune status in patients with asymptomatic hemophilia are caused by repeated exposure to viral pathogens and/or the possible presence of impurities in factor VIII preparations (for example, IgG). To achieve satisfactory clinical results, in addition to the initially calculated dose, an additional dose may be administered. If there is no 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 side effects, it is recommended to use no later than 1 hour after dilution, administer only IV, for at least 3 hours (at a rate of 10 ml/min), do not freeze the solution and do not reuse it. The development of antibodies to coagulation factor VIII is possible; 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 hemophiliacs.
Structure
The factor VIII protein consists of six domains: A1-A2-B-A3-C1-C2 and is homologous to factor V.
Domains A are homologous to domains A of the copper-binding protein ceruloplasmin.[15] The C domains belong to the phospholipid-binding discoidin domain family, and the C2 domain mediates membrane binding.[16]
Activation of factor VIII to factor VIIIa is accomplished by cleavage and release of the B domain. The protein is now divided into a heavy chain consisting of domains A1-A2 and a light chain consisting of domains A3-C1-C2. Both form a complex non-covalently in a calcium-dependent manner. This complex is the procoagulant factor VIIIa.[17]
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Pollution scandal
Main article: Contaminated hemophilia blood products
In the 1980s, some pharmaceutical companies such as Baxter International and Bayer caused controversy by continuing to sell contaminated Factor VIII after new heat-treated versions became available.[23] Under pressure from the FDA, the unheated product was withdrawn from US markets but sold to countries in Asia, Latin America and some European countries. The product was contaminated with HIV and the issue was discussed between Bayer and the US. Food and Drug Administration (FDA).[23]
In the early 1990s, pharmaceutical companies began producing recombinant synthesized factor products that now prevent almost all forms of disease transmission during replacement therapy.
