Hemostasis disorders. Bol.Schönlein-Henoch – damage to blood vessels by immune complexes. Provoking factors: drugs, viruses, bacteria

The state of the hemostatic system determines the course and outcome of pregnancy for the mother and fetus. In recent years, there has been a significant number of publications indicating the large role of thrombophilic complications in recurrent miscarriage, intrauterine fetal death, placental abruption, the development of eclampsia, and intrauterine growth retardation.

Basic mechanisms of hemostasis

The hemostasis system or the system for regulating the aggregation state of the blood (PACK) is a biological system that provides regulation of the aggregation state of the blood and maintaining the hemostatic potential necessary for the body. The PACK system is mosaic, i.e. the hemostatic potential in different areas of the bloodstream is not the same. This state is normal for a functional system. The system for regulating the state of blood aggregation includes:

• central organs of the system - bone marrow, liver, spleen;
• peripheral formations - mast cells, endometrium and other layers of the vascular wall, blood cells;
• local regulatory systems - autonomic nervous system, subcortical structures.

The hemostatic system is regulated by complex neurohumoral mechanisms. These mechanisms create conditions under which the coagulation process that has begun locally, necessary to stop bleeding, does not, during normal functioning of the system, transform into the process of general intravascular coagulation.

There are four main links in the hemostasis system:

1. Vascular-platelet link;
2. Procoagulants;
3. Fibrinolytic link;
4. Blood clotting inhibitors.

Vascular-platelet link

The vascular-platelet link of the hemostasis system is often referred to as primary hemostasis. The endothelium of blood vessels plays an important role in maintaining the state of aggregation of circulating blood. This is due to the following features:

1. the ability to form and release into the blood a powerful inhibitor of platelet aggregation - prostacyclin (a metabolite of arachidonic acid);
2. production of tissue activator of fibrinolysis;
3. inability to contact activate the blood coagulation system;
4. creating an anticoagulant potential at the blood/tissue interface by fixing the heparin-antithrombin III complex on the endothelium;
5. ability to remove activated coagulation factors from the bloodstream.

The participation of platelets in hemostasis is determined by their ability to adhere to the site of endothelial damage, the process of their aggregation and formation of a primary platelet plug, as well as their ability to maintain vascular spasm through the secretion of vasoactive substances - adrenaline, norepinephrine, serotonin, ADP, etc., as well as to form, accumulate and secrete substances that stimulate adhesion and aggregation.

Thus, numerous studies have led to the conclusion that primary hemostasis is carried out mainly by platelets, and not by blood coagulation. The leading role in the implementation of primary hemostasis belongs to the adhesive-aggregation function of platelets.

Adhesion is the adhesion of platelets to the site of damage to the vascular wall, to the collagen fibers of the vascular wall, to microfibrin and elastin. The most important plasma cofactors of this process are calcium ions and the protein synthesized in the endothelium - von Willebrand factor and platelet membrane glycoproteins. The physiological purpose of adhesion is to close a defect in the vascular wall. Platelet aggregation occurs simultaneously with adhesion. In this case, the platelets not only stick together, but also stick to the adhered platelets, resulting in the formation of a hemostatic plug. During the process of adhesion and aggregation, platelets actively secrete granules containing substances that enhance the aggregation process and form its second wave. The reaction of release of platelet factors - ADP, adrenaline, norepinephrine, serotonin, antiheparin factor, beta-thromboglobulin, etc. Later, granules containing lysosomal enzymes are secreted (release reaction II). The release of adrenaline, norepinephrine and serotonin not only enhances aggregation, but also promotes secondary spasm of blood vessels, which is accompanied by reliable fixation of the platelet plug at the site of vessel damage. As a result of the interaction of platelet and plasma factors, thrombin is formed in the hemostasis zone, which not only enhances platelet aggregation, but at the same time is a stimulator of blood coagulation; the resulting fibrin forms a thrombus, which becomes dense and impermeable to plasma and serum, and its retraction occurs.

To a large extent, the mechanism of platelet aggregation became clear after the discovery of prostaglandins in platelets and the vascular wall. Various aggregating agents activate phospholipase A1, which causes the cleavage of arachidonic acid, a powerful aggregating substance, from phospholipids. Under the influence of prostaglandin synthetase, cyclic prostaglandin endoperoxides are formed, which stimulate fibril contraction in platelets and have a powerful aggregating effect. Thromboxane A1 is synthesized in platelets under the influence of thromboxane synthetase. The latter promotes the transport of Ca 2+ in the platelet, which leads to the formation of ADP, the main endogenous stimulator of aggregation. The level of cAMP, a universal biological transporter, is regulated by adenylate cyclase, which catalyzes the ATP-cAMP reaction.

A similar process occurs in the vascular endothelium - under the influence of prostaglandin synthetase, prostaglandin endoperoxides are formed from arachidonic acid. Further, under the influence of prostacyclin synthetase, prostacyclin (prostaglandin L) is formed, which has a powerful disaggregating effect and activates adenylate cyclase.

Thus, the so-called thromboxane - prostacyclin balance - one of the main regulators of the tone of the vascular wall and platelet aggregation.

Procoagulant component of hemostasis

Compounds contained in plasma (procoagulants) take part in the process of blood clotting. This is a complex multi-stage enzymatic process that can be divided into 3 stages.

• Stage I is a complex of reactions leading to the formation of prothrombin active complex or prothrombinase. The complex includes factor X, third platelet factor (phospholipid), factor V and Ca 2+ ions. This is the most difficult and lengthy phase.
• Stage II - under the influence of prothrombinase, prothrombin transforms into thrombin.
• Stage III - under the influence of thrombin, fibrinogen turns into fibrin.

The key point in the formation of prothrombinase is the activation of blood coagulation factor X, which can be carried out by two main mechanisms for triggering the coagulation process - external and internal.

With the external mechanism, coagulation is stimulated by the entry into the plasma of tissue thromboplasmin (III or the phospholipid-apoprotein III complex). This mechanism is determined by the prothrombin time (PT) test.

With the internal mechanism, coagulation occurs without the participation of tissue thromboplastin. The triggering factor in this coagulation pathway is the activation of factor X. Activation of factor X can occur through contact with collagen upon damage to the vascular wall or enzymatically under the influence of kallikrein, plasmin or other proteases.

In both the external and internal coagulation pathways, the interaction and activation of factors takes place on phospholipid membranes, on which protein coagulation factors are fixed with the help of Ca ions.

Nomenclature of plasma coagulation factors:

• I - fibrinogen;
• II - prothrombin;
• III - tissue thromboplastin;
• IV - calcium;
• V - accelerating factor;
• VI - factor V activator;
• VII - proconvertin;
• VIII - antihemophilic globulin A;
• IX - antihemophilic factor B (Christmas factor);
• X - prothrombinase;
• XI - plasma precursor of thromboplastin;
• XII - Hageman factor;
• XIII - fibrinase.

The external and internal mechanisms of activation of the blood coagulation system are not isolated from each other. The inclusion of “bridges” between them serves as a diagnostic sign in recognizing intravascular activation of the coagulation system. When analyzing the results of basic coagulation tests, the following should be considered:

1. Of the plasma coagulation factors, only factor VII is involved in the extrinsic coagulation mechanism, and with its deficiency, only the prothrombin time is prolonged.
2. Factors XII, IX, XI, VIII and prekallikrein are involved only in the internal mechanism of activation, and therefore, when they are deficient, the APTT and autocoagulation test are impaired, while the prothrombin time remains normal.
3. With a deficiency of factors X, V, II, I, on which both coagulation mechanisms are closed, pathology is detected in all of the listed tests.

In addition to the external and internal mechanisms of hemocoagulation, the body has additional reserve activation pathways that are activated on demand. The most important route is the macrophage-monocyte mechanism of hemocoagulation. When activated by endotoxins or other infectious antigens, these cells begin to secrete greater amounts of tissue thromboplastin.

Endogenous coagulation inhibitors

Physiological anticoagulants are necessary to maintain blood in a fluid state and to limit the process of thrombus formation. It is now known that natural anticoagulants represent a large group of compounds that act on various phases of the hemostasis process. Moreover, many anticoagulants simultaneously affect fibrinogenesis, the generation of the kallikrein-kinin system, and the complement system.

Natural anticoagulants are divided into primary, constantly present in plasma and blood cells and acting regardless of the formation or dissolution of a blood clot, and secondary, which arise during the process of blood coagulation and fibrinolysis, due to the proteolytic action of the enzyme on the substrate. Antithrombin III (AT III) accounts for up to 75% of the natural anticoagulant potential. Antithrombin III is capable of blocking prothrombinase both by an external and internal mechanism, since, being an inhibitor of factors XII a, XIa, IX a, VIII a, kallikrein, A III binds plasmin. The activity of antithrombin III is enhanced by more than 100 times when complexed with heparin. Heparin, without connection with antithrombin III, does not have an anticoagulant effect. When the level of antithrombin III decreases, a severe thrombophilic condition occurs, which is characterized by recurrent thrombosis, pulmonary embolism, and heart attacks. When antithrombin III decreases below 30%, patients die from thromboembolism, and heparin does not have an anticoagulant effect on their blood. Antithrombin III deficiency results in heparin resistance.

Natural anticoagulants include protein C, protein S, alpha2-macroglobulin.

Protein C is a proenzyme, activated by thrombin and factor Xa. Activation occurs in combination with phospholipid and calcium. The process is enhanced by the influence of thrombomodulin and protein S, which weakens the ability of thrombin to activate factors VIII and V. With a deficiency of protein C, there is a tendency to thrombosis, which is observed in acute disseminated intravascular coagulation syndrome, respiratory distress syndrome, etc.

During the process of blood coagulation and fibrinolysis, secondary, natural anticoagulants are formed as a result of further enzymatic degradation of coagulation factors.

Pathological anticoagulants are absent in the blood under normal conditions, but appear in various immune disorders, these include antibodies to blood clotting factors, most often to factors VIII and V (often occurring after childbirth and massive blood transfusions and immune complexes - lupus anticoagulant, antithrombin V) .

Fibrinolytic system

The fibrinolytic system consists of plasminogen and its activators and inhibitors.

Plasminogen activators are a group of factors that convert plasminogen into plasmin. These include substances such as urokinase and bacterial enzymes. Active plasmin is quickly blocked by antiplasmins and eliminated from the bloodstream. Activation of fibrinolysis, as well as activation of blood coagulation, occurs through both external and internal pathways.

The internal pathway of fibrinolysis activation is determined by the same factors as blood coagulation, i.e. factors XIIa or XIII with kallikrein and kininogen. The external activation pathway is carried out due to tissue-type activators synthesized in the endothelium. Tissue-type activators are found in many tissues and fluids of the body, and blood cells. Fibrinolysis is inhibited by antiplasmins alpha2-globulin, alpha2-macroglobulin, antitrypsin, etc. The plasmin system is adapted to the lysis of fibrin in clots (thrombi) and soluble fibrin-monomer complexes (SFMC). And only with its excessive activation does lysis of fibrin, fibrinogen and other proteins occur. Active plasmin causes the sequential cleavage of fibrinogen/fibrin with the formation of their degradation products (PDP), the presence of which indicates the activation of fibrinolysis.

As a rule, in most clinical observations, activation of fibrinolysis is secondary and associated with disseminated intravascular coagulation.

In the process of coagulation and fibrinolysis, secondary, natural anticoagulants appear - PDF and other waste coagulation factors - biologically active, which act as antiplatelet agents and anticoagulants.

Currently, a distinction is made between immune thrombophilic complications and hereditary hemostasis defects.

Hemostatic system during pregnancy

The dominant point of view is that certain conditions are created in the body of a pregnant woman for the development of disseminated intravascular coagulation syndrome. This is expressed in an increase in the total coagulant potential (total activity of coagulation factors), an increase in the functional activity of platelets with a slight decrease in their number, a decrease in fibrinolytic activity with an increase in PDP, a decrease in the activity of antithrombin III with a slight decrease in its content. These features are compensatory and adaptive in nature and are necessary both for the normal formation of the fetoplacental complex and for limiting blood loss during childbirth. Changes in general hemodynamics in the body of a pregnant woman play an important role in the activation of the hemostatic system. For the normal functioning of the fetoplacental system in conditions of high coagulation potential of the blood, compensatory and adaptive mechanisms come into play: an increase in the number of small-caliber terminal villi with hyperplasia and peripheral location of capillaries, a decrease in the thickness of the placental barrier with thinning of the syncytium, the formation of syncytiocapillary membranes, syncytial nodules.

Features of the functioning of the hemostasis system are associated with certain changes in the system of spiral arteries of the uterus. This is the invasion of trophoblast cells into the wall of the spiral arteries, replacement of the internal elastic membrane and internal media with a thick layer of fibrin, disruption of the integrity of the endothelium and exposure of collagen subendothelial structures. In this process, the deployment of the intervillous space with its inherent morphological and hemodynamic features is also important.

The features of the hemostasis system during a physiologically occurring pregnancy are determined by the formation of the uteroplacental circulation.

The platelet level during uncomplicated pregnancy remains virtually unchanged, although there are studies where a decrease in platelet levels was noted. When the platelet level decreases below 150,000/ml, studies are necessary to identify the causes of thrombocytopenia.

During pregnancy, an increase in coagulant potential is observed; the body seems to be preparing for possible bleeding during childbirth. An increase in all coagulation factors was noted, with the exception of factors XI and XIII.

An increase in fibrinogen levels begins from the 3rd month of pregnancy and despite an increase in the volume of circulating plasma, the level of fibrinogen at the end of pregnancy increases by at least two times compared to the non-pregnant state.

The activity of factor VIII (von Willebrand factor) also increases not only in healthy women, but also in hemophilia patients and patients with von Willebrand disease. It should be borne in mind that with mild to moderate degrees of this disease, the level of this factor can be almost normal. In contrast to the general increase in coagulation factors, a slight decrease in factor XI at the end of pregnancy and a more noticeable decrease in factor XIII (fibrin-stabilizing factor) were noted during pregnancy. The physiological role of these changes is not yet clear.

The coagulation potential of the blood also increases due to the fact that the level of antithrombin III decreases, protein C increases mainly in the postpartum period, and protein S is reduced during pregnancy and significantly reduced after childbirth.

During pregnancy, a decrease in fibrinolysis was observed at the end of pregnancy and during childbirth. In the early postpartum period, fibrinolysis activity returns to normal. There are conflicting data in the literature regarding the presence of PDF in the bloodstream. According to the results of the study, there was a slight increase in PDF in the last months of pregnancy. According to research, during uncomplicated pregnancy, an increase in the content of degradation products is not detected until the onset of labor. According to J. Rand et al. (1991), the level of some fragments of fibrin degradation products increases from 16 weeks of pregnancy and reaches a plateau at 36-40 weeks. However, a significant increase in PDF during pregnancy is most likely a reflection of the fibrinolytic process due to the activation of intravascular coagulation.

Changes in the hemostatic system in pregnant women with antiphospholipid syndrome

The indicators of the hemostasis system in pregnant women with antiphospholipid syndrome differ significantly from the indicators in women with a physiological course of pregnancy. Since the onset of pregnancy, most patients have noted changes in the platelet component of hemostasis. Platelet aggregation during ADP stimulation is 55-33% higher than during the physiological course of pregnancy. The tendency to increase aggregation persists against the background of antiplatelet therapy.

Platelet aggregation under the influence of collagen is 1.8 times higher than during the physiological course of pregnancy. Platelet aggregation under the influence of adrenaline is 39% higher than in the control group. If, under the influence of the ongoing therapy, it is not possible to reduce these indicators, then such persistent platelet hyperactivity is the basis for increasing the dose of antiplatelet agents or prescribing additional antiplatelet agents. Indicators of ristomycin - aggregation on average in the first trimester remain within normal limits. Studies have shown that from early pregnancy, patients with APS have an increased response of platelets to the effects of biological inducers, identified mainly in tests of functional activity of platelets, such as aggregation under the influence of ADP 1x10 3 M and 1x10 5 M, arachidonic acid.

When assessing the qualitative characteristics by types of aggregograms, not a single observation noted disaggregation (reversible aggregation) under the influence of even weak stimuli ADP 1 x 10 7 M. This is evidenced by a change in the profile of the curves towards the so-called “atypical” hyperfunctional aggregograms.

Indicators of the plasma component of hemostasis in the first trimester of pregnancy were also changed compared to the control: a significant acceleration of AVR was noted, the r+k indicator on the thromboelastogram was shortened, and the indicator of the structural properties of the fibrin clot - ITP - was significantly higher.

Thus, in pregnant women with APS, already in the first trimester there is moderate hypercoagulation in the plasma part of hemostasis, which develops earlier than the hypercoagulation associated with adaptation of hemostasis during physiological pregnancy. These changes, which determine the hyperactivity of hemostasis in general in the first trimester of pregnancy, are not considered as pathological activation of intravascular thrombus formation, because extremely rarely at this stage of pregnancy we observed the appearance of markers of disseminated intravascular coagulation - fibrin and fibrinogen degradation products (FDP). The PDF content in the first trimester did not exceed 2x10 g/l. This was the basis to regard the hyperactivity of the platelet and plasma components of hemostasis as hypercoagulation inappropriate for the duration of pregnancy and a background for the development of disseminated intravascular coagulation.

In the second trimester of pregnancy, despite therapy, changes in the plasma hemostasis were noted. It was revealed that APTT is 10% and AVR is 5% shorter than during physiological pregnancy. These data indicate increasing hypercoagulation. The same trend was noted in the thrombo-elastogram: chronometric coagulation indicators r+k, Ma parameters and ITP values ​​are higher than in physiological pregnancy.

In the platelet component of hemostasis, there is a statistically significant increase in aggregation and an increase in hyperfunctional types of curves when exposed to weak stimulants, which indicates persistent platelet hyperactivity in pregnant women with APS, resistant to therapy.

In the third trimester of pregnancy, the same tendency towards an increase in hypercoagulation phenomena was noted, despite the therapy. Indicators of fibrinogen concentration, AVR and APTT, indicate developed hypercoagulation. Although, due to greater control of hemostasiograms, therapeutic measures manage to keep hypercoagulation within limits close to physiological parameters.

Considering that the main, natural inhibitors of blood coagulation are synthesized by the vascular wall, including the placental vessels, it is of great interest to assess the total activity of plasminogen activator inhibitor (PAI) as pregnancy progresses in women with antiphospholipid syndrome. Determinations of PAI content carried out during pregnancy showed that in pregnant women with antiphospholipid syndrome there is no increase in the blocking effect of PAI 1 and placental PAI 2.

The maximum increase in plasminogen activator inhibitor in individual observations was 9.2-9.7 U/ml (normally this figure is 0.3-3.5 U/ml) against the background of fairly high activity and content of plasminogen, the main fibrinolytic substrate (112 -115% and 15.3-16.3 g/l, with the norm being 75-150% and 8 g/l, respectively). Early signs of pathological activity of the hemostatic system (thrombinemia) in the first trimester based on the level of inactive antithrombin III complex (TAT) were noted only in isolated observations, which confirms the actual intravascular generation of procoagulant activity.

Studies of the components of the anticoagulant mechanisms of the hemostatic system have revealed great variability in the content of protein C (PrC); in most observations, the decrease in its level does not depend on the duration of pregnancy. The maximum PrS activity did not exceed 97%, in most observations - 53-78% (normal 70-140%).

Individual analysis of the content of plasminogen activator inhibitor in the second trimester of pregnancy revealed a sharp increase in plasminogen activator inhibitor to 75 U/ml in only 1 case, while there was a combination of an increase in plasminogen activator inhibitor with severe AT III pathology, activity 45.5%, concentration 0.423 g /l. In all other observations, the content of plasminogen activator inhibitor ranged from 0.6-12.7 U/ml, with an average of 4.7±0.08 U/ml. Further, in the third trimester, the content of plasminogen activator inhibitor also remained low, fluctuations ranged from 0.8 to 10.7 U/ml, on average 3.2 ± 0.04 U/ml, in only one observation - 16.6 U/ml ml. Considering that usually a sharp increase in the content of plasminogen activator inhibitor contributes to a decrease in fibrinolytic activity and local thrombus formation (due to the suppression of reparative fibrinolysis), the facts we noted can be considered as the absence of an endothelial reaction in pregnant women with APS, aimed at the synthesis of the endothelial component PAI 1, synthesized by the vascular endothelium walls, and, more importantly, the absence of the placental component PAI 2 system produced by the placental vessels. A possible explanation for the factors we noted may be a dysfunction of endothelial cells and, first of all, placental vessels in pregnant women with antiphospholipid syndrome, probably due to the fixation of antigen-antibody complexes on the endothelium.

Noteworthy is the significant decrease in PrS activity in the second trimester of pregnancy, 29% lower than in the control group.

Evaluation of the fibrinolytic system showed the following results: plasminogen activity in most cases was high in the first trimester of 102±6.4% and concentration 15.7±0.0Eg/l; in the second trimester, plasminogen activity was subject to even greater fluctuations from 112 to 277% and concentration from 11.7 g/l to 25.3 g/l, on average 136.8 + 11.2% concentration 14.5 + 0.11 g /l. In the third trimester, similar conditions remained: plasminogen activity ranged from 104 to 234% (normal 126.8±9.9%), concentration from 10.8 to 16.3 g/l, on average 14.5+0.11 g/l . Thus, the fibrinolytic potential in pregnant women with antiphospholipid syndrome is quite high.

In contrast, the content of the main fibrinolysis inhibitor alpha2-macroglobulin (alpha 2Md) was quite high in the first trimester of pregnancy, ranging from 3.2 to 6.2 g/l (normal 2.4 g/l), with an average of 3.36 ±0.08 g/l; in the second trimester, respectively, from 2.9 to 6.2 g/l, on average 3.82±0.14 g/l.

Similar data were obtained regarding the content of alpha1-antitrypsin (alphaAT), which in all trimesters of pregnancy ranged from 2.0 to 7.9 g/l. Since CL-Mg and a1-AT are slow-acting and indirect-acting buffer inhibitors, their effect on the activation of the fibrinolytic system, even under conditions of high plasminogen content, was manifested by a decrease in fibrinolytic potential in pregnant women with antiphospholipid syndrome, similar to that during the physiological course of pregnancy.

The listed features of the hemostatic system emphasize the great importance of control studies of hemostasis during pregnancy to optimize antithrombotic therapy and prevent iatrogenic complications.

A study of the hemostatic system before birth showed that the hemostatic potential remains preserved and, despite antiplatelet therapy, the tendency to platelet hyperfunction remains.

Considering that patients with antiphospholipid syndrome receive antithrombotic drugs during pregnancy, and after childbirth there is a high risk of thromboembolic complications inherent in patients with antiphospholipid syndrome, the study of hemostasis in the postpartum period is extremely relevant.

Underestimation of hemostasiograms and cessation of therapy immediately after childbirth can lead to rapidly developing hypercoagulation and thromboembolic complications. Studies have shown that blood clotting potential remains high after childbirth, even in those observations where patients received heparin therapy. It is advisable to conduct studies of the hemostasis system on days 1, 3 and 5 after birth. Moderate hypercoagulation was noted in 49% of postpartum women, and in 51% of postpartum women activation of the hemostatic system was noted - an increase in hypercoagulation and the appearance of PDF.

Congenital defects of hemostasis

Currently, much attention is paid to genetically determined forms of thrombophilia, which, like antiphospholipid syndrome, are accompanied by thromboembolic complications during pregnancy and lead to pregnancy loss at any stage. The main causes of hereditary thrombophilia: deficiency of antithrombin, protein C and S, heparin cofactor H, deficiency of factor XII, dys- and hypoplasminogenemia, dysfibrinogenemia, deficiency of tissue plasminogen activator, Leiden mutation of the coagulation factor V gene.

In addition to these disorders, in recent years hyperhomocysteinemia has been classified as a hereditary thrombophilic condition - a condition in which, due to a hereditary defect in the enzyme methylenetetrahydrofolate reductase, there is a risk of developing venous and arterial thrombosis and, in connection with this, pregnancy loss with the possible early development of eclampsia. It should be noted that one of the latest publications noted that hyperhomocysteinemia was detected in 11% of the European population. Unlike other hereditary hemostasis defects, with this pathology early pregnancy losses are observed already in the first trimester. In case of hyperhomocysteinemia, the use of folic acid is a very effective prevention of thrombosis.

When identifying pregnant women with hereditary thrombophilias, a very careful assessment of family history is necessary. If close relatives have a history of thromboembolic complications at a young age, during pregnancy, or while using hormonal therapy, including oral contraceptives, it is necessary to be examined for hereditary hemostasis defects, in which the risk of thromboembolic complications is extremely high.

Antithrombin inactivates thrombin, factors IXa, Xa, XIa and CPA. Alpha1-antithrombin deficiency is highly thrombogenic and accounts for up to 50% of cases of thrombosis during pregnancy. Due to the heterogeneity of the disorders, the frequency of occurrence of this defect varies from 1:600 ​​to 1:5000.

Protein C inactivates factors Va and VIIIa. Protein S acts as a cofactor for protein C, enhancing its effects. Protein C and S deficiency occurs with a frequency of 1:500. Protein C remains virtually unchanged during pregnancy; protein S decreases in the second half of pregnancy and returns to normal shortly after birth. Therefore, if the determination of protein S is carried out during pregnancy, false-positive results may be obtained.

In recent years, there have been many publications about thrombophilia due to mutation of the factor V gene, this is the so-called Leiden mutation. As a result of this mutation, protein C does not affect factor V, which leads to thrombophilia. This pathology is found in 9% of the European population. This mutation must be confirmed by DNA testing for factor V Leiden. The incidence of the Leiden mutation varies significantly. Thus, according to Swedish researchers, the incidence of this hemostasis defect among pregnant women with thrombosis ranged from 46 to 60%, while in England - only 14% and in Scotland - 8%.

November 16-17, 2017 Department of Radiation Diagnostics and Radiation Therapy of Volgograd State Medical University invites you to take part in a scientific and practical conference “Current issues of radiation diagnostics in pediatrics.”

Organizers: Federal State Budgetary Educational Institution of Higher Education "Volgograd State Medical University" of the Ministry of Health of Russia; Health Committee of the Volgograd Region; Radiation Diagnostics Development Foundation; Volgograd Regional Clinical Cardiology Center; Central Research Institute of Radiation Diagnostics; ROO "Society of Radiologists, Radiologists and Ultrasound Diagnostic Specialists in Moscow."

On November 8, 2017, at a meeting of the Academic Council of Volgograd State Medical University, the Decision of the Academic Council of October 11, 2017 was announced.(Minutes No. 2, reg. No. 17) on awarding the title of Honorary Professor of Volgograd State Medical University to A.G. Beburishvili - Head of the Department of Faculty Surgery with a course of endoscopic surgery at the Faculty of Medicine and with a course of cardiovascular surgery at the Faculty of Medicine of Volga State Medical University, Honored Doctor of the Russian Federation, Honored Scientist of the Russian Federation, Doctor of Medical Sciences, Professor - for special personal merits, significant contribution to medical activities, scientific and pedagogical , educational, social life and development of the university’s potential. Along with the diploma, Andrei Georgievich was awarded the robe and confederate of Honorary Professor of Volgograd State Medical University.

The Academic Council, administration and staff of Volgograd State Medical University with best wishes for good health and further success in professional activities sincerely congratulate Andrei Georgievich Beburishvili on being awarded the well-deserved title!

The community of Vietnamese students decided to celebrate the Day of National Unity of Russia with a big sports festival. Having turned to the teachers of the Department of Physical Education and Health of our university for help, they received a positive response and the holiday took place!

More than 50 students from Volgograd State Medical University, VolSU. Volga State Technical University and the Academy of the Ministry of Internal Affairs took part in competitions in badminton, volleyball, table tennis, chess, and darts. Throughout the entire competition, an atmosphere of fun and goodwill reigned in the hall.

OnI At the All-Russian Forum of Tutors in Saratov, representatives of 35 universities in the country defended projects to develop this movement in various directions. The result of the forum was the adoption of a resolution on the creation of the All-Russian movement of tutors of student academic groups of medical and pharmaceutical universities of the Russian Ministry of Health.

On the second day of the forum, master classes “A friendly team is the key to success” were given by members of the presidium - the head of the Moscow State University Scientific Research Center Andrei Andrianov, the ex-chairman of the Russian Academy of Music Tamara Achisova, and the president of the International Public Organization FMNO Valery Zagrebin.

Also in the anatomical amphitheater of SSMU, forum participants presented their group projects in the areas of work of 8 educational thematic platforms:

“If you look at the history of all new research and diagnostic methods,
then we will see through what obstacles a new thought made its way each time,
sometimes despite the opposition of prominent scientists.”
Professor A.M. Aminev

The VI regional scientific and practical seminar was held in Volgograd “Fast track surgery: the optimal perioperative period from the perspective of evidence-based medicine.” And although the event is aimed at surgeons and anesthesiologists-resuscitators of Volgograd and the region, it was attended not only by doctors of these specialties, but also by orthopedic traumatologists, obstetricians-gynecologists, as well as senior students of the medical and pediatric faculties of Volgograd State Medical University. A total of more than 120 people.

The conference was opened by the chief freelance specialist in anesthesiology and resuscitation of the VO Health Committee, head of the department of anesthesiology and resuscitation No. 2 of the Volgograd Regional Neurosurgical Center I.Yu. Baranov.

Recently, a popular science lecture dedicated to coffee was held in the city. It was organized by students of Volgograd State Medical University as part of the “Volgograd Science Cafe” project. This time at HARAT’S PUB, listeners were told about the benefits and harms of caffeine, and were also introduced to all the stages that coffee beans go through before becoming a popular drink.

The lecture hall was visited by about 70 people - there were students, practicing doctors, teachers, and also those who are far from the scientific and educational environment. The first speaker was Viktor Sirotenko, assistant at the Department of Pharmacology of Volgograd State Medical University, with the topic “CAFFEINE: FOR OR AGAINST?”. He said that caffeine consumption has both positive and negative sides.

At the Saratov State Medical University named after. IN AND. Razumovsky held the first working day of the First Forum of Tutors of Student Academic Groups of Medical and Pharmaceutical Universities of the Ministry of Health of Russia. The delegation of 8 people representing Volgograd State Medical University did not stand aside.

Mentoring is becoming more and more important in our lives. This is due to the development of new student directions, still unknown to a large number of student societies. The main goal of the forum was precisely the exchange of experience in conducting and creating new actions and directions. The event will take place over 2 days, during which participants will enjoy a rich educational and cultural program.

The hemostasis system is a remarkable achievement of evolution, which constantly maintains a balance between two multidirectional processes: the fastest possible formation of a clot (thrombus) in order to prevent blood loss in response to damage to the vessel and at the same time maintaining the liquid aggregate state of blood in the circulation. The solution to this difficult problem is provided by the complex interactions of the vascular endothelium, the plasma coagulation cascade, anticoagulant mechanisms, the fibrinolytic system, platelets and leukocytes. The rheological characteristics of blood movement through vessels of various diameters, especially viscosity in the microcirculation system, are of great importance.
In critical care medicine, hemostasis disorders develop frequently, the degree of their severity depends on the deregulatory effect of damaging factors on homeostasis - trauma, infection, surgery, medications, as well as the compensatory capabilities of the cardiovascular and respiratory systems. Deciphering the leading role of hemostasis disorders, in particular disseminated intravascular coagulation syndrome (DIC), in the pathogenesis of most critical conditions requiring intensive care, and the appearance in the doctor’s arsenal of effective targeted means of its correction is a distinctive feature of modern medical practice.
Clinically, hemostasis disorders are manifested more often by bleeding, less often by thrombosis, but there is often a simultaneous manifestation of pathological bleeding and microthrombosis.
Physiology of normal hemostasis
Damage to the wall of a blood vessel causes immediate vasoconstriction of both the damaged vessel itself and adjacent capillaries and arterioles, which leads to an initial slowdown in blood flow in the damaged area. Further, the interaction of several functional components leads to the formation of a primary platelet plug (clot), which is quickly stabilized by fibrin threads. Under normal conditions, this procoagulant process is limited in time and place, and is controlled by the same functional components. These include platelets, the plasma coagulation cascade, natural anticoagulants, the fibrinolysis system and endothelial cells.
When the endothelium is damaged, platelets come into contact with the subendothelial layer of collagen, platelet adhesion (sticking) to collagen occurs, platelet granules are formed with the release of serotonin, lysosomal enzymes, fibrinogen and platelet factor IV, and prostaglandin synthesis is stimulated. Activated platelets aggregate, forming a primary platelet plug (primary hemostasis). Quantitative and qualitative pathological changes in platelets are manifested by bleeding and hemorrhages. Bleeding time is the optimal screening test for assessing platelet function.
The coagulation cascade is responsible for the formation of a stable fibrin thrombus. The factors that make it up are listed in table. 2-10.
Table 2-10. Coagulation factors Factor 1 Fibrinogen Factor II Prothrombin Factor III Tissue thromboplastin (tissue factor) Factor IV Calcium Factor V Accelerin Factor VII Proconvertin Factor VIII Antihemophilic factor Factor IX Christmas factor Factor X Stewart factor Factor XI Plasma precursor of thromboplastin Factor XII Hageman factor Factor XIII Fibrin-stabilizing factor
The synthesis of most coagulation factors occurs in the liver. Factor VIII, in addition to the liver, is partially synthesized by megakaryocytes and endothelial cells. Factors II, VII, IX and X are vitamin K dependent, i.e. for their synthesis by hepatocytes, vitamin K is required. The diagram of the coagulation cascade of coagulation is shown in Fig. 2-8.
The beginning of the coagulation cascade is the interaction of factor VII with tissue factor (III) in the area of ​​damage (external coagulation pathway). The resulting complex of activated factor VII with tissue factor activates factors IX and X, which leads to the formation of thrombin. Thrombin converts fibrinogen to fibrin, activating factor XIII and platelets. The action of thrombin is controlled by a natural anticoagulant - activated protein C. An alternative to the external coagulation pathway is the internal one, starting with the activation of factor XII by collagen due to contact of blood with a foreign surface. Factor XHa activates factor X1a, then the external and internal coagulation pathways are identical.
Internal path External path
(contact factor) (tissue damage)
RSH

RHa
RUA

RHSha
RHS
Rice. 2-8. Scheme of the coagulation cascade.
Screening tests - prothrombin time, activated partial thromboplastin time (aPTT) and thrombin time - make it possible to judge the state of the links of coagulation hemostasis. Congenital or acquired defects of the coagulation cascade cause hemorrhages in the brain, joints, soft tissues and muscles, and gastrointestinal bleeding.
Natural anticoagulants are represented by two important factors - antithrombin III and vitamin K dependent proteins C and 5. Antithrombin III inhibits thrombin and factor Xa, and is involved in the inactivation of factors 1Xa, X1a, XIa. By interacting with heparin, antithrombin III significantly enhances its anticoagulant effect. Activated protein C in combination with protein 5 has an anticoagulant effect on enzymes that inhibit factors Va and Va (important cofactors of the procoagulant process). In addition, protein C enhances fibrinolysis by inhibiting tissue plasminogen activator, facilitating the transition of plasminogen to plasmin. Protein C plays an important role in pathogenesis
DIC syndrome. Deficiency of antithrombin III, protein C and protein 5 (more often acquired than congenital) is accompanied by a high incidence of thrombotic complications.
Fibrinolysis (similar to coagulation) is a normal response to damage to the vascular wall. Tissue plasminogen activator (1-PA), produced by endothelial cells in response to injury or stimulation by thrombin, converts plasminogen to plasmin. Plasmin destroys fibrin and fibrinogen, forming various fibrin degradation products. At the same time, the plasminogen activator inhibitor (PA1-1, formed by hepatocytes and endothelial cells, and PA1-2, formed in the placenta and macrophages) circulates in the plasma in an inactive form. Their physiological significance lies in controlling fibrinolysis and preventing its transition to the pathological stage. Therapeutic fibrinolysis inhibitors are tranexamic acid and aminocaproic acid. On the contrary, streptokinase is a fibrinolytic drug that increases the formation of plasmin.
Under normal conditions, endothelial cells are responsible for the antithrombotic interaction between blood and tissues, maintaining the fluid state of the blood. They produce anticoagulants such as glycosaminoglycans, heparin sulfates, thrombomodulin (activate antithrombin III and protein C), nitric oxide and prostaglandin (inhibit platelet aggregation and promote vasodilation), tissue plasminogen activator, which initiates fibrinolysis. But endothelial cells are capable, in response to stimulation by bacterial endotoxins, of producing von Willebrand factor and tissue factor on their surface, which trigger the coagulation cascade. These properties must be taken into account when treating hemostasis disorders.
Laboratory screening for hemostatic system disorders
Tests to assess primary hemostasis, performed urgently in intensive care settings, are the determination of bleeding time and platelet count. Platelet aggregation and adhesion, the content of von Willebrand factor are studied in specialized coagulation laboratories.
The process of coagulation hemostasis can be assessed by tests such as aPTT, prothrombin time and thrombin time, which provide a summary assessment of several coagulation factors. Separate determination of coagulation factors is possible only in specialized laboratories.
Screening for the anticoagulant system can be performed by determining the concentration of antithrombin III; other clotting inhibition tests take a long time and are performed in a specialized laboratory.
The state of the fibrinolytic system can be judged by examining the amount of fibrinogen degradation products, fibrin monomers, B-dimers, as well as by specific studies of the content of fibrinolysis activators and inhibitors in plasma.
Normal values ​​of coagulation parameters are given in table. 2-11.
Table 2-11. Blood coagulation indicators Test Normal APTT 27.4-40.3 s Prothrombin time 12.3-16.1 s Thrombin time Control ±3 s Fibrinogen 1.7-3.1 g/l P-dimers End of table. 2-11 Coagulation factors II, V, VII, VIII, IX, X, XI, XII 50-150% Antithrombin III 80-120% Activated protein C 73-121% Protein 3: total 55-125% free 21-53% Von Willebrand factor (antigen) 50-150%
The bleeding time corresponds to the time required for the formation of a platelet plug. It may be prolonged in thrombocytopenia, platelet dysfunction, and von Willebrand disease, but is never prolonged in coagulation disorders (eg, hemophilia).
Platelet count should be included in routine laboratory screening in intensive care unit patients. It should be remembered that the platelet count may be reduced in the first days of menstruation.
APTT reflects the total content of all factors of the internal coagulation pathway - from activation of factor XII to the formation of soluble fibrin, except for factors VII and XIII. A prolonged APTT reflects an increased tendency to bleed and may indicate a deficiency of one or more intrinsic hemostasis factors (for example, VIII in hemophilia or von Willebrand disease). Therapy with sodium heparin or warfarin prolongs the aPTT. APTT does not reflect disturbances in primary hemostasis.
Prothrombin time characterizes the process of clot formation. It determines the sum of coagulation factors I, II, V, VII and X that make up the extrinsic pathway, and is lengthened when one or more of them is deficient. This indicator is often used to monitor therapy with indirect anticoagulants (warfarin) - vitamin K antagonists, which, accordingly, do not act on fibrinogen and factor V. More informative for these purposes is the study of the prothrombin complex, which determines only the sum of factors II, VII and X (for the synthesis of these factors requires vitamin K). In order to compare the results of studies from different laboratories using different test systems, the prothrombin time and prothrombin complex indicators are recalculated into the international normalized ratio (INR). In healthy individuals, the INR is about 1. When treated with warfarin, vitamin K deficiency, liver failure, or an isolated deficiency of one of the factors (usually VII), the INR values ​​should be between 2 and 3.
Thrombin time tests the final stage of thrombosis. Its lengthening may indicate fibrinogenopenia less than 1 g/l or dysfibrinogenemia. Sodium heparin therapy also prolongs thrombin time.
Low fibrinogen levels may result from decreased fibrinogen production or increased consumption. A high fibrinogen content is an indicator of an acute inflammatory state, especially in the liver, where its synthesis occurs. An increase in the concentration of fibrinogen lysis products (fibrin degradation products, B-dimer) with a simultaneous decrease in its amount indicates the development of DIC syndrome.
Deficiency of antithrombin III (the most powerful natural proteolytic plasma anticoagulant) is often a manifestation of acute massive blood loss, inadequately replenished [without transfusion of fresh frozen plasma (FFP)], or disseminated intravascular coagulation syndrome accompanying sepsis. Much less frequently, a decrease in the amount of antithrombin III occurs as a manifestation of a hereditary disease of an autosomal dominant nature. The use of screening tests for the differential diagnosis of acquired hemorrhagic syndromes or diseases, the main clinical manifestation of which is the pathology of the hemostatic system, is shown in Table. 2-12.
Table 2-12. Study of hemostasis indicators in certain diseases and syndromes Test Hemophilia Disease
Von Willebrand Acute
internal combustion engine
illness syndrome
liver Heparin
sodium Warfarin Platelets Normal Normal Reduced Normal Normal Normal Fibrinogen Normal Normal Reduced Reduced Normal Normal Prothrombin
time Normal Normal Extended Extended Normal Extended APTT Extended Normal or extended Normal or extended Normal or extended Extended Extended Thrombin time Normal Normal Extended Normal or extended Extended Normal
However, the listed classical tests for monitoring hemostasis, unfortunately, do not provide an integral, whole picture of his condition, reflecting the interaction of numerous factors. In intensive care, it is often necessary to know about the state of the patient’s blood coagulation system at the time of the study, both for the purpose of selecting medications or transfusion means of correction, and for the purpose of assessing the correctness of therapy carried out to correct hemostasis disorders. The thromboelastography method allows you to quickly and reliably obtain data characterizing both the general state of hemostasis and the state of its individual components during their pathological changes.
The thromboelastography method is based on measuring the physical parameters of a clot (thrombus) during its formation. From the moment the coagulation begins until its completion and subsequent lysis, a change in the density of the clot is recorded using an electromechanical converter, which in modern thromboelastograph models is transmitted to the computer display. The following main parameters of thromboelastography are distinguished (Fig. 2-9):
K (min) - time from the beginning of coagulation to the formation of the first fibrin fibers;
K (min) - time of change in the amplitude of coagulation, its increase or deceleration;
K+K - correlates with blood clotting time, which is normally 6-8 minutes;
angle a - reflects the rate of blood clotting, the process of fibrin polymerization;
MA (mm) - the maximum amplitude of the curve, characterizing the strength and rigidity of the formed clot, which depend primarily on the function and number of platelets and, to a lesser extent, on the concentration of fibrin in the blood;
EP, LYSO (%) - assessment of the degree of fibrinolysis.
As can be seen from Fig. 2-9, with hypercoagulation syndrome, the temporary indicators of KIK are shortened, the angle a and MA increase. On the contrary, with a hypocoagulation status, KIK increases, angle a and MA decrease. In addition to the general characteristics of the state of hemostasis, thromboelastography data can also be used to judge violations of its individual components. Thus, with an overdose of sodium heparin, all thromboelastogram parameters will be lengthened and reduced - K, K, a, MA; with thrombocytopenia, K will remain within normal limits, but K will be prolonged with reduced MA; with increased fibrinolysis, # is normal, but MA is sharply and long-term reduced by Eb and Lyso; for thrombocytopathy and platelet dysfunction
Start

Rice. 2-9. Thromboelastogram options: A - normal; B - hypercoagulation; B - hypocoagulation.
K is lengthened, angle a and MA are reduced. The ability to repeatedly perform thromboelastography, its graphical recording, minimal time spent on research with a very small volume of blood required for its implementation, make thromboelastography one of the mandatory attributes of laboratory equipment for express laboratories in intensive care units.
INTENSIVE CARE OF SPECIFIC FORMS OF DISORDERS OF THE HEMOSTASIS SYSTEM
In critical care medicine, a complete coagulological study often cannot be performed due to the severity of the patient’s condition, lack of time and the urgency of surgery. It should be noted that suspicion of bleeding due to a systemic disorder of hemostasis in the vast majority of cases can be excluded if the patient has a hematocrit >30%, platelet count >100x109/l, fibrinogen concentration >1.5 g/l and at the same time aPTT and prothrombin time are no more than 3-5 s above the upper limits of normal values. With such indicators, it is possible to safely perform invasive procedures (central venous catheterization or arterial puncture). At the same time, bleeding with these indicators may indicate a defect in surgical local hemostasis (usually after surgery) or the development of acute disseminated intravascular coagulation syndrome.
The most common systemic disorders of hemostasis requiring intensive care are given in Table. 2-13.
Table 2-13. Disturbances of hemostasis in critical conditions Diagnosis Pathology of hemostasis Liver diseases Decreased content of all coagulation factors except VII and von Willebrand factor Decreased concentration of protein C and 5 Reduced number of platelets and their dysfunction DIC syndrome Dysfibrinogenemia opn Platelet dysfunction Decreased concentration of antithrombin III DIC syndrome Coronary artery bypass grafting with using AIK Platelet dysfunction Decreased platelet count Decreased fibrinogen concentration Decreased content of factors II, V, VII, X, XI DIC syndrome TBI, crash syndrome Increased concentration of fibrin degradation products DIC syndrome Massive transfusions Decreased content of factors V and VII DIC syndrome Warfarin Decrease in the content of factors II, VII, IX, X Decrease in the concentration of protein C and 5 Sodium heparin Thrombocytopenia Decrease in the content of factor Xa Thrombolytic
therapy Increased concentration of fibrin degradation products, plasmin Decreased fibrinogen content DIC syndrome Decreased fibrinogen content Decreased platelet count Decreased protein C and 5 content Decreased concentration of antithrombin III Reduced content of factors V, VIII, IX, XI Increased concentration of fibrin degradation products
The minimum sufficient content of plasma coagulation factors in the bloodstream required to ensure hemostasis during surgical interventions is illustrated in Table. 2-14.
The minimum sufficient platelet count is 80-100x109/l.
Table 2-14. Minimum content of coagulation factors required for surgical hemostasis Factor Hemostatic level, % of normal Fibrinogen 50-100 Prothrombin 40-50 Factor V 10-30 Factor VII 10-20 Factor VIII 30-70 Von Willebrand factor 20-50
End of table. 2-14 Factor IX 20-60 Factor X 10-20 Factor XI 20-80 Factor XIII 10
Primary hemostasis disorders
Hemorrhagic diathesis caused by damage to primary hemostasis includes thrombocytopenia (see Chapter 9), von Willebrand disease and platelet dysfunction. Characteristic symptoms are hemorrhagic rashes on the skin or mucous membranes, the appearance of bruises, petechiae with minimal exposure. Intensive therapy is necessary for local bleeding, especially often with nasal bleeding and menorrhagia.
Thrombocytopenia caused by bone marrow damage (aplastic anemia, hemoblastosis, cancer metastases) is most often recorded. Less often in the practice of an intensive care physician, there are patients whose hemorrhagic thrombocytopenic diathesis is due to congenital causes (Wiskott-Aldrich syndrome, May-Hegglin anomaly) or radiation damage, deficiency of iron, vitamin B12, chronic alcoholism.
Idiopathic thrombocytopenic purpura is the most common form of autoimmune thrombocytopenia, which is characterized by a shortened life of platelets due to their increased consumption. Platelet function is not affected. When bleeding occurs or to prevent it, glucocorticoids are prescribed. The use of high doses of intravenous immunoglobulin is effective. Often, especially when complications of glucocorticoid therapy (Cushing's syndrome, hyperglycemia) or recurrent bleeding occur, splenectomy is resorted to. On the day of surgery and in the immediate postoperative period, glucocorticoid therapy is continued, its withdrawal should be gradual (dose reduction by 2.5-5 mg of prednisolone per day). Platelet transfusions are not considered a treatment of choice, except in extremely rare cases (ineffectiveness of conservative therapy and the need to prevent increased bleeding during surgery).
Immune conflict also serves as the basis for heparin-induced thrombocytopenia. The patient's body, in response to the administration of sodium heparin, begins to form IgC antibodies, which bind to the Pc receptors of platelets, contributing to a shortening of their life. The frequency of occurrence of such conflict is
5% of persons receiving sodium heparin. Thrombocytopenia develops slowly, local bleeding is rare, and platelet transfusions are not necessary. When sodium heparin is discontinued, the platelet count is restored within 2-5 days.
Many medications used in intensive care can cause platelet dysfunction, but these are usually not clinically significant. Only a few can cause bleeding.
Acetylsalicylic acid blocks platelet aggregation, inhibition continues throughout the life of platelets in circulation (7-10 days), therefore, even a single dose of acetylsalicylic acid can block the most important function of primary hemostasis for a sufficiently long period. If it is necessary to perform operations in such a situation, the administration of desmopressin is indicated, which temporarily (for three hours) eliminates the prolongation of bleeding time. Repeated administration of desmopressin prolongs its action.
NSAIDs block the synthesis of thromboxane A2, an important mediator of platelet aggregation. Their effect can also be neutralized by the administration of desmopressin.
Dextran solutions reduce plasma concentrations of factor VIII and von Willebrand factor and inhibit platelet function, prolonging bleeding time. Despite its good volume-substituting effect, transfusion of dextrans in case of acute massive blood loss or in the presence of initially strained hemostasis (hemophilia, diseases of the blood system, liver diseases, etc.) should currently be kept to a minimum.
Clopidogrel, ticlopidine, as well as modern inhibitors of the platelet receptor PPL/IIIa (abciximab), used in patients with coronary heart disease (CHD) who have suffered a stroke or myocardial infarction, cause platelet dysfunction and increase the risk of developing hemorrhagic complications. Almost always in these cases, the administration of desmopressin helps, with the exception of the situation with the use of CPHb/IIIa inhibitors. In the latter case, platelet transfusion may be necessary.
Von Willebrand disease is an autosomal dominant inherited hemorrhagic diathesis caused by a defect or absence of von Willebrand factor in the plasma. Von Willebrand factor has two main functions. It is essential for platelet plug formation and protects factor VIII from degradation in the plasma. There are three main types of von Willebrand disease (Table 2-15).
Table 2-15. Von Willebrand Disease: Types and Therapy Von Willebrand Factor Therapy Quantitative defect Desmopressin in most cases Qualitative defect Desmopressin in mild cases; factor VIII concentrates containing von Willebrand factor; cryoprecipitate Complete absence Factor VIII concentrates containing von Willebrand factor, cryoprecipitate
Epidemiological studies have shown that the incidence of von Willebrand disease does not exceed 1% in the population, but it is usually diagnosed less frequently. The disease predominates among women with menorrhagia. In all patients suffering from bleeding, the amount of von Willebrand factor in the blood should be determined.
The first type of disease is the most common, accounting for 70-80% of all individuals suffering from von Willebrand disease. In this form of the disease, the amount of normally functioning von Willebrand factor is reduced. The tendency to bleeding is usually moderate, but there are also severe manifestations.
The second type is characterized by a qualitative defect in von Willebrand factor, caused by a mutation in the gene for this factor.
The third type is characterized by the absence of von Willebrand factor and a decrease in the concentration of factor VIII in plasma, usually Diagnosis is based on laboratory tests, mainly on determining the concentration and function of von Willebrand factor and the activity of factor VIII.
Therapy is aimed at normalizing three parameters - the content of von Willebrand factors and VIII, bleeding time. This is achieved by administering desmopressin, which stimulates endogenous hemostasis, and by administering factor VIII concentrate containing von Willebrand factor. Desmopressin is effective in the first, less often in the second type of von Willebrand disease and is ineffective in the third type. When administered intravenously, the effect is almost lightning fast; if it is necessary to continue treatment, repeated doses are administered after 8-12 hours. In the second and third types of von Willebrand disease and in the absence of effect from the administration of desmopressin in the first type, therapy is carried out with factor VIII concentrates containing von Willebrand factor. Pure factor VIII concentrates are not used because factor VIII has a very short half-life in the absence of von Willebrand factor. All factor VIII concentrates containing von Willebrand factor are obtained from plasma, therefore, to avoid transfusion-borne viral infections, it is necessary to use concentrates that have undergone viral inactivation. It is the viral unsafety of cryoprecipitate that limits its use in the treatment of von Willebrand disease. Sometimes, especially with severe bleeding of the mucous membranes, they resort to prescribing a fibrinolysis inhibitor - the administration of tranexamic acid.
Anticoagulants, antiplatelet agents, and dextran transfusions are contraindicated for persons with von Willebrand disease. They should not be given intramuscular injections, as there is a high risk of developing intramuscular hematomas.
Disorders of the coagulation cascade
In diseases caused by pathology of the coagulation cascade, fibrin formation is ultimately disrupted. With the congenital nature of the disease, any one coagulation factor is absent in the plasma, while with acquired diseases, a deficiency of several factors is observed (for example, with secondary disorders of hemostasis due to liver disease, vitamin K deficiency, the use of anticoagulants).
HEMOPHILIA AIV
Hemophilia is a congenital disease of the coagulation system, inherited in a sex-linked recessive manner and caused by a deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B). Clinically, these two forms of the disease are identical; they are differentiated only by studying the concentration of each factor in the blood.
The frequency of hemophilia A is one in 5,000 newborn boys, and hemophilia B is one in 30,000 newborn boys. Accordingly, 80% of patients with hemophilia have hemophilia A, 20% have hemophilia B.
The genes for factors VIII and IX are linked to the female X chromosome, so hemophilia affects only men, and women become carriers. For female carriers, the risk of having a boy with hemophilia is 25%, and a carrier girl is also 25%. In men with hemophilia, the daughter will always be a carrier, and the son will always be healthy.
Clinical manifestations of hemophilia depend on the concentration of factor VIII or IX in the blood. Their activity is determined in international units (IU). Normally, the activity of factors VIII or IX is about 1 IU per 1 ml of plasma. There are three degrees of severity of hemophilia (Table 2-16).
Table 2-16. Degree of severity of hemophilia Degree of severity Concentration of factor VIII, t/t Concentration of factor IX, IU/dl Mild hemophilia A 5-25 100 Moderate hemophilia A 1-4 100 Severe hemophilia A Patients with severe forms of hemophilia, as a rule, need intensive care, in which spontaneous bleeding and hemorrhage can occur in any organs and tissues and be recurrent in nature. Hemorrhages in the joints lead to the development of hemophilic arthropathy, in the muscles - they can cause compartment syndrome, in soft tissues - the formation of a pseudotumor, which is encapsulated and, slowly increasing as a result of repeated hemorrhages, compresses the surrounding tissues. Intracranial hemorrhage is one of the most common causes of death in patients with hemophilia.
Mild hemophilia is often not recognized until boys are adults, when it may be first discovered if surgery is required. Severe hemophilia is usually diagnosed in boys 1-2 years of age, when they begin to walk. The first signs may be hemorrhages in the joints, subcutaneous hematomas due to childhood pranks or intramuscular injections. The coagulogram shows a prolongation of APTT with normal prothrombin and thrombin times, as well as bleeding time. The diagnosis is confirmed by studying the concentration of factors VIII, IX and von Willebrand.
For treatment, concentrates of factors VIII or IX are used, obtained from donor plasma or using genetic technology. Modern concentrates of virus coagulation factors are safe and highly effective. When calculating the dose of factor concentrate, it is based on the need to maintain a hemostatic concentration in the recipient’s blood of at least 50% on the day of surgery and during
14 days postoperative period. Typically, the amount of factor VIII or IX IU required for a single administration is calculated as follows:
blood volume (ml) = 7% body weight (kg); for example, 7% of 70 kg = 4900 ml;
plasma volume (ml) = 60% blood volume (ml); 60% of 4900 ml = 2940 ml;
amount of IU factor VIII = 50% plasma volume (ml); those. in our example, 1470 IU.
The frequency of intravenous administration for factor VIII concentrates is every
h, for factor IX - every 12 hours.
In approximately 30% of patients with hemophilia A, during treatment with factor VIII concentrates, antibodies appear in the blood that block the procoagulant activity of the drug and are therefore called inhibitors. In hemophilia B, the incidence of the inhibitor is lower. The inhibitor titer is measured in Bethesda units (BU). One BU is equal to the amount of inhibitor that inhibits 50% of one unit of factor VIII introduced into the test system. A low titer of BU (5-10 BU) can be overcome by increasing the dose of the factor, but a high titer of BU (more than 10 BU) makes it impossible to obtain a hemostatic effect, since the entire amount of the administered drug will be blocked by antibodies. To remove antibodies, plasmapheresis is recommended (the removed plasma should not be replaced with donor FFP, since it contains factor VIII), and the administration of glucocorticoids. Recently, recombinant activated factor VII and activated prothrombin complex concentrate have become widely used in such situations. When carrying out therapy for such patients, consultation with a coagulologist is mandatory.
FACTOR VII DEFICIENCY
Coagulation factor VII, binding to tissue factor, is activated and becomes the trigger that begins the coagulation process. The genetic variant of congenital factor VII deficiency is diagnosed very rarely. Clinically, it is manifested by the formation of bruises with minor injuries, prolonged intractable nasal and uterine bleeding. With severe deficiency of factor VII (less than 1%), bleeding may occur, as in hemophilia - hemarthrosis, retroperitoneal hematomas and intracerebral hemorrhages. In this case, the APTT remains within normal limits, but the prothrombin time and INR increase. For final diagnosis, it is necessary to study the activity of factor VII in the blood.
Acquired factor VII deficiency develops with liver disease, warfarin treatment, and vitamin K deficiency. In this case, the concentrations of other vitamin K-dependent coagulation factors - II, IX, X - will be reduced in the blood.
Therapy is of a replacement nature. FFP transfusion is used as a source of factor VII, and prothrombin complex concentrate is prescribed. Recently, recombinant activated factor VII has appeared in the doctor’s arsenal, which has proven itself both in the treatment of factor VII deficiency and in the treatment of inhibitory forms of hemophilia and thrombocytopenic bleeding. To achieve hemostasis, it is necessary to increase the concentration of factor VII in the patient's blood to 15-20%. The recommended dose of recombinant activated factor VII is 90-120 mg/kg intravenously every
3 hours until bleeding stops. Laboratory monitoring is necessary to monitor effectiveness and adjust the dose, as well as to exclude the possible risk of thromboembolic complications.
OTHER CONGENITAL DEFICIENCIES OF PLASMA CLOTTING FACTORS
Factor XI deficiency (hemophilia C) is a congenital hemorrhagic diathesis that has a pronounced ethnic character and is diagnosed mainly among Jews and Armenians. Repeated bleeding of various locations (nasal bleeding, menorrhagia, postpartum, post-traumatic) develops when factor XI levels are less than 10%. APTT is prolonged, prothrombin time is within normal limits. If it is impossible to laboratory verify factor XI deficiency with increased bleeding, transfusion of donor FFP should be prescribed. The administration of antifibrinolytics (tranexamic and aminocaproic acid) is ineffective and is contraindicated for hematuria.
Afibrinogenemia is a very rare hemorrhagic diathesis, manifested by frequent spontaneous heavy bleeding. With hypofibrinogenemia, spontaneous bleeding appears only when the fibrinogen concentration is less than 0.5 g/l. APTT and prothrombin time are significantly prolonged. The diagnosis is confirmed by laboratory testing of fibrinogen content. Therapy is transfusion of FFP, cryoprecipitate or fibrinogen concentrate.
Dysfibrinogenemia is a heterogeneous group of hereditary diseases with fibrinogen dysfunction. Sometimes this dysfunction is manifested by resistance of the fibrin clot to fibrinolysis, more often by increased sensitivity to fibrinolysis. In the first case, there is a tendency to increased thrombus formation, in the second - to bleeding. Treatment after verification of the diagnosis (with the involvement of a coagulologist) is transfusion of FFP, less often - prescription of fibrinogen.
Isolated congenital deficiency of prothrombin, factors V, X,
XII, XIII are extremely rare in the practice of an intensive care physician. These disorders do not have a specific clinical picture; their diagnosis requires not only screening studies of the coagulogram, but also specific analyzes of the concentration of specific coagulation factors. If an etiological cause of bleeding is detected, FFP is transfused.
ANTIPHOSPHOLIPID SYNDROME AND LUPUS ANTICOAGULANT
Bleeding of the mucous membranes in combination with manifestations of venous or arterial thrombosis against the background of thrombocytopenia with the simultaneous detection of antiphospholipid antibodies and/or lupus anticoagulant in the blood characterizes antiphospholipid syndrome and its severe form - catastrophic antiphospholipid syndrome. This syndrome occurs with systemic lupus erythematosus, collagenosis, cancer, infections and pregnancy. Many cases of catastrophic antiphospholipid syndrome are idiopathic. This syndrome is based on the formation of autoantibodies directed against phospholipids, in particular cardiolipin. The latter forms a complex with protein (32-glycoprotein-1 (p2-CP1), which is part of prothrombin. For this reason, the plasma of patients with catastrophic antiphospholipid syndrome has anticoagulant activity, and the degree of this activity can be judged by the content of “lupus anticoagulant". In case of antiphospholipid syndrome, all prothrombin-dependent tests will be prolonged.At the same time, despite the prolongation of the aPTT t HIGO, the clotting time t V1YO is not impaired, which determines the high risk of thrombosis in antiphospholipid syndrome.
Therapy for catastrophic antiphospholipid syndrome is complex. During plasmapheresis, UFH and prednisolone are prescribed. If ineffective, pulse therapy with methylprednisolone is performed. The removed plasma is replenished with donor FFP. Often, with total thrombosis of the mesenteric vessels, it is necessary to resort to surgical intervention, which significantly worsens the prognosis.
CIRRHOSIS OF THE LIVER
A complex disturbance of the hemostatic balance due to a decrease in the synthesis of many coagulation factors and inhibitors in liver diseases is accompanied by the development of pathological bleeding. At the same time, the number and function of platelets decreases, fibrinolysis increases, prothrombin time lengthens, and INR increases. Splenomegaly, observed in liver cirrhosis, often aggravates thrombocytopenia. In case of severe bleeding or surgical intervention, transfusion of FFP, administration of recombinant activated factor VII, prothrombin complex are prescribed. Tranexamic acid and desmopressin are short-acting.
Disseminated intravascular coagulation
DIC is a complete disruption of the interaction of all hemostatic balance systems that determine its balance, which include endothelial cells, platelet (primary) hemostasis, plasma coagulation system and fibrinolysis. DIC is characterized by the simultaneous presence of bleeding and microthrombosis, leading to the rapid development of organ failure and MODS. Decoding the phenomenon of internal combustion engine (in which in our country the leading role was played by the works of M.S. Machabeli and Z.S. Barkagan) explained many seemingly disparate phenomena accompanying such formally different critical conditions as sepsis, massive blood loss, burns, snake bites , pregnancy complications, etc.
In intensive care practice, DIC most often develops against the background of sepsis, massive blood loss (especially in obstetrics), trauma, oncological and hematological diseases.
ETIOLOGY AND DEVELOPMENT MECHANISM
The development of ICE can be due to various reasons and conditions, as presented below. More often, DIC takes on the character of an acute (fulminant) course, less often a chronic course is observed.
Reasons for the development of DIC syndrome:
Shock (hypovolemia and hypoxia) of any etiology.
Infections.
Sepsis.
Bacterial.
Viral.
Fungal.
Injury
Burns.
Crash syndrome.
-TBI.
Fat embolism.
Major surgical operations.
Complications of pregnancy and childbirth
Severe eclampsia.
Placental abruption.
Intrauterine fetal death.
Amniotic fluid embolism.
HENR syndrome.
Anaphylaxis
Stroke
Acute intravascular hemolysis
Vascular prosthetics
Snake bites
Neoplasms
Adenocarcinoma.
Hemoblastoses.
Liver diseases
Cirrhosis.
Acute fulminant hepatitis.
Pathological activation of the hemostasis system can be caused by various factors. Activation of endothelial cells by endotoxin during infections, poisoning, acidosis and hypoxemia is accompanied by the appearance of tissue factor on the surface of their membrane. The plasma coagulation system is activated by the release of tissue factor as a result of trauma, sepsis, pregnancy complications, blastemia in hematological malignancies.
Systemic activation of coagulation results in the formation of excessive amounts of circulating thrombin in the bloodstream, which causes generalized fibrin formation, activation and consumption of factors VIII and V, and platelet activation. As a result, the process of massive microthrombotic formation in the microcirculation system is launched, leading to the development of MODS and aggravating damage to endothelial cells. On the other hand, generalized fibrin formation activates the fibrinolytic system; fibrinolysis activators are released from activated endothelial cells, platelets and leukocytes, which are actively consumed.
This massive systemic activation of hemostasis results in rapid consumption of all coagulation factors, platelets, and inhibitors. The consumption of platelets in DIC can occur extremely quickly; their bone marrow production does not have time to replenish the circulating pool of platelets. In addition, circulating platelets become functionally defective as a result of exposure to fibrin degradation products. In liver diseases, reduced protein synthesis due to liver failure contributes to a worsening deficiency of coagulation factors and their inhibitors. In addition, the pathological destruction of coagulation factors by bacterial proteases in sepsis, pancreatic enzymes in pancreatic necrosis, or amniotic fluid in amniotic fluid embolism is important. The result of these processes is bleeding caused by thrombocytopenia, hyperfibrinolysis and deficiency of coagulation factors.
CLINICAL MANIFESTATIONS
The range of clinical manifestations of DIC depends both on the cause that caused it (DIC is always secondary, it is not a nosological form, but a syndrome, always associated with any underlying disease), and on the conditions accompanying its development. In the acute course of DIC, its manifestations may include signs of MODS, indicating damage to the central nervous system, renal, hepatic, and pulmonary dysfunction. Characterized by metabolic acidosis, proteinuria, hypoxia, hypotension and fever. Hemorrhagic signs include petechiae and ecchymoses on the skin, spontaneous bleeding of mucous membranes, bleeding from injection sites and surgical wounds, and in severe cases, intracerebral hemorrhages. Microthrombosis causes ischemic damage to internal organs, mainly the brain, lungs, kidneys and liver. Thrombosis of the vessels of the dermis and subdermis is accompanied by acrocyanosis and the possible development of gangrene of the fingers or toes. Ischemic signs of DIC are manifested by neurological disturbances of consciousness (lethargy, rapid exhaustion and monosyllabic answers to questions), hypoxemia and hypoxia with disturbances in the frequency and rhythm of breathing, oliguria or anuria, hypoalbuminemia and hypoprothrombinemia.
DIAGNOSTICS
The primary diagnosis of DIC is entirely based on the clinical picture, including hemorrhagic and ischemic signs. There are hyper- and hypocoagulable phases of acute DIC syndrome, while the hypercoagulable phase of DIC syndrome must be differentiated from chronic hypercoagulable syndrome (status), which is fundamentally different from DIC syndrome both pathogenetically and according to clinical and laboratory data.
Hypercoagulation syndrome is an increased readiness of blood to clot, compensated by anticoagulation mechanisms. With it, there are no local or disseminated blood clots in the vascular system, and accordingly there are no clinical manifestations of thrombosis. But laboratory data indicate a shortening of APTT, prothrombin time, increased platelet activity, decreased fibrinolysis, and rapid clot formation in vitro.
The hypercoagulable phase of DIC syndrome is often fleeting, and the doctor may not diagnose it. Clinical signs of organ ischemia appear. All laboratory signs of hypercoagulation (aPTT, prothrombin, platelet activation) are pronounced, but at the same time the first initial signs of consumption of coagulation factors appear - the number of platelets, the concentration of antithrombin III, protein C decreases slightly. A clot in a test tube forms quite quickly , but it is loose and unstable. An important symptom is often rapid thrombosis of a needle or catheter during intravenous puncture.
The hypocoagulable phase of DIC syndrome is characterized by signs of diffuse hemorrhagic diathesis (bleeding of the petechial-ecchymotic type) and laboratory markers of consumption of coagulation factors of the hemostatic system - prolongation of bleeding time, aPTT, prothrombin time, a significant decrease in the number of platelets and their dysfunction, a decrease concentrations of fibrinogen, factor VIII, the appearance of B-dimers.
TREATMENT
The basis of therapy for DIC is the relief of the pathological process that started it. However, etiological therapy for these diseases (antibiotics for sepsis, chemotherapy or surgery for tumors, plasmapheresis for acute intravascular hemolysis, etc.) produces an effect only after a certain period of time. That is why concomitant therapeutic measures are so important to ensure the restoration and maintenance of bcc, adequate oxygenation, and correction of hypotension in order to improve microcirculation.
At the same time, the critical condition of the patient, aggravated by manifestations of disseminated intravascular coagulation, necessitates rapid transfusion correction of disturbances in the hemostatic system.
In the treatment of the hypercoagulable phase of DIC syndrome, when there are clinical manifestations of organ ischemia due to microthrombosis, sodium heparin is prescribed. Heparin sodium inhibits thrombin activity, thereby reducing fibrin formation. Usually 8-10 MEDkghch are prescribed with constant intravenous administration using a drug dispenser (infusion pump). It should be remembered that sodium heparin works effectively provided there is a sufficient amount of antithrombin III in the blood plasma. If it decreases, transfusion of FFP (10 ml/kg) or prescription of commercial antithrombin III preparations (up to 3000 IU/day) is necessary. The criterion for the effectiveness of sodium heparin therapy will be a decrease in the concentration of fibrin degradation products and B-dimers, an increase in fibrinogen content, and a shortening of prothrombin time. The use of low molecular weight heparins in this situation is inappropriate due to their lack of effectiveness and the impossibility of monitoring. Activated protein C, which, being an anticoagulant, inhibits the activation of factors V and VIII and reduces the formation of thrombin, has proven itself well in the treatment of DIC syndrome of septic etiology.
Much more often, an intensive care physician encounters the hypocoagulation phase of DIC syndrome, in which transfusion therapy plays a leading role in replenishing the deficiency of coagulation factors. Disseminated intravascular coagulation is a complex disorder of the hemostatic system, therefore, the “first violin” in its treatment is played by the transfusion of FFP - a complex transfusion medium in which the optimal set contains all the necessary coagulation factors. The purpose of transfusion of FFP is to increase fibrinogen concentration above 1-1.5 g/l. The therapeutic dose is considered to be transfusion of FFP at the rate of 15-20 ml/kg. If hemostasis is not achieved, it is possible to re-introduce FFP under laboratory monitoring of the concentration of coagulation factors. Sometimes it is necessary to add antithrombin III drugs to the FFP transfusion, especially if its concentration in the blood is less than 70%. If there is a threat of circulatory overload, in order to reduce the volume, they resort to transfusion of cryoprecipitate (one dose per 10 kg of body weight). The use of plasmapheresis in the treatment of DIC is aimed both at treating the underlying disease (for example, acute intravascular hemolysis due to transfusion of erythrocytes incompatible with ABO antigens) and at preventing circulatory overload when transfusion of large volumes of plasma is necessary.
Platelet transfusion in DIC is indicated only when bleeding develops and their number decreases to less than 50x109/l. The goal of platelet transfusion is to exceed this value, which typically requires one unit of platelet concentrate (55-70x109) per 10 kg of body weight per transfusion. If platelet consumption is significant, repeat transfusions are necessary every 24 hours.
Transfusion of red blood cells is indicated only for health reasons with verified signs of hypoxemia and tissue hypoxia due to a lack of red blood cells in the bloodstream.
It is important to remember that some patients with laboratory signs of disseminated intravascular coagulation do not have clinical manifestations of thrombosis or a tendency to bleed. Such patients do not require transfusion correction of hemostasis; they need to undergo therapy for the underlying disease.
REFERENCES ^
Practical transfusiology / Ed. G.I. Kozinets. - M.: Practical Medicine, 2005. - 544 p.
Shevchenko Yu.L., Shabalin V.N., Zarivchatsky M.F., Selivanov E.A. Guide to general and clinical transfusiology. - St. Petersburg: Foliant, 2003. - 608 p.
KN^aags! T., Tabanega U.R.K., Voyzhs! K. e* a1. RNagtasokte1ls$ o^ gesotypaSH: asPua^es! ^acShg VII t 1gaita rayep^ t1\\ zeuere Lieec11n§ // Sp1. Sage. - 2006. - Uo1. 10. - R. 104.
MagIposhIg II., Kepe* S., 5e§a1 E. e1 a1. KesoshYpap!; asPua^es! Gas^og VII bg afipsyue betor-gHa§e con1go1t 1;gaita //]. Tgaita. - 2001. - Uo1. 51. - R. 431-438.
Utsep!:].b., Ko$$at1: K., Cui V. e* a1. Kesotteps1a1:yn$ op 1be i$e o!" gesotbtan! acj- ua*es1 ^ac1;og VII az an af"ipsNue 1;gea1:tep1; Gog ta$$1ue yees11n§ - aEigoreap regresIue // Sp(. Sage. - 2006. - Vo1. 10. - R. 120.

A patient with scurvy has bleeding gums and petechiae on the skin. What causes impaired hemostasis in this disease?

A. @ Impaired collagen synthesis

B. Thrombocytopenia

C. Excess of anticoagulants

D. Activation of fibrinolysis

E. Deficiency of procoagulants

After suffering from a sore throat, the girl developed a petechial rash on the skin of her limbs and torso. Objectively: platelet count 80 G/l, antiplatelet antibodies. Which type of allergic reactions (according to Coombs and Jell) underlie this disease?

@ Type II (humoral cytotoxic)

Type I (anaphylactic)

Type III (immune complex)

Type V (stimulating)

The patient has impaired platelet adhesion to collagen and bleeding from small vessels. What part of hemostasis can be disrupted in a patient?

@ Vascular-platelet

Coagulation, And phase

Coagulation, phase III

Fibrinolysis

Coagulation, phase II

The patient was diagnosed with thrombocytopenia. What clinical manifestations are typical for disorders of platelet-vascular hemostasis?

@ Petechiae, ecchymosis (bruising)

Hemarthrosis

Hematomas

Reduced bleeding time

Increased clotting time

During examination, the patient was found to have thrombocytopathy. Indicate which change plays an important role in the pathogenesis of thrombocytopathies?

@ Production of pathological platelets by bone marrow

Reduced activity of anticoagulants

Hyperactivation of thrombocytopoiesis

Increased concentration of procoagulants in the blood

Inhibition of fibrinolysis.

Before surgery, it was discovered that the person’s bleeding time was increased to 10 minutes. Deficiency of what formed elements in the blood can cause such changes?

@Platelets

Red blood cells

Monocytes

Lymphocytes

Leukocytes

In the patient, long-term use of aspirin caused hemorrhages. Objectively: thrombocytopenia with impaired functional activity of platelets. Thrombocytopathy in this case is caused by inhibition of activity:

@Cyclooxygenase

Cytochrome oxidases

Lipoxygenases

Superoxide dismutase

Phospholipase A 2.

The patient was diagnosed with a decrease in the production of von Willebrand factor by the vascular endothelium. What violation of vascular-platelet hemostasis is observed in this case?

@Platelet adhesion disorder

Platelet aggregation disorder

Hypercoagulation

Impaired fibrin polymerization

Increased fibrinolysis

A child with a hemorrhagic rash that arose after an acute respiratory viral infection was diagnosed with hemorrhagic vasculitis (Schönlein–Henoch disease). Which type of allergic reactions (according to Coombs and Jell) underlie this disease?

@ Type III (immune complex)

Type I (anaphylactic)

Type II (humoral cytotoxic)

Type IV (cellular cytotoxic)

Type V (stimulating)

A child with a hemorrhagic rash that arose after an acute respiratory viral infection was diagnosed with hemorrhagic vasculitis (Schönlein–Henoch disease). What causes impaired hemostasis in this disease?

@ Damage to the vascular wall

Hereditary defect of the connective tissue of the vascular wall

Hereditary deficiency of anticoagulants

Inhibition of fibrinolysis

Hereditary deficiency of procoagulants

A woman suffering from cholelithiasis has been diagnosed with hemorrhagic syndrome caused by vitamin K deficiency. Which of the following factors is deficient in hypovitaminosis K?

@ Stewart - Prower (f. X)

von Willebrand factor

Fibrin stabilizing (form XIII)

Fibrinogen (form I)

During examination, the patient was found to have thrombophilia (acceleration of the blood clotting process). What could have caused the violation?

@ Deficiency of proteolytic enzyme inhibitors

Increased prostacyclin concentration

Decrease in thrombin concentration in the blood

Increased concentration of heparin in the blood

Increased concentration of fibrinolysin in the blood

A patient with liver disease has a decrease in prothrombin levels in the blood. This will lead to a violation first of all:

@ Second phase of coagulation hemostasis

Fibrinolysis

Third phase of coagulation hemostasis

Vascular-platelet hemostasis

The first phase of coagulation hemostasis

A 7-year-old boy developed hemarthrosis of the knee joint after falling from a bicycle. The administration of cryoprecipitate and pumping of blood from the joint led to a significant improvement in the child's condition. What disease should you think about?

@ Hemophilia A

Hemorrhagic vasculitis.

Thrombocytopathy

Thrombocytopenia

Rheumatoid arthritis

A boy with severe hemorrhagic syndrome has no antihemophilic globulin A (factor VIII) in his blood plasma. What phase of hemostasis is primarily impaired in this child?

@Intrinsic prothrombinase activation pathway

Blood clot retraction

Extrinsic prothrombinase activation pathway

The boy suffers from hemophilia. What are the clinical signs of impaired coagulation hemostasis?

Petechial hemorrhages

Microhematuria

Ecchymosis (bruising)

Impaired visual acuity

@ Hematomas, prolonged bleeding

Some time after suffering polytrauma, a victim of a road accident developed disseminated intravascular coagulation (DIC). What factor was the initiator of this complication?

@ Tissue thromboplastin (form III)

Fibrinogen (form I)

Antihemophilic globulin A (f. VIII)

A patient with acute pancreatitis developed disseminated intravascular coagulation (DIC). What substance was the initiator of this complication?

@Trypsin

Fibrinogen (form I)

Antihemophilic globulin A (f. VIII)

Stewart–Prower factor (f. X)

Antihemophilic globulin B (f. IX)

In a patient with polytrauma and acute renal failure, the condition was complicated by internal bleeding. What is the main link in the pathogenesis of this stage of DIC syndrome?

@ Consumption of clotting factors

Release of leukocytes from the depot

Thrombocytosis

Activation of prothrombinase

Inhibition of fibrinolysis

A patient with burn disease developed DIC syndrome as a complication. What stage of DIC syndrome can be suspected if it is known that the patient’s blood clots in less than 3 minutes?

@ Hypercoagulation

Hypocoagulation

Recovery

Latent

Terminal

A patient with trauma developed disseminated intravascular coagulation syndrome. What changes in hemostasis are observed in phase II of DIC syndrome?

@Hypocoagulation

Hypercoagulation.

Fibrinolysis

Thrombocytopenia

Thrombocytopathy

A patient developed disseminated intravascular coagulation syndrome after transfusion of incompatible blood. What is the main link in the pathogenesis of this complication during hemolysis?

@ Entry into the blood of intracellular proteases

Accumulation of bilirubin in the blood

Excess thromboplastin in the blood

Excess prothrombin in the blood

Increased plasminogen content

The patient developed DIC syndrome due to chronic renal failure. The examination revealed an increase in blood clotting time, thrombocytopenia, an increase in the level of fibrin-monomeric complexes and fibrin degradation products. What stage of DIC should you think about?

@ Hypocoagulation

Hypercoagulability

Recovery

Latent

Unstable

A patient with chronic lymphocytic leukemia developed hemorrhages as a result of the development of DIC syndrome. What changes in peripheral blood parameters will be observed in this case?

@ Hypocoagulation, thrombocytopenia

Erythrocytosis, increased blood viscosity

Thrombocytosis, decreased clotting time

Hypercoagulability, increased platelet aggregation

Increased activity of procoagulants

A woman with sepsis developed petechial hemorrhages, the content of platelets and fibrinogen in the blood decreased, and fibrin degradation products appeared. What could be the reason for the noted changes?

@DIC syndrome

Leukopenia

Lymphopenia

Thrombocytosis

1. A boy with hemorrhagic syndrome does not have antihemophilic globulin A (factor VIII) in his blood. What mechanism of hemocoagulation is insufficient in this patient?

   @ Internal mechanism of prothrombinase formation

   Conversion of fibrinogen to fibrin

   External mechanism of prothrombinase formation

   Conversion of prothrombin to thrombin

   Blood clot retraction

   A man who has been suffering from chronic myeloid leukemia for two years was admitted to the hospital in a state of acute renal failure. What could be the cause of acute renal failure in this patient?

   @ ICE – syndrome

2. Lymphopenia

   Neutropenia

   Thrombocytopenia

   Insufficient activity of which blood coagulation factors causes the development of hemorrhagic syndrome in patients with hypovitaminosis K?

   @X, IX, VII, II

4. von Willebrand factor

   A patient who systematically uses acetylsalicylic acid developed hemorrhage. The development of thrombocytopathy in this case is associated with a decrease in the activity of which platelet enzymes?

   @Cyclooxygenase

   Lipoxygenases

   Peroxidases

   Cytochrome oxidases

   Glucose-6-phosphate dehydrogenase

   The girl periodically experiences nosebleeds and small hemorrhagic rashes on the skin. The examination revealed: bleeding time - 10 minutes, reduced adhesive ability of platelets and low activity of f. VIII (VIII:C). What disease does the child have?

   @ von Willebrand disease

   Hemophilia A

   Hemophilia B

   Hereditary dysfibrinogenemia

   Thrombocytopenia

   After suffering from a sore throat, a 5-year-old girl has a petechial rash on the skin of the torso and limbs and bleeding from the gums. The examination revealed a decrease in the number of platelets in the blood. At what level of thrombocytopenia (G/l) do its clinical signs appear?

   What could be the main link in the pathogenesis of thrombophilia in a patient who suffers from thrombophlebitis of the veins of the lower extremities?

   @ Anticoagulant deficiency

5. Thrombocytopenia

   Thrombocytopathy

   Insufficiency of procoagulants

   In order to diagnose what shift in the hemocoagulation system is a study of the level of fibrin degradation products in the blood prescribed?

   Thrombocytopathy

   Thrombocytopenia

   Hemorrhagic vasopathy

6. The patient was diagnosed with a genetic defect in the membrane receptor for von Willebrand factor - glycoprotein (GP) Ib, which is responsible for the initial stage of platelet adhesion to collagen. What is this disease called?

   @ Bernard – Soulier

   von Willebrand

   Addison–Beermer

   Wilson – Konovalov

   Glanzman–Negeli

   The patient was diagnosed with a hereditary defect of GP IIb–IIIa, a membrane receptor that ensures the connection of fibrin with the platelet membrane and is needed for their aggregation. What disease are we talking about?

   @ Glanzman – Naegeli

   von Willebrand

   Addison–Beermer

   Wilson – Konovalov

   Bernard–Soulier

   In a child with combined immunodeficiency, a blood examination revealed a decrease in platelet adhesion to collagen, their aggregation, weakening of blood coagulation and blood clot retraction. In what immunodeficiency are such changes observed?

   @Wiscott–Aldrich

   Swiss type

   Di – Georgie

   Nezelofa

7. The sick girl was diagnosed with Glanzmann's thrombasthenia. What disturbance in the hemostasis system occurs in this case?

   @ Disaggregative thrombocytopathy

   Absolute thrombocytopenia

   Disadhesive thrombocytopathy

   Deficiency thrombocytopathy

   Dysdegranulation thrombocytopathy

   Expedition members who were in the north complained of bleeding gums and petechial hemorrhages on the skin. From the anamnesis it is known that the diet lacked ascorbic acid, and this led to fragility of the vascular wall. What is the pathogenesis of vasopathy?

   @Dysplastic

   Inflammatory

   Metaplastic

   Dystrophic

   Immune

   After a long operation on the pancreas, a patient had a postoperative wound that bled for a long time. According to the coagulogram, a significant increase in plasmin levels was detected. What pathogenesis of coagulopathy is observed in this case?

   @ Fibrinopathy

   Prothrombinasopathy

   Thromboplastinopathy

   Thrombinopathy

   Vasopathy

   The patient was diagnosed with a genetic defect of factor V, which becomes insensitive to inactivation by the antithrombotic complex thrombomodulin–protein C, which reduces the ability of the vascular wall to limit fibrin formation. What blood coagulation pathology will occur with this anomaly?

   @ Thrombophilia

   Thrombocytopenia

   Thrombocytopathy

   Hemorrhagic syndrome

   This group includes genetically determined hypocoagulations, characterized by deficiency, as well as molecular abnormalities of blood coagulation factors.

   Thus, 83-90% of all hereditary bleeding disorders are represented by 2 types of factor VTII deficiency, hemophilia A (70-78%) and von Willebrand disease (9-18%); another 6-13% are due to factor IX deficiency (hemophilia B). Thus, deficiency of only two coagulation factors - VIII and IX - accounts for about 96-98% of all hereditary coagulopathies. Deficiency of factors VII and V is registered in 0.5-1.5%, factor X - in 0.3-0.5% of cases.

   Not all disorders in the blood coagulation system are accompanied by bleeding: it may be absent or mild.

   Hemophilia A. This disease is the most common coagulopathy, which is based on deficiency of factor VIII (antihemophilic globulin), and is the only form among them with recessive, X-linked inheritance.

   The variety of forms of factor VIII pathology reflects the complexity of its structure. Factor VIII circulates in the blood as a protein complex consisting of a number of similar subunits.

   Inheritance. The hemophilia gene, located on the X chromosome, is inherited from a sick man by all his daughters, who in the future inevitably become carriers of the disease, while the sons of the patient remain healthy (due to the fact that they receive the X chromosome from a healthy mother).

   It should also be noted that a woman who is a carrier of hemophilia has the opportunity in 50% of cases to give birth to a healthy son, and half of her daughters become carriers of the hemophilia gene.

   Female carriers, as a rule, do not suffer from bleeding, since the second normal X chromosome provides the synthesis of factor VIII, which in most cases is sufficient to ensure hemostasis.

   However, the norm of factor VIII varies within very wide limits (60-250%). In this regard, in some transmitters the level of factor VIII in plasma can be 11-20%, which creates a risk of bleeding during injuries, operations and childbirth. The doctor should remember this danger when performing surgical interventions on mothers, sisters and especially daughters of patients with hemophilia. Before surgery and before delivery, their plasma factor VIII levels should be checked and, if levels are below 25%, cryoprecipitate should be administered prophylactically at 7-10 U/kg per day.

   Detection of hemophilia gene carriage is facilitated by a detailed study of the family hemorrhagic history of all blood relatives of the patient on the maternal side.

   Hereditary genesis is established in hemophilia A in 70-75% of cases, and in hemophilia B in 90-91%. The hemophilia A gene undoubtedly mutates frequently, since the number of patients has not decreased over many centuries, although until recently a significant proportion of them died before reaching childbearing age, which led to a natural loss of abnormal X chromosomes.

   Symptoms of Coagulation Hemostasis Disorders

   The severity of bleeding depends on the deficiency of factor VIII in the plasma, the content of which is genetically programmed in various hemophilic families.

   The level of factors with a clear antihemophilic effect (VIII or IX), ranging from 0 to 1%, determines the extremely severe course of the pathology in question, the level of factors from 1 to 2% determines severe, from 2 to 5% - moderate, and over 5% - mild course of the disease. In the latter case, there is a possibility of bleeding that poses a serious danger to the patient’s life, which is of particular importance when he undergoes various surgical interventions or in the event of injury.

   The clinical picture of hemophilia is dominated by hemorrhages in large joints of the extremities, deep subcutaneous, intermuscular and intramuscular hematomas, heavy and prolonged bleeding from injuries, hematuria (the appearance of blood in the urine). Other bleedings are observed less frequently, including such severe and dangerous ones as retroperitoneal hematomas, hemorrhages in the abdominal organs, gastrointestinal bleeding, and intracranial hemorrhages.

   A clear age-related evolution of the manifestations of the disease can be traced. At birth, more or less extensive cephalohematomas (bleeding under the periosteum of the skull bones), subcutaneous and intradermal hemorrhages, and late bleeding from the umbilical cord may be observed. Sometimes the disease is detected with the first intramuscular injection, which can cause a large, life-threatening intermuscular hematoma. Teething is often accompanied by not very heavy bleeding.

   In the first years of life, there is often bleeding from the oral mucosa associated with injury from various sharp objects. When a child learns to walk, falls and bruises are often accompanied by heavy nosebleeds and hematomas on the head, hemorrhages in the orbit, as well as postorbital hematomas, which can lead to loss of vision. In a child who has begun to crawl, hemorrhages in the buttock area are typical.

   Then hemorrhages in the large joints of the limbs come to the fore. Acute hemorrhages in the joints appear earlier, the more severe the hemophilia. The first hemorrhages predispose to repeated ones in the same joints. Each patient is affected with particular persistence and frequency by hemorrhages of the 1st - 3rd joint. This is due to morphological restructuring and secondary inflammatory changes in joint tissue.

   It has been established that the synovial membrane is the main, and perhaps the only source of hemorrhage in the joint, since after complete synovectomy (removal of the synovial membrane) such hemorrhages disappear and do not recur. The knee joints are most often affected, followed by the ankle and elbow joints, and then, with a significant difference, the hip joints. Hemorrhages in the small joints of the hands and feet (less than 1% of all lesions) and intervertebral joints are relatively rare. In each patient, depending on the age and severity of the disease, from I - II to VIII - XII joints are affected.

   It is clinically important to distinguish between acute hemorrhages in the joints (primary and recurrent), chronic hemorrhagic destructive osteoarthritis (arthropathy), and secondary immune rheumatoid syndrome as a complication of the main process.

   Acute hemarthrosis is a sudden appearance (often after a minor injury) or a sharp increase in pain in the joint. The skin in the joint area is red and hot to the touch. The pain quickly (within several hours) is relieved after the first transfusion of cryoprecipitate or antihemophilic plasma and disappears almost immediately with the simultaneous removal of blood from the joint. If the pain syndrome is not eliminated with this treatment, then additional pathology should be looked for - intra-articular fracture, condyle avulsion, tissue entrapment.

   Osteoarthritis is divided into stages based on clinical and radiological data. The classification distinguishes 4 stages of joint damage.

   In stage I, or early stage, the volume of the joint may be increased (with widening of the joint space) as a result of hemorrhage. During the “cold” period, the function of the joint is not impaired, but x-rays may reveal thickening and compaction of the joint capsule due to its infiltration with hemosiderin.

   In stage II, typical changes are revealed in the subcartilaginous part of the epiphyses - marginal patterns, the formation of single oval small cellular destructions and cysts. Osteoporosis is more pronounced, the joint space is preserved, but may be moderately narrowed.

   In stage III, the joint is sharply enlarged, deformed, has an uneven and tuberous structure, and pronounced muscle wasting 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 the muscles and tendons. Radiologically, the joints are thickened, sharply deformed, the articular surfaces are flattened, the epiphyses are expanded due to the proliferation of bone tissue, the diaphyses are reduced, and the joint space is narrowed. Osteoporosis is pronounced, intra-articular fractures easily occur. In the femur, a crater- or tunnel-like destruction of the bone substance in the area of ​​the intercondylar fossa, typical of hemophilia, is noted. The patella is partially destroyed. The intra-articular cartilages are destroyed, and movable fragments of these cartilages, often immured in old organized blood clots, are found in the joint cavity. Various types of subluxations and bone displacements are possible.

   In stage IV, the function of the joint is almost completely lost, the joint space is narrowed, is poorly visualized on an x-ray, and is often overgrown with connective tissue. Sclerosis of the peri-cartilaginous parts of the bone is pronounced, combined with the formation of cracks and the formation of cysts in the area of ​​the epiphyses. Pathological intra-articular fractures are possible. Bone ankylosis is extremely rare and, in fact, is never observed unless there has been a history of improper treatment (with prolonged immobilization of the limb).

   With age, the severity and prevalence of articular damage steadily progresses and is aggravated by the occurrence of periarticular hematomas.

   Secondary rheumatoid syndrome (Barkagan-Egorova syndrome), first described by the authors in 1969, is a common form of joint damage in patients with hemophilia. In many cases, it is visible because it is layered on previous hemorrhages in the joints and destructive processes in the joints characteristic of hemophilia. A careful examination of patients makes it easy to diagnose secondary rheumatoid syndrome, which is essential for further proper treatment. This 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, followed by their typical deformation, pain in large joints, which is not relieved, and often worsens after plasma transfusions and cryoprecipitate injections. Also, this syndrome occurs with severe morning stiffness in the joints, steady progression of the articular process regardless of fresh hemorrhages, the appearance or sharp increase in laboratory signs of the inflammatory process, including immunological ones, with an increase in the level of globulins in the blood serum, sialic acids, fibrinogen, an increase in the concentration of circulating immune complexes and, in some cases, the titer of rheumatoid factor. In most patients, 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%.

   With age, the prevalence and severity of all joint lesions steadily progress, which leads to disability and forces patients to use crutches, wheelchairs and other devices.

   The progression of joint damage depends on the frequency of acute hemorrhages in the joints, the timeliness and completeness of their treatment (early transfusion of blood substitutes is very important), the quality of orthopedic care for the patient, the correct use of physical therapy, physiotherapeutic and balneological effects, the choice of profession and a number of other circumstances. Currently, all these questions are extremely relevant, since the life expectancy of patients with hemophilia has increased sharply due to the success of correctional therapy.

   The following types of extensive and intense hematomas are quite severe and pose a danger to the patient: subcutaneous, intermuscular, subfascial and retroperitoneal. Gradually increasing, they can reach enormous sizes, contain 0.5-3 liters of blood or more, lead to the development of anemia in patients, cause compression (compression) and destruction (destruction) of surrounding tissues and the vessels feeding them, necrosis. For example, retroperitoneal hematomas often completely destroy large areas of the pelvic bones (the diameter of the destruction zone is up to 15 cm or more), hematomas on the legs and arms destroy tubular bones and the heel bone. The death of bone tissue is also caused by hemorrhages under the periosteum. These bone destructions on radiographs are similar to tumor destructions (for example, with osteosarcomas). Hematomas often calcify and sometimes lead to the formation of new bones (osteoneogenesis). They can lock joints and completely immobilize them.

   Many hematomas, putting pressure on nerve trunks or muscles, cause paralysis, impaired mobility, sensitivity, and rapidly progressive muscle atrophy. For hemorrhages in the area of ​​the iliopsoas muscle, hip flexion movements are especially characteristic. Particular attention is paid to those hematomas that can cause the development of stenosis of the upper respiratory tract. Such hematomas include hematomas of the soft tissues of the submandibular region, hematomas of the neck, pharynx and pharynx.

   14-30% of all patients with hemophilia develop heavy and prolonged renal bleeding, which poses a serious threat to the patient’s life and is difficult to treat. Such bleeding can occur both spontaneously and in connection with injuries to the lumbar region, concomitant pyelonephritis, and, possibly, due to increased excretion of calcium in the urine due to the destruction of bone tissue in patients with hemophilia. The appearance or intensification of such bleeding can be facilitated by the use of analgesics (acetylsalicylic acid, etc.), abundant blood and plasma transfusions, leading to the development of secondary thrombocytopathy due to additional negative effects on the kidneys. Renal bleeding is often preceded by prolonged microhematuria (a small number of red blood cells in the urine), which is also recorded in the intervals between episodes of macrohematuria (a large number of red blood cells in the urine, visible to the eye).

   The appearance of blood in the urine is often accompanied by severe dysuric symptoms and attacks of renal colic caused by the formation of blood clots in the urinary tract. These phenomena are especially intense and pronounced during the treatment of patients, when normal hemostasis is temporarily restored. The cessation of hematuria is often preceded by renal colic, and often by a temporary absence of urine with azotemia.

   Kidney bleeding is prone to resumption, which over the years can lead to severe dystrophic-destructive changes in this organ, secondary infection and amyloidosis, death from uremia (metabolic products that are normally excreted in the urine enter the blood).

   Heavy bleeding from the gastrointestinal tract in patients with hemophilia can occur spontaneously, although in most cases they are provoked by taking acetylsalicylic acid, butadione and other drugs. The second source of bleeding is clinically pronounced or “hidden” ulcers of the stomach or duodenum, as well as erosive gastritis of various origins. However, diffuse capillary bleeding is sometimes observed without any destructive changes in the mucous membrane. These diapedetic bleedings, in which the intestinal wall is saturated with blood over a large area, quickly lead to anemic coma, acute vascular failure and death.

   Hemorrhages in the mesentery, as well as in the greater and lesser omentum, often create a false impression that the patient has developed an acute surgical pathology of the abdominal organs, such as acute appendicitis, intestinal obstruction, which is especially pronounced in the case of hemorrhage under the serosa in the intestinal wall. The only guideline in such situations can be the rapid effectiveness of intensive replacement therapy. The immediate start of such therapy is recommended in any case - both to eliminate bleeding and in order to prepare the patient for surgery. Then everything depends on the result of the treatment. If, following the jet administration of factor VIII (or IX) concentrate, pain and other signs of an acute abdomen quickly subside, then the patient can be continued to be monitored while intensive replacement therapy continues (uncomplicated internal hemorrhage). If the effect of replacement therapy is not sufficiently pronounced, then surgical intervention is necessary.

   Hemorrhages in the brain, spinal cord and their membranes in hemophilia are almost always associated either with trauma or with taking drugs that impair the hemostatic function of platelets. Between the moment of injury and the development of hemorrhage, there may be a light interval lasting from 1-2 hours to a day.

   A characteristic symptom that distinguishes hemophilia from other pathologies is prolonged bleeding in case of injury and surgery. Lacerated wounds are much more dangerous than linear ruptures. Bleeding often does not occur immediately after injury, but after 1-5 hours.

   Tonsillectomy (removal of the tonsils) for hemophilia is much more dangerous than abdominal surgery.

   Removal of teeth, especially molars, is often accompanied by many days of anemic bleeding not only from tooth sockets, but also from hematomas formed at the site of tissue infiltration with novocaine. These hematomas cause destruction of the jaw. In case of hemophilia, teeth should be removed under the influence of antihemophilic drugs under general anesthesia. It is better to remove several teeth at once.

   Some complications in hemophilia are caused by blood loss, compression and destruction of tissue by hematomas, and infection of hematomas. A large group of complications is also associated with immune disorders. The most dangerous of them is the detection in the blood of patients of a large number of antibodies against blood coagulation factor VIII (or IX), modifying hemophilia into the so-called inhibitory form, in which the main method of treatment - transfusion therapy - almost completely loses its effectiveness. Moreover, repeated administration of antihemophilic drugs often causes a rapid increase in the amount of these antibodies in patients, as a result of which transfusion therapy, which initially gave some effect, soon becomes useless.

   The frequency of the inhibitory form of hemophilia ranges from 1 to 20%, more often from 5 to 15%. In severe forms of hemophilia, inhibitors appear in the blood of patients much more often than in mild forms, and in persons over 12 years of age - much more often than at an earlier age. With inhibitory forms, the hemostatic function of platelets is noticeably impaired, hemorrhages in the joints, blood in the urine become more frequent, and joint damage is significantly higher.

   Other immunoallergic disorders include thrombocytopenia, sometimes combined with leukopenia, autoimmune hemolytic anemia with a positive Coombs test, major eosinophilia, and renal amyloidosis.

   Diagnosis of Coagulation Hemostasis Disorders

   Hemophilia is diagnosed in all patients with hematoma type of bleeding and damage to the musculoskeletal system, as well as in cases of persistent late bleeding during operations. For an indicative diagnosis, it is crucial to identify a decrease in the intensity of blood coagulation (clotting) in such general tests as blood clotting time, activated partial thromboplastin time, and in an autocoagulation test with normal thrombin and prothrombin times.

   In order to determine which of the blood coagulation factors is deficient, correction tests are used using a thromboplastin generation test or an autocoagulation test.

   The type of hemophilia can also be identified by “mixing tests”: plasma samples that lack one of the coagulation factors (VIII, IX or XI) are successively added to the plasma of the examined patient in different test tubes. The absence of normalization of coagulation in one of the test tubes indicates a deficiency of the same factor in both mixed plasmas, i.e., its deficiency in the patient.

   Diagnosis of hemophilia ends with the determination of factor deficiency in quantitative terms, which is important for the correct assessment of the severity of the disease and the implementation of replacement therapy.

   Treatment of Coagulation Hemostasis Disorders

   The main method of treatment and prevention of hemophilic bleeding of any location and any origin is the intravenous administration of sufficient doses of blood products containing factor VIII. Factor VIII is variable and practically not preserved in preserved blood, native and dried plasma. Only direct blood transfusions from a donor to a patient with hemophilia, as well as intravenous infusions of blood products with preserved factor VIII (antihemophilic plasma, cryoprecipitate, factor VIII concentrates of various purifications) are suitable for replacement treatment.

   Direct transfusions from a donor are resorted to only when the doctor does not have any other antihemophilic drugs. It is a serious mistake to receive a blood transfusion from the patient's mother, since she is a carrier of the disease and her factor VIII level is sharply reduced.

   Due to the short half-life of factor VIII in the patient’s blood (about 6-8 hours), blood transfusions, as well as transfusions of antihemophilic plasma, should be repeated at least 3 times a day. To stop massive bleeding and reliably cover various surgical interventions, when the level of antihemophilic factor must be maintained above 30-40%, such blood and plasma transfusions are unsuitable. Although clotting time and recalcification time (saturation of the blood with calcium) are normalized in hemophilia patients when the concentration of factor VIII is increased to 3-4%, this level is not enough to prevent bleeding during surgery. Therefore, during treatment and preoperative preparation, one should focus only on the quantitative determination of factor VIII (or on an autocoagulogram), but not on indicators of total coagulation time, prothrombin consumption test and other methods with a low sensitivity threshold.

   An equal volume of antihemophilic plasma is approximately 3-4 times more effective than fresh canned blood. In single doses of 10-15 ml/kg and daily doses of 30-50 ml/kg, divided into 3 parts (the first dose is 1.5 times more than the next 2), antihemophilic plasma allows you to briefly maintain a 10-15% level of factor VIII . The main danger of such treatment is overload of the patient’s blood circulation with volume, which can lead to the development of pulmonary edema. The use of antihemophilic plasma in concentrated form does not change the situation, since the high concentration of administered albumin (protein) causes intensive movement of fluid from tissues into the blood, as a result of which the volume of circulating blood increases in the same way as when transfusing plasma in normal dilution. Concentrated dry antihemogeneic plasma has only the advantage that factor C is more concentrated in it and in a small volume it is more quickly introduced into the patient’s bloodstream. Before use, dry antihemophilic plasma is diluted with distilled water to 1/3-1/2 of the original volume. Treatment with antihemophilic plasma is quite sufficient to relieve most acute hemorrhages in the joints (except for the most severe), prevent and treat minor bleeding.

   Factor VIII concentrates are the most reliable and effective for hemophilia. The most accessible of them remains cryoprecipitate - a protein concentrate isolated from plasma using cooling (cryoprecipitation), which contains enough factor VIII, fibrinogen and factor XIII, but little albumin and a number of other proteins. The low content of albumin in the drug allows it to be introduced into the bloodstream of patients in very large quantities and increase the concentration of factor VIII to 100% or more, without fear of circulatory overload and pulmonary edema. The main disadvantage of cryoprecipitate is its non-standard activity.

   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 factor VIII concentrates do not have these disadvantages. They can be stored in a regular refrigerator and used in the field.

   The unit of activity of an antihemophilic drug is taken to be the amount of factor VIII contained in 1 ml of “average” donor plasma, i.e. plasma with 100% content of antihemophilic globulin.

   To relieve hemorrhages in the joints and minor bleeding, including their prevention during tooth extraction, it is usually sufficient to increase the level of factor VIII to 15-20%. More dangerous internal and external bleeding, as well as the development of hematomas in soft tissues, require maintaining the factor VIII level above 30-40%, for which cryoprecipitate or other factor VIII concentrates are administered at 20-30 U/kg; for major operations and injuries, hematuria and gastrointestinal bleeding, the dose of cryoprecipitate is increased to 40-60 U/kg, and in some cases - more.

   At the same time, excessive administration of cryoprecipitate is undesirable, since it creates a high concentration of fibrinogen in the blood, as a result of which microcirculation in organs is disrupted and there is a danger of thrombosis and disseminated intravascular coagulation syndrome.

   The frequency of administration of antihemophilic drugs is determined by the extent to which each administration was able to increase the concentration of factor VIII in the plasma. So, if the factor concentration was increased to 40%, then after 6-8 hours it will drop to 20%, and with an initial increase to 120%, the 20% level will be reached only after a day. Modern concentrated preparations of factor VIII (cryoprecipitate, etc.) allow you to limit yourself to 1-2 intravenous administrations per day. A sufficient effect of replacement therapy is achieved only if the following conditions are met: all antihemophilic drugs are administered intravenously only as a stream, in the most concentrated form possible and as quickly as possible after they are re-preserved without mixing with other infusion solutions. One of the main reasons for the failure of replacement therapy is the drip administration of blood products that do not increase the level of factor VIII in plasma.

   Until the bleeding has stopped permanently, the administration of any blood substitutes and blood products (blood products) that do not contain antihemophilic factors should be avoided, as this leads to dilution of factor VIII and a decrease in its concentration.

   Early removal (aspiration) of blood spilled into the joint not only immediately relieves pain, prevents further blood clotting in the joint, but also reduces the threat of the development and rapid progression of osteoarthritis. To prevent and relieve secondary inflammatory changes after blood aspiration, the doctor prescribes the injection of 40-60 mg of hydrocotisone into the joint. Maintenance transfusion therapy carried out during the first 36 days prevents further bleeding and allows you to start physical therapy exercises early, which contributes to a faster and more complete restoration of the function of the affected limb and prevents muscle atrophy.

   Movements in the affected joint should be developed in stages: in the first 5-7 days after removing the immobilizing bandage, active movements are performed both in the affected joint and in other joints of the limb, gradually increasing the frequency and duration of exercises. Subsequently, from the 6th-9th day, they switch to load-bearing exercises, using bicycle ergometers, pedal gates for the arms, and elastic traction bands. And only on the 11-13th day, in order to eliminate residual stiffness and restrictions on maximum flexion or extension, passive load exercises are performed with caution under the control of antihemophilic plasma transfusions or small doses of cryoprecipitate.

   At the same time, from the 5-7th day, physiotherapeutic effects are prescribed - hydrocortisone electrophoresis, anodic galvanization.

   For hemorrhages in soft tissues, more intensive therapy with antihemophilic drugs is required than for hemorrhages in the joints. When the patient becomes anemic, red blood cell transfusions are additionally prescribed. If signs of hematoma infection occur, broad-spectrum antibiotics are immediately prescribed. Any intramuscular injections for hemophilia are contraindicated, as they can cause extensive hematomas and pseudotumors. Penicillin and its semisynthetic analogues are also undesirable, since in large doses they cause platelet dysfunction and increase bleeding.

   Early and intensive therapy with antihemophilic drugs contributes to the rapid reverse development of hematomas. Puncture of hematomas and aspiration of blood from them should be avoided. Transfusion therapy is continued for 5-7 to 14 days. If possible, encysted hematomas are removed surgically along with the capsule under the cover of intensive therapy with antihemophilic factor concentrates.

   In case of nosebleeds, the doctor should not resort to tight tamponade, especially the posterior one, since immediately after removing the tampons, bleeding in such patients almost always resumes with even greater force.

   To stop nosebleeds as quickly as possible, it is necessary to use antihemophilic plasma, as well as antihemophilic drugs in combination with irrigation of the nasal mucosa with a solution of aminocaproic acid, thrombin or adroxon.

   Renal bleeding poses a serious danger to patients, in which transfusions of antihemophilic plasma and small doses of cryoprecipitate are ineffective. The recommended average doses of antihemophilic drugs (30-40 IU/kg) also do not always stop these bleedings or stop them for a maximum of 1-2 days. Prednisolone (20-30 mg/day for adult patients) enhances the effectiveness of antihemophilic drugs.

   To stop gastrointestinal bleeding, large doses of antihemophilic factor concentrates should be used together with aminocaproic acid at a dosage of up to 0.2 g/kg.

   It is worth noting that the use of prednisolone for bleeding in the gastrointestinal tract should be avoided; the most dangerous use of prednisolone for peptic ulcers of both the stomach and duodenum.

   It should be remembered that gastric bleeding is often provoked by taking acetylsalicylic acid, brufen, indomethacin, butazolidones in connection with joint pain, toothache or headache. In patients with hemophilia, even a single dose of acetylsalicylic acid can cause gastric bleeding.

   In the prevention and treatment of chronic osteoarthritis and other lesions of the musculoskeletal system, various methods of protecting joints and preventing limb injuries should be provided. To do this, foam shields are sewn into clothing around the knee, ankle and elbow joints, and all sports associated with jumping, falling and bruising (including cycling and motorcycle riding) are prohibited. An important role is played by the earliest possible and complete treatment of acute hemorrhages in muscles and joints, and intensive year-round physical therapy. To do this, they create complexes of atraumatic exercises in water, on soft mats and loading devices - bicycle ergometers, manual gates. Classes should begin in preschool or primary school age, i.e. before chronic osteoarthritis, mobility impairment and other severe disorders of the musculoskeletal system develop.

   Complex treatment is complemented by physiotherapeutic (high frequency currents, electrophoresis of glucocorticosteroids) and balneological methods of therapy, which include: mud therapy, brine and radon baths. For frequent and persistently recurring hemorrhages in the same joints, the methods of choice are radiotherapy and synovectomy (removal of the synovial membrane of the joint).

   X-ray therapy is carried out at a single dose from 25-50 R (for acute hemorrhages) to 50-100 R for chronic osteoarthritis. Sessions are repeated after 1-2 days, the total dose ranges from 400 to 1000 R. In children under 14 years of age, certain caution is required due to the possibility of damage to bone growth zones, and therefore the total dose should not exceed 400 R. In recent years, it has been used and internal irradiation by injecting radioactive isotopes into the joints.

   Synovectomy, performed through a single incision, is a highly effective method of treating hemophilic joint lesions and preventing severe osteoarthritis. This type of treatment eliminates subsequent hemorrhages in the operated joint and ensures the preservation of its normal configuration and function. This effect is expressed when the operation is performed relatively early - for arthrosis of degrees I - II, and for lesions of degrees III - IV, synovectomy, as a rule, is no longer advisable. Like all other surgical interventions, synovectomy is performed against the background of the use of cryoprecipitate or other concentrates of antihemophilic factors.

   Among other orthopedic interventions, achilloplasty, bone lengthening to restore the joint space, and, in advanced cases, closure of the joints by compression in a physiological position are most often performed. In this case, the devices of Volkov-Oganesyan, Ilizarov and other authors provide an invaluable service, making it possible to reliably and quickly obtain correction without long-term immobilization of the limbs, which is extremely dangerous for patients. Restoring the joint space without using these devices is practically impossible.

   With sufficient replacement therapy with cryoprecipitate (in the first 7-8 days - 30-40 units/(kg h day), then - half as much) patients are provided with completely reliable hemostasis; no bleeding or hemorrhage was observed at the sites where the wires were inserted.

   Modern methods of replacement therapy and the use of orthopedic devices have radically changed the prognosis for bone fractures in patients with hemophilia. If until recently such fractures healed poorly, were often complicated by false joints and even led to the loss of a limb, then under the influence of large doses of cryoprecipitate, while bringing the bones closer together and good fixation with the help of the above-mentioned devices, healing of fractures is ensured in the usual time frame.

   Unsolved therapeutic problems include the fight against osteoporosis, intraosseous cysts and pseudotumors that do not have a tendency to encyst. These processes cause severe complications and sometimes force one to resort to amputation of a limb.

   Treatment of complicated forms of hemophilia. The most dangerous is the detection in the blood of patients with hemophilia of a large number of antibodies against factor VIII, which determine the transformation of hemophilia into an inhibitory form. The inhibitor is capable of inactivating very large amounts of externally administered factor VIII, and therefore the main method of treatment - transfusion replacement therapy - becomes ineffective or completely ineffective.

   During transfusion therapy (from days 4-6), the antibody titer can increase sharply.

   If replacement therapy is needed for health reasons, then it is possible to temporarily overcome the effect of antibodies by administering huge quantities of factor VIII concentrate (500-1000 units/kg) or plasmapheresis (removing several liters of plasma from the patient and replacing it with fresh antihemophilic) together with the administration of megadoses of factor VIII .

   The use of the so-called bypass treatment for the inhibitory form of hemophilia A - the administration of concentrates of factors IX, X and II - turned out to be more promising. Their use in medium doses ensures bleeding stops in half of patients with inhibitory hemophilia. At the same time, the thrombogenicity of these drugs and their ability to provoke the development of disseminated intravascular coagulation and thrombosis are known, especially with the simultaneous use of aminocaproic acid and other hemostatic agents. Such disorders may also develop during bypass therapy for the inhibitory form of hemophilia. For example, cases of the development of myocardial infarction in young hemophilia patients with repeated use of prothrombin complex factor concentrates have been described. According to a number of authors, for inhibitory hemophilia, it is not the usual, but the so-called activated preparations of the prothrombin complex or the factor IX complex that are more effective. However, they are 10 or more times more expensive than non-activated concentrates of the same factors. To reduce the risk of developing DIC and thrombosis, it is recommended to administer these factors with antithrombin III or with pre-deep frozen plasma along with small doses of Contrical.

   Data on the effect of prednisolone on the amount of antibodies in the blood are contradictory, but most authors still note that in patients with hemophilia such treatment is rarely effective. Immunosuppressants (azathioprine, etc.) often reduce the number of antibodies, but their use is dangerous due to the development of thrombocytopenia, which in hemophilia can significantly aggravate hemorrhagic phenomena.

   If patients with an inhibitory form of hemophilia do not have positive dynamics, then when carrying out replacement therapy before surgical interventions, you should always carefully check whether the specified inhibitor is present in the plasma.

   In case of exacerbation of secondary rheumatoid syndrome, as well as during courses of intensive replacement therapy, especially if it does not alleviate, but increases joint pain, prednisolone has a good effect (20-40 mg per day for a month, followed by a gradual reduction in the dose to a minimum).

   Of great importance in the prevention of bleeding is minimizing from early childhood the danger of injuries, cuts, etc. Easily breakable toys (including metal and plastic), as well as unstable and heavy objects, are excluded from everyday life. Furniture should have rounded edges, protruding edges should be wrapped with cotton wool or foam rubber, and the floor should be covered with a pile carpet. It is preferable for patients to communicate and play with girls rather than with boys.

   The correct choice of profession and place of work is important for the patient. In the most severe cases, the only effective method of mitigating the disease is the systematic, once every 10 days, intravenous administration of cryoprecipitate or any other available factor VIII concentrate. A single dose of the drug for such prophylaxis is 400-800 units.

   Of great importance for the prevention of severe damage to the musculoskeletal system is the earliest possible administration of factor VIII drugs for bruises and other injuries, as well as for acute pain in the joint, indicating that blood has begun to leak into it. Immediate administration of concentrates of antihemophilic factors (by a special ambulance team or hemophilic center or by trained parents of the patient) stops the formation or exacerbation of hemorrhages at the very beginning, and prevents destructive changes in the joint. Emergency first aid is the most important component of the physical rehabilitation of patients, the prevention of severe and irreversible changes in joints, bones and muscles. It sharply reduces the number of hospitalizations, the average annual length of hospital stay, and does not distract children from their studies.

   With the intensification of replacement transfusion therapy, the number of people infected with serum hepatitis virus increases, severe reactions to the administration of hemotherapy become more frequent, and a number of other immune disorders occur.

   Genetic prophylaxis for hemophilia has not yet been developed. Determination of sex by examining the sex chromatin and karyotype of amniotic cells obtained by amniocentesis allows for timely termination of pregnancy, but does not indicate whether the fetus is a carrier of the hemophilia gene. Pregnancy is maintained if the fetus is male, since all sons of patients are born healthy, and terminated if the fetus is female, since all daughters of patients with hemophilia are carriers of the disease.

   In female carriers of hemophilia, who have a 50% chance of giving birth to a patient (if the fetus is male) or a transmitter 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, and also simultaneously increases the total number of carriers of the disease.

   The Russian Ministry of Health has approved the drug Revolade (Eltrombopag) for use in children. The new drug is indicated for patients suffering from chronic immune thrombocytopenia (idiopathic thrombocytopenic purpura, ITP), a rare disease of the blood system.

   03.03.2017

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