Drugs preventing thrombosis and improving blood rheology

In the prevention of the formation of multiple microthrombi during shock and their destruction, various pharmacological approaches can be used that use drugs that prevent thrombus formation and improve blood rheology:

• elimination of systemic hemodynamic and microcirculation disorders using vasoactive and inotropic agents;
• measures to improve blood rheology using rational infusion therapy and drugs that restore the elasticity of erythrocyte membranes (trental or pentoxifylline);
• prevention of platelet aggregation and the formation of initial “white” thrombi in small arterial vessels with subsequent initiation of the coagulation cascade;
• inhibition of thrombus formation after activation of the systemic coagulation cascade;
• activation of fibrinolysis with the aim of dissolving newly formed blood clots (fibrinolysin, streptokinase, streptodecase, urokinase, etc.) or, on the contrary, inhibition of fibrinolysis when it is generalized in some patients with traumatic shock and sepsis (aminocaproic acid, amben, contrical, etc.).

Most of the listed approaches are traditional, well-developed in the practice of treating shock, have their own hemorheological indications and are specified in the relevant chapters. Therefore, in this section it is advisable to dwell on the consideration of the general approach to the prevention of thrombus formation in shock using pharmacological agents that affect the prophase of blood coagulation. It is this level of prevention of coagulation complications - the occurrence, formation and growth of "white arterial thrombi" - that attracts the greatest attention of researchers.

Various and often multidirectional disorders of blood coagulation with deterioration of its rheology are characteristic of different types of shock. The most characteristic of septic, endotoxin, burn, traumatic and hemorrhagic types of shock is the formation of multiple microthrombi in the smallest vessels, caused by disorders of systemic hemodynamics, vasospasm and microcirculation disorders, blood thickening, sludge, decreased elasticity of erythrocyte membranes, as well as numerous general and local factors (autocoids) initiating local changes in coagulation hemostasis and the inclusion of the prophase of blood coagulation.

In a schematic (abbreviated) form, the initial stage of hemocoagulation and the mechanism of local hemocoagulation homeostasis are presented as follows.

It begins with the activation of membrane phospholipase A2 as a result of the impact of a combination of damaging factors (direct membrane damage, hypoxia, lipid peroxidation, the impact of endogenous chemical factors, etc.). As a result of the breakdown of membrane phospholipids, non-esterified long-chain fatty acids are released, of which arachidonic acid is the most important as an initial substrate. Its transformation (arachidonic acid cascade) occurs via the lipoxygenase (synthesis of leukotrienes) and cyclooxygenase (synthesis of prostaglandins, thromboxanes, prostacyclin) pathways.

The resulting leukotrienes (B4, C4, E4, D4, etc.) - substances with extremely high biological activity, which include the slowly reacting substance of anaphylaxis - are of great importance in the initiation of local vascular, inflammatory and immune reactions, including autoimmune processes. Leukotrienes cause microcirculation disorders, increased blood clotting, release of autolytic lysosomal enzymes and the release into the blood of a factor that inhibits myocardial contractility and bronchial spasm.

Due to their ability to cause smooth muscle contraction, leukotrienes significantly affect systemic hemodynamics, coronary vessels and myocardium, exerting a powerful coronary constrictor and negative inotropic effect, which is accompanied by a decrease in cardiac output and plays an important role in the development of hypotension.

Reduced cardiac output and hypotensive response to leukotrienes are associated with weakening of the cardiac muscle and limitation of venous return to the heart. Of significant importance in limiting venous return is the ability of leukotrienes to increase the permeability of the vascular wall and cause plasma extravasation. Leukotrienes are considered to be important in the pathogenesis of myocardial infarction.

In anaphylactic and septic (endotoxin) shock, their role apparently increases even more, as evidenced by the ability of leukotrienes to accumulate in significant quantities in plasma during allergic reactions and to cause changes in systemic blood flow characteristic of anaphylactic shock, as well as the protective effects of leukotriene receptor blockers and lipoxygenase inhibitors. The development of selective leukotriene receptor blockers is being carried out quite intensively and is a promising direction of science. In this area, some success has already been achieved and the effectiveness of such blockers in myocardial ischemia, endotoxin and hemorrhagic shock has been experimentally confirmed. However, it will probably take several more years before this direction is clinically implemented.

If in venous vessels thrombi are formed with equal participation of thrombocytes and plasma coagulation factors, then in arteries thrombocytes are the main initiators of the process. They contain ADP, Ca2+, serotonin, phospholipids, enzymes of prostaglandin and thromboxane synthesis, thrombosthenin (like muscle actomyosin provides contractile ability of these cells), thrombogenic growth factor of epithelium and muscle cells of the vascular wall and a number of other substances. Humoral regulation of thrombocyte functions is carried out through specialized receptors of their membranes (alpha2- and beta2-adrenoreceptors, receptors for histamine and serotonin, acetylcholine, thromboxane, adenosine and a number of others). A special property of thrombocytes is a high affinity for collagen and other subendothelial elements of the vascular wall, for non-wetting and negatively charged surfaces. This property provides thrombocytes with an exceptional ability to adhere (stick) to a section of a vessel with damaged endothelium, which has ample opportunity to be damaged during shock. In this case, thrombocytes spread out and release pseudopodia, which can adhere to each other and to the vessel wall. Membrane permeability increases, and ADP, serotonin, thromboxane, and some coagulation factors adsorbed on the surface of the thrombocyte are released from the thrombocytes. These substances interact with the corresponding receptors on the membrane and, with the participation of calcium ions, cause aggregation (initially reversible). The process becomes self-sustaining, which is facilitated by humoral regulatory factors; other factors, on the contrary, can stop it and even reverse it, causing disaggregation.

With the predominance of thrombus-forming influences and conditions, the adhesion and reversible aggregation phases are replaced by the third phase - irreversible aggregation, which is carried out with the participation of thrombosthenin and leads to constriction of the clot; the reaction of strengthening of the aggregant and constriction also occurs with the participation of Ca +, ATP and leads to the formation of a white thrombus.

The cyclooxygenase pathway of arachidonic acid conversion in platelets, vascular endothelial cells and other tissues ensures local (the half-life of metabolites is very short) coagulation homeostasis, since powerful pro- and antiaggregant substances are formed during this metabolism. The main factor activating platelet aggregation in the cyclooxygenase chain of reactions is thromboxane A2, and its no less powerful antagonist is prostacyclin, produced by endothelial cells and, to a lesser extent, prostaglandins of the E and G series. Finally, platelet aggregation is strongly influenced by additional local and systemic humoral factors.

Platelet aggregation activators and inhibitors

Initiators and activators of platelet aggregation	Platelet aggregation inhibitors
Collagen	-
ADP	Adenosine and its stabilizers
Norepinephrine (via alpha2 receptors)	Alpha-adrenergic blocking agents
Serotonin	Antiserotonin agents
Histamine	Antihistamines
Thrombin	Heparin
Ca2+	Ca2+ antagonists
CGMP - its inducers (acetylcholine?) and stabilizers	CAM - its inducers (via beta-adrenergic receptors) and stabilizers (phosphodiesterase inhibitors)
Arachidonic acid	Dextrans, albumin
Thromboxane A2	Prostacyclin I2

Pharmacological interventions in the initial phase of thrombus formation in shock and acute ischemic processes in the heart and brain suggest the following possibility:

1. inhibition of initial reactions (total and partial) of the arachidonic acid cascade;
2. inhibition of a particular reaction of thromboxane synthesis;
3. blockade of receptors for leukotrienes and thromboxanes in platelets, smooth muscle and other cells;
4. the use of substances that modulate platelet aggregation, i.e. weaken in other ways the latter’s reaction to the influence of initiating factors (collagen, thromboxane A2, leukotrienes, etc.).

The implementation of the listed ways of correction of disorders of rheological properties of blood provides for the solution of the main tactical task: to protect receptors of aggregation and adhesion of platelets from the effect of activators or to suppress intracellular mechanisms of synthesis of these receptors. Inhibition of initial reactions of the arachidonic acid cascade can be achieved by protection of platelet receptors that react to polymer activators, using low-molecular dextrans, the molecules of which compete with fibrin, collagen, aggregated immunoglobulin (IgE) and components of the complement system.

By masking the receptors on the platelet membrane and competing with large-dispersed proteins on the surface of erythrocytes, low-molecular dextrans displace them and destroy the bridges between cells. This is due to the fact that dextrans, enveloping the vascular endothelium and the surface of blood cellular elements, increase their negative charge, thereby enhancing antiaggregation properties.

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Dextrans

Low molecular weight dextrans reduce collagen- and ADP-induced platelet aggregation, as well as the activating effect of thrombin on platelets, inhibit the growth of the initial white platelet thrombus, improve blood flow, reduce the postoperative increase in plasma fibrinogen content, and change the structure and stability of fibrin.

Intravenous infusions of dextrans in trauma and shock not only reduce platelet aggregation and adhesion, but also mobilize endogenous heparin, thereby promoting the formation of a loose and poorly retractable blood clot, which is easily lysed by fibrinolytics. The antithrombin activity of low-molecular dextrans is associated with their specific effect on the structure and function of blood coagulation factor VIII. Factor VIII (antihemophilic globulin), a large molecule with a complex structure and function, is involved in platelet aggregation and the stability of the resulting clot. Dextrans interfere with the action of factor VIII, thereby slowing platelet aggregation and reducing clot stability.

Low molecular weight dextrans are not true anticoagulants and their corrective effect in hemorheological disorders is associated mainly with hemodilution, replenishment of circulating plasma volume and improvement of blood flow in the microcirculation system.

The ability of dextrans to improve blood flow in hemodynamic disorders (shock, blood loss) is due to a complex of factors. The occurrence of a high transient concentration of the polymer in the blood not only leads to "direct hemodilution", but also creates conditions for the flow of fluid into the bloodstream from the interstitial space and the subsequent balancing of the osmotic effect of dextran. As a consequence of hemodilution, blood viscosity decreases, venous inflow to the heart increases, and cardiac output increases. Along with these effects, dextrans form complexes with fibrinogen and have an antilipemic effect.

Thus, the antiaggregation action and hemodynamic effects of low-molecular dextrans help to reduce blood viscosity, which is especially important at low shear rates. Disaggregation of blood cells improves systemic blood flow and microcirculation, especially in its venous part, where velocity gradients are the lowest. The use of low-molecular dextran solutions in various types of shock, during surgical treatment of injuries and their consequences, and then in the postoperative period helps to prevent hypercoagulation and reduce the likelihood of thrombotic processes and embolism.

However, it should be noted that in some cases, infusions of dextran solutions are accompanied by anaphylactic and allergic reactions (dangerous in the presence of sensitization and anaphylactic shock). This is due to the fact that dextrans, which have a large molecular weight and many side chains, can act as an antigen. Therefore, to establish individual sensitivity, it is recommended to pre-administer intravenously up to 20 ml of a low-molecular dextran solution as a hapten (15% solution, molecular weight 1000) and conduct infusions of a plasma substitute before the introduction of anesthesia.

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Thrombin inhibitors

Pharmacological protection of platelet receptors interacting with platelet activators can also be achieved using agents that compete with non-polymeric platelet activators or inhibit them. Such agents include thrombin inhibitors (heparin and hirudin, a number of synthetic inhibitors, adrenaline antagonists), alpha-receptor blockers (phentolamine, dihydroergotamine), ADP antagonists (dipyridamole, adenosine and its structural analogs, phosphocreatine), serotonin antagonists (methysergide). Only a few of the listed agents are actually used for the prevention and therapy of shock of various origins.

Protection of intracellular mechanisms of synthesis of protein receptors that react with activators of platelet aggregation and adhesion, and inhibition of thromboxane synthesis processes are possible with drugs of various groups:

1. inducers and stabilizers of cATP, prostacyclin and prostaglandin PgE2;
2. phospholipase and phosphodiesterase inhibitors.

Intensive development of special antiplatelet agents began relatively recently and has not yet led to reliable results. Currently, in clinical practice, in addition to dextran solutions, such antiplatelet agents as acetylsalicylic acid, indomethacin, dipyradamole, sulfinpyrazone (persantin), prostacyclin (eicoprostenone), and heparin are widely used to prevent the formation of white platelet thrombi.

Nonsteroidal anti-inflammatory drugs

It has been established that the pharmacological effects of nonsteroidal anti-inflammatory drugs - acetylsalicylic acid and indomethacin - are due to their effect on the metabolism of eicosanoids (thromboxanes and prostaglandins). Almost all drugs in this group inhibit the enzyme complex known as prostaglandin synthetase, thereby exerting their specific and antiaggregant effects.

Acetylsalicylic acid is absorbed very quickly after oral administration. The product of its hydrolysis, salicylic acid, causes inhibition of platelet cyclooxygenase, which disrupts the conversion of arachidonic acid into prostaglandin O2 and, ultimately, thromboxane A2. Acetylsalicylic acid inhibits aggregation induced by collagen, ADP, adrenaline and serotonin. Although its GG0 5 is 15 minutes, the antiaggregant effect lasts for several days, which is apparently explained by irreversible inhibition of prostaglandin synthesis reactions and suppression of platelet aggregation function throughout their entire life (6-10 days). Along with inhibition of platelet cyclooxygenase, acetylsalicylic acid in high doses inhibits cyclooxygenase of the vascular wall and simultaneously with suppression of thromboxane A2 synthesis inhibits prostacyclin synthesis in endothelial cells. Therefore, acetylsalicylic acid should be prescribed as an antiaggregant in small doses (3000-5000 mg/day), which predominantly inhibit platelet aggregation.

Considering that acetylsalicylic acid blocks platelet cyclooxygenase for several days, and endothelial cyclooxygenase - no more than a day, it is rational to prescribe the drug not daily, but every 3-4 days. The selection of the optimal dose of acetylsalicylic acid for the patient should be carried out individually, since there is a different sensitivity of patients to the antiplatelet effect of the drug. In reactive patients, acetylsalicylic acid in a dose of 0.5 g inhibits platelet aggregation by 40-50%, in hyperreactive patients - completely or by 80-90%, and for areactive patients, the absence of an antiplatelet effect is characteristic when taking the same dose of the drug.

Selective thromboxane synthetase inhibitors are imidazole and its analogues, which do not block cyclooxygenase. Dipyridamole, used in clinical practice in the treatment of chronic ischemic heart disease as a coronary dilator, like imidazole selectively inhibits thromboxane synthetase, preventing the synthesis of thromboxane A2. The drug and its analogues are believed to also inhibit platelet phosphodiesterase, thereby increasing the concentration of cAMP in platelets. Along with this, dipyridamole inhibits the activity of adenosine deaminase and the uptake of adenosine by platelets, blocks the absorption of serotonin by platelets and their aggregation induced by adrenaline and collagen. There are reports of weak antiplatelet activity of the drug and its ability in small doses to enhance platelet aggregation. The most reliable antiplatelet effect can be achieved with a combination of dipyridamole and acetylsalicylic acid.

Heparin

Among antithrombotic agents, one of the most effective regulators of the aggregate state of blood is heparin, especially when used early. Heparin has a high negative charge and is capable of interacting with both large and small ions and molecules (enzymes, hormones, biogenic amines, plasma proteins, etc.), so the spectrum of its biological action is quite wide. The drug has antithrombin, antithromboplastin and antiprothrombin effects, prevents the conversion of fibrinogen to fibrin, suppresses clot retraction, and increases fibrinolysis.

The mechanism of the anticoagulant action of heparin is quite complex. It has now been established that the anticoagulant effects of heparin are associated with the potentiation of the action of antithrombin III and the enhancement of the ability of the heparin-antithrombin III complex to quickly inactivate most of the serine proteases of the blood coagulation system. In the antithrombotic effect of heparin, its ability to increase and maintain a high electronegative potential of the vascular intima, preventing platelet adhesion and the formation of platelet microthrombi, is of great importance. Heparin most actively suppresses thrombus formation in veins, preventing both local thrombus formation and disseminated intravascular coagulation.

Prostacyclin and its stable analogues

Among antiplatelet agents, the most powerful inhibitors of aggregation are prostacyclin and its stable analogues. The antiplatelet effect of prostacyclin is due to stimulation of adenylate cyclase and, as a consequence, an increase in the concentration of cAMP in platelets, a decrease in the content of thromboxane, a decrease in the content of thromboxane A2 and blockade of its receptors. Prostacyclin is unstable and quickly hydrolyzes to inactive products, so it is administered intravenously by drip at a rate of 2 to 20 ng / kg per minute for 30-60 minutes up to 6 times a day.

Prostacyclin, along with a strong antiaggregatory effect, has a powerful vasodilator and bronchodilator effect. The drug dilates the vessels of the brain, heart, kidneys, skeletal muscles and mesenteric vessels. Under the influence of prostacyclin, coronary blood flow increases, the energy supply of the myocardium increases and its need for oxygen decreases. Despite its instability in the body, clinically favorable effects can last for several weeks and even months. The mechanism of such prolonged action is not yet clear.

Prostacyclin is a low-toxic drug, but its use may cause side effects: facial flushing, headaches, decreased blood pressure, abdominal pain, anorexia. Along with prostacyclin, its synthetic stable analogues (iloprost, etc.) are promising inhibitors of platelet aggregation.

Medicines that improve blood viscosity

Disturbances in the rheological properties of blood during trauma and shock are caused not only by changes in the functional activity of platelets, but also by an increase in blood viscosity. The structural viscosity of blood as a complex dynamic dispersed system is largely determined by the viscosity of plasma and the ability of erythrocytes to deform. Plasma viscosity depends mainly on the concentration of proteins in the blood. Proteins with a small molecular weight, such as albumin, have little effect on plasma viscosity, while proteins with a large molecule (fibrinogen, alpha- and gamma-globulins, other macromolecules) significantly increase it.

At low shear rates, adsorption of fibrinogen and globulins on the surface of erythrocytes leads to the formation of bridges between adjacent cells and the formation of aggregates from erythrocytes. The rate of formation of aggregates is a complex biophysical process and depends not only on the magnitude of the shear, but also on the electrokinetic properties of erythrocytes, the concentration, mass and sorption capacity of the macromolecules-aggregators, on the shape and plasticity of erythrocytes.

Maintaining the shape and mechanical properties of the erythrocyte membrane requires significant energy expenditure. It is believed that the energy produced in erythrocytes during glycolysis is spent on phosphorylation of spectrin, which results in changes in the secondary structure of the protein and interaction with neighboring components of the inner membrane. The interaction between the structural proteins of the membrane, spectrin and actin, plays an important role in the formation of the mechanical properties of the erythrocyte membrane, in maintaining a constant surface area of the erythrocyte and its thickness under any deformation.

In case of systemic hemodynamic and organ blood flow disorders, the increase in the rigidity of erythrocyte membranes and the formation of erythrocyte aggregates leads to a decrease in the rate of passage of erythrocytes through capillaries, thereby disrupting the gas transport function of the blood. Therefore, the correction of disorders of the rheological properties of blood in shock should include, along with the prevention of erythrocyte aggregation, the normalization of plasma and blood viscosity, aggregation and deformation of erythrocytes.

In addition to low-molecular dextrans, albumin solutions are one of the effective means of increasing the suspension stability of blood. In the late period of shock, generalized aggregation of erythrocytes occurs against the background of a decrease in the concentration of albumin in the blood plasma and an increase in the concentration of fibrinogen and globulins, especially the alpha2 fraction, lipoproteins and lipids. Under these conditions, the rheological effects of albumin are due to two main factors: hemodilution and normalization of the ratio between micro- and macroglobular proteins in plasma. At the same time, albumin binds free acids, the labilization of which during trauma and shock stimulates the aggregation of cellular structures of the blood and intravascular coagulation and can cause fat embolism.

Anti-shock measures aimed at replenishing the volume of circulating blood, eliminating tissue hypoxia and metabolic acidosis, contribute to the normalization of the elasticity of erythrocyte membranes, since hypoxia and acidosis significantly reduce the deformability of erythrocytes. Increased rigidity of erythrocyte membranes in shock is probably associated with inhibition of ATP synthesis in erythrocytes. In turn, a decrease in the concentration of ATP contributes to an increase in the concentration of Ca2+ in erythrocytes, which, by binding to membrane proteins, increases the rigidity of the membrane.

One of the pharmacological drugs that increases the ATP content in erythrocytes and the elasticity of erythrocyte membranes is Trental (pentoxifylline), which is used in clinical practice to treat ischemic disorders.

Along with reducing the rigidity of erythrocyte membranes, Trental causes vasodilation, improves tissue oxygenation, inhibits phosphodiesterase activity in tissues, increases cAMP concentration and inhibits platelet aggregation.

Among other pharmacological agents that maintain the elasticity of the erythrocyte membrane, it is worth noting Ca2+ antagonists, which limit the flow of ions into erythrocytes (flunarizine, nifedipine, etc.).

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