Indirect anticoagulants in the therapeutic practice of treatment and prevention of venous thromboembolism

Features of the use of indirect anticoagulants

Indirect anticoagulants disrupt the synthesis of coagulation factors in the liver (prothrombin and proconvertin). Their effect appears 8-12 hours after administration and lasts from several days to two weeks. The most important advantage of these drugs is that they have a cumulative effect. Vitamin K antagonists (the second name for indirect anticoagulants) have been used for primary and secondary prevention of thromboembolism for more than 50 years. Vitamin K is an integral part of the coagulation process.

Vitamin K antagonists are called indirect anticoagulants.

Warfarin and other coumarin derivatives are the most commonly used indirect anticoagulants. VKAs (short name for vitamin K antagonists) have many limitations, so you should not start taking them on your own. Only a qualified doctor can select the correct dose based on test results. Regular monitoring of blood counts is of great importance for timely dosage adjustment. Therefore, you need to keep in mind that if your doctor has prescribed you to take warfarin 2 times a day, then you are prohibited from reducing or increasing the dose on your own.

It is also not recommended to resume taking the drug at the same dosage after a long break. Warfarin has a half-life of 40 hours and takes at least 7 days to take effect. The drug is metabolized in the liver and excreted from the body in the urine. Currently, warfarin remains the optimal treatment option for patients with ischemic stroke.

Antiplatelet agents

Antiplatelet agents are medications that prevent thrombosis by interfering with platelet aggregation (sticking together).

Indications for use

Antiplatelet agents are prescribed to prevent thrombosis and its complications (ischemic stroke and myocardial infarction) in high-risk patients: patients with atherosclerotic disease or those who have had a heart attack or ischemic stroke.

pharmachologic effect

Platelets are blood cells involved in the first cellular phase of blood clotting. Normally, they are in the bloodstream in an unactivated form, but when tissue is damaged, platelets are activated, aggregating (sticking together) and adhesion (sticking to the wall of the damaged vessel). Under physiological conditions, this reaction is necessary to clog the damaged vessel with platelet mass and stop bleeding. But under pathological conditions, a rupture of an atherosclerotic plaque may occur inside the vessel, the contents of which have a powerful thrombogenic effect. In this case, platelets are activated, gluing them to each other, forming a blood clot and blocking the lumen of the vessel. In the area of ​​the basin of this artery, acute oxygen starvation occurs. If blood flow is not restored, tissue death – necrosis – will occur.

Classification

• Cyclooxygenase inhibitors (acetylsalicylic acid)
• Thienopyridines (ticlopidine, clopidogrel)
• Phosphodiesterase inhibitors (dipyridamole)
• Glycoprotein receptor blockers (abciximab, tirofiban, eptifibatide)

Basics of therapy

Antiplatelet agents are used primarily for primary and secondary prevention of heart attack and ischemic stroke. Primary prevention is the use of a drug before the onset of a stroke or heart attack in patients with atherosclerotic disease and those at high risk; secondary prevention is the use of a drug after a cardiovascular event has occurred, the main goal of which is to prevent a recurrent stroke or heart attack.

Features of application

Acetylsalicylic acid is used for primary and secondary prevention of cardiovascular accidents, myocardial infarction and ischemic stroke. When using acetylsalicylic acid, it should be taken into account that, along with its pronounced antiplatelet effect, it increases the risk of bleeding; in addition, it may be poorly tolerated by some patients due to its damaging effect on the stomach. If discomfort occurs in the stomach, acetylsalicylic acid is discontinued.

Clopidogrel is an effective antiplatelet agent with proven efficacy. Unlike acetylsalicylic acid, it does not have a specific damaging effect on the stomach, with the associated risk of gastrointestinal bleeding. But it is prescribed for secondary prevention in patients with myocardial infarction, ischemic stroke, or diagnosed peripheral arterial disease.

Dipyridamole currently has extremely limited use. In addition, it can cause steal syndrome in patients with coronary heart disease, manifested by an attack of chest pain when using dipyridamole.

Glycoprotein receptor blockers, a new group of antiplatelet agents, are prescribed in hospital settings for acute coronary syndrome in combination with oral antiplatelet agents.

List of indirect anticoagulants and their mechanism of action

The list of indirect anticoagulants is headed by warfarin (another trade name “Coumadin”). It is one of the most popular medications prescribed to prevent blood clots. Less popular vitamin K antagonist drugs are syncumar, acenocoumarol and dicumarol. The mechanism of action of these drugs is identical: a decrease in the activity of vitamin K absorption, which leads to the depletion of vitamin K-dependent blood clotting factors.

Patients taking warfarin and synonymous anticoagulants should limit daily intake of vitamin K from food and dietary supplements. Sudden changes in vitamin K levels in the body can significantly increase or decrease the effect of anticoagulant therapy.

Recommendations for therapy

The attending physician determines an individual “corridor” within which your coagulability should be. This corridor is determined by your initial disease and the characteristics of your body.

It is important that you realize that going beyond the “corridor”, either in one direction or the other, is very dangerous.

If coagulability is higher than the limit specified for you, the risk of thrombosis increases. If your clotting rate falls below your limit, your risk of bleeding increases.

Regardless of which anticoagulant you are prescribed, you need to check your blood clotting regularly (at least once every 2-4 weeks).

, and depending on the test results, the dose of the drug you take will be adjusted.

When taking anticoagulants, any special diet is usually not recommended. However, it must be taken into account that changes in vitamin K intake from food can change the effect of drugs. You should not exclude foods containing vitamin K from your diet, but it is recommended to consume them in constant quantities (Appendix on vitamin K content in foods)

The full daily dose of warfarin should be taken in one dose (the dose of phenylin is divided into 2 doses), at the same time. The drug is taken orally. If necessary, the tablet or part of it can be chewed and washed down with water. It takes 4-5 days for the full effect of taking warfarin to occur (for phenyline this period is shorter: about 2 days). The effect of the taken dose of the drug lasts for the same amount of time. It is advisable to calculate the weekly total dose of the drug; this will allow you to take an even number of tablets without splitting them (only your attending physician can advise on the exact regimen).

• Never take the drug in a larger dose or more often than prescribed!
• No two people are alike; the dose prescribed for you depends on your disease and your body’s reaction to the drug.
• Regardless of which anticoagulant you are prescribed, you need to regularly check your blood clotting, and depending on the test results, the dose of the drug you take will be adjusted.
• Tell all doctors, dentists, pharmacists and other health care providers who care for you that you are taking anticoagulants. It is advisable to carry with you a “Patient Card Taking Anticoagulants” and a medallion indicating that you are taking anticoagulants!
• Do not take aspirin or products containing aspirin without talking to your doctor. Taking medications from this group together with anticoagulants may cause bleeding. Discuss with your doctor which drug you can take for pain relief (some clinics recommend acetaminophen (Paracetamol).
• Do not take any additional medications that affect blood clotting without consulting your doctor (see Appendix 1 for information on the effect of medications on the effect of anticoagulants).
• Alcohol can affect clotting rates. Small doses are probably not harmful, but in large doses and with sudden changes in intake, it significantly increases the risk of bleeding.
• Many herbal preparations affect susceptibility to anticoagulants, this applies to Ginko Biloba, garlic, coenzyme Q10, cranberry and others. Check with your doctor before you start taking them.
• If you are pregnant, planning a pregnancy, or breastfeeding, discuss this with your doctor! Taking anticoagulants can have a negative impact on the baby's development, so a switch to other medications (for example, heparin injections) may be necessary during pregnancy.

Disadvantages of Vitamin K Antagonists

Warfarin is a real “old-timer” of the pharmaceutical market

Until the end of 2010, a vitamin K antagonist (warfarin) was the only oral anticoagulant approved by the World Health Organization for the prevention of thromboembolic complications in patients with non-valvular atrial fibrillation and the treatment of venous thromboembolism. For half a century, pharmacists have studied in detail the effectiveness of the drug, and also clearly identified the disadvantages and side effects.

The most common include:

• narrow therapeutic window (for poisoning it is enough to take a minimum number of tablets);
• interaction with foods rich in vitamin K (taking the tablets in combination with daily consumption of green vegetables can lead to hyperkalemia);
• delayed anticoagulant effect (this means that several weeks must pass between the start of therapy and the first results). For the prevention of venous thrombosis, this period is too long;
• the need for frequent blood monitoring and dose adjustments;
• the possibility of bruising and bleeding.

What you need to know

Patients prescribed oral anticoagulants should be aware that they have a large number of contraindications and side effects. When taking these medications, you need to follow a diet and take additional blood tests. It is important to calculate your daily dose of vitamin K, since anticoagulants interfere with its metabolism; Regularly monitor laboratory indicators such as INR (or INR). The patient should know the first symptoms of internal bleeding in order to seek help in time and change the drug.

Advantages and disadvantages of direct anticoagulant drugs

Over the past 6 years, new direct anticoagulants have appeared on the pharmaceutical market. They are an alternative to vitamin K antagonists for the treatment of thromboembolism and the prevention of thrombosis. Direct oral anticoagulants (DOAs) are a more effective and safer analogue of vitamin K antagonists.

Direct anticoagulants are the only alternative to vitamin K antagonists

The popularity of PPA among cardiologists and patients is not surprising, because the advantages include:

• rapid onset of action;
• relatively short half-life;
• the presence of specific antidote agents (may be useful in the treatment of acute ischemic strokes, as well as for eliminating post-stroke negative symptoms);
• fixed dosage;
• no direct effect of dietary supplements on the daily dose of the drug;
• no need to undergo regular laboratory blood monitoring.

The most common side effect that occurs after taking DOACs is an increased risk of bleeding. But the perceived threat of severe bleeding is quite small compared to the benefits provided by direct anticoagulants.

Anticoagulant drugs

Artificial anticoagulants, of which a large number have been developed, are indispensable drugs in modern medicine.

Indications for use

Indications for taking oral anticoagulants are:

• myocardial infarction;
• pulmonary infarctions;
• heart failure;
• thrombophlebitis of the leg veins;
• thrombosis of veins and arteries;
• phlebeurysm;
• thrombotic and embolic strokes;
• embolic vascular lesions;
• chronic aneurysm;
• arrhythmias;
• artificial heart valves;
• prevention of atherosclerosis of blood vessels in the brain, heart, and peripheral arteries;
• mitral heart defects;
• thromboembolism after childbirth;
• prevention of thrombosis after surgery.

Heparin is the main representative of the class of direct anticoagulants

Classification of anticoagulants

Medicines in this group are divided into direct and indirect depending on the speed and mechanism of action, as well as the duration of the effect. Direct directly affect blood clotting factors and inhibit their activity. Indirect ones act indirectly: they slow down the synthesis of factors in the liver. Available in tablets, injection solutions, and ointment form.

Direct

Medicines in this group act directly on coagulation factors, which is why they are called fast-acting drugs. They prevent the formation of fibrin threads, prevent the formation of blood clots and stop the growth of existing ones. They are divided into several groups:

• heparins;
• hirudin;
• low molecular weight heparin;
• sodium hydrogen citrate;
• danaparoid, lepirudin.

Heparin ointment is excellent against bruises and is used to treat thrombophlebitis and hemorrhoids

Heparin This is the most famous and widespread direct-acting anticoagulant. It is administered intravenously, subcutaneously and intramuscularly, and is also used as a topical ointment. Heparin-type drugs include:

• Nadroparin;
• Adreparin;
• Parnaparin;
• Tinzaparin;
• Dalteparin;
• Reviparin;
• Enoxaparin.

Topical heparins have low tissue permeability and are not very effective. Used to treat varicose veins of the legs, hemorrhoids, and bruises. The most well-known and often used are the following heparin products:

• Lyoton gel;
• Heparin ointment;
• Trombless gel;
• Venolife;
• Hepatrombin;
• Troxevasin NEO.

Lyoton is a popular heparin-containing agent for external use for varicose veins.

Heparins for intravenous and subcutaneous administration are a large group of medications that are selected individually and are not replaced by one another during the treatment process, since they are not equivalent in action. The activity of these drugs reaches its maximum after about three hours, and the effect continues throughout the day. These heparins reduce the activity of tissue and plasma factors, block thrombin, prevent the formation of fibrin threads, and prevent platelet aggregation.

For the treatment of deep vein thrombosis, heart attack, pulmonary embolism, and angina, Nadroparin, Enoxaparin, and Deltaparin are usually prescribed.

To prevent thromboembolism and thrombosis, Heparin and Reviparin are prescribed.

Sodium hydrogen citrate This anticoagulant is used in laboratory practice. To prevent blood from clotting, it is added to test tubes. It is used for the preservation of blood and components.

Indirect

They reduce the production of certain coagulation factors in the liver (VIII, IX, X, prothrombin), slow down the formation of proteins S and C, and block the production of vitamin K.

These include:

1. Indan-1,3-dione derivatives. Representative - Fenilin. This oral anticoagulant is available in tablets. Its action begins 8 hours after administration, reaching maximum effectiveness within a day. During administration, it is necessary to monitor the prothrombin index and check the urine for the presence of blood in it.
2. Coumarin. In the natural environment, coumarin is found in plants (bison, sweet clover) in the form of sugars. For the first time, its derivative, dicoumarin, which was isolated in the 20s of the 20th century from clover, was used to treat thrombosis.

Indirect anticoagulants include the following drugs:

• Warfarin,
• Acenocoumarol,
• Neodicoumarin.

It is worth dwelling in more detail on Warfarin, the most popular drug. Available in tablets. Its effect occurs after 1.5 - 2 days, maximum effectiveness - after about a week. Warfarin is prescribed for heart defects, atrial fibrillation, and pulmonary embolism. Treatment is often lifelong.

Warfarin should not be taken in case of certain kidney and liver diseases, thrombocytopenia, acute bleeding and tendency to bleed, during pregnancy, lactase deficiency, congenital deficiency of proteins C and S, disseminated intravascular coagulation syndrome, if the absorption of galactose and glucose is impaired.

Warfarin is the main representative of the class of indirect anticoagulants

Side effects include abdominal pain, vomiting, diarrhea, nausea, bleeding, urolithiasis, nephritis, alopecia, allergies. A skin rash, itching, eczema, and vasculitis may appear.

The main disadvantage of Warfarin is the high risk of bleeding (gastrointestinal, nasal and others).

New generation oral anticoagulants (NOACs)

Modern anticoagulants are an indispensable means for the treatment of many diseases, such as heart attacks, thrombosis, arrhythmias, ischemia and many others. Unfortunately, drugs that have proven to be effective have many side effects. But developments do not stop, and new oral anticoagulants periodically appear on the pharmaceutical market. PLAs have both advantages and disadvantages. Scientists are trying to obtain universal remedies that can be taken for various diseases. Drugs are being developed for children, as well as for patients for whom they are currently contraindicated.

New anticoagulants have the following advantages:

• when taking them, the risk of bleeding is reduced;
• the effect of the medicine occurs within 2 hours and quickly ceases;
• the drugs can be taken by patients for whom Warfarin is contraindicated;
• the influence of other drugs and food consumed is reduced;
• inhibition of thrombin and thrombin-binding factor is reversible.

The new drugs also have disadvantages:

• many tests for each product;
• it is necessary to drink regularly, while old medications can be skipped due to their long-term effects;
• intolerance by some patients who had no side effects when taking the old pills;
• risk of bleeding in the gastrointestinal tract.

The list of new drugs is still small. One of the direct NOACs is Dabigatran. It is a low molecular weight anticoagulant and thrombin inhibitor. Most often it is prescribed as a prophylactic agent for venous thromboembolism.

As for indirect anticoagulants, they have not yet been developed that are radically different from Warfarin, Dicumarin, and Sinkumar.

New drugs Apixaban, Rivaroxaban, Dabigatran may become an alternative for atrial fibrillation. Their main advantage is that they do not require constant blood donation while taking them, and they do not interact with other medications. At the same time, these drugs are just as effective and can prevent stroke due to arrhythmia. As for the risk of bleeding, it is either the same or lower.

Trade names of direct anticoagulants and their mechanism of action

The classification of direct-acting drugs is a little more extensive. Dabigatran etexilate (trade name Pradaxa) is a direct thrombin inhibitor. This drug was the first direct oral anticoagulant approved by the medical community. Literally within a few years, rivaroxaban inhibitors (xalerto and edoxaban) were added to the list of direct anticoagulants. Long-term clinical trials have shown the high effectiveness of the above drugs in the prevention of stroke and treatment of thrombosis. DOACs have clear advantages over warfarin, and most importantly, the drugs can be administered without regular monitoring of blood counts.

Pradaxa is the most studied direct-acting anticoagulant

The mechanism of action of DOACs differs significantly from the mechanism of vitamin K antagonists. Each direct anticoagulant contains small molecules that selectively bind to the catalytic site of thrombin. Because thrombin promotes coagulation by converting fibrinogen into fibrin filaments, dabigatran has the effect of blocking these fibrin filaments.

Additional effective mechanisms of direct anticoagulants include platelet deactivation and reduction of blood clotting activity. The half-life of this group of drugs is 7-14 hours, the time for the onset of the therapeutic effect ranges from one to four hours. Direct anticoagulants accumulate in the liver with the formation of active metabolites and are excreted from the body in the urine.

Also, two types of heparins are used as anticoagulants - unfractionated (UFH) and low molecular weight (LMWH). Low-fraction heparin has been used for the prevention and treatment of mild thrombosis for several decades. The disadvantages of UFH are that it has a variable anticoagulant effect, as well as limited bioavailability. Low molecular weight heparin is obtained from low-fraction heparin by depolymerization.

Low molecular weight heparin has a specific molecular weight distribution, which determines its anticoagulant activity and duration of action. The advantage of LMWH is that you can easily calculate the required dosage and not have to worry about severe side effects. For these reasons, it is the low molecular weight heparin that is used in most hospitals around the world.

Heparin solution is used as an anticoagulant.

Consistency and regularity are essential for effective treatment with direct anticoagulants. Because this type of drug has a short half-life, patients who miss doses intentionally or accidentally are at risk for thrombosis or inadequate coagulation. Considering that the positive effect of taking PPA quickly disappears when the drug stops entering the body, it is extremely important to follow the dosage schedule prescribed by your doctor.

Interaction:

Vf interacts with a wide range of drugs, the most important of which are: salicylates, NSAIDs, broad-spectrum antibiotics, barbiturates, phenytoin, clofibrate, oral antidiabetic agents, statins.
These medications can either enhance or weaken the effect of Vf. Therefore, prescribing new drugs, changing the dose or discontinuing medications taken require careful and balanced analysis, as well as more frequent laboratory monitoring. Sinkumar (Acenocoumarol, Acenocoumarin) Release form:
4 mg tablets.

Pharmacodynamics:

Onset of action within 12-24 hours, peak effect on 2-3 days, duration of action up to 4 days.

Pharmacokinetics:

Its properties are close to Vf.

Indications

, contraindications, side effects and complications: see Vf.

Application :

initial doses are 4-8 mg. Maintenance doses are determined by the target INR level.

Phenilin (Atrombone, Fenindione, Emandione, Thrombozol, Thrombofen)
Release form:
in tablets of 30 mg.

Pharmacodynamics:

Onset of action after 8-10 hours, peak effect after 24-30 hours, duration of action up to 3-4 days.

Pharmacokinetics:

Its properties are close to Vf.

Indications, contraindications, side effects and complications:

see Vf.

Application:

initial doses are 30-60 mg.
Maintenance doses are determined by the target INR level. Thrombolytics
The drugs stimulate endogenous fibrinolysis, a natural mechanism for destroying formed blood clots.

The fibrinolytic system of the blood consists of plasminogen and related enzymes, its function is to remove excess fibrin clots to restore vessel patency.

Plasminogen is a glycoprotein that is synthesized in the liver and constantly circulates in the plasma; it is able to bind to the fibrin of the blood clot. After enzymatic transformation (activation) from inactive plasminogen, plasmin is formed - a serine protease, which breaks down fibrin, fibrinogen, as well as blood coagulation factors V, VIII, XII, reduces platelet adhesion and causes their disaggregation.

The main and specific plasminogen activator is tissue plasminogen activator (tPA), produced by endothelial cells. The mechanism of action of tPA can be divided into three stages: a) tPA binds to plasminogen located on fibrin, forming a ternary complex; b) tPA promotes the penetration of plasminogen into fibrin, converting plasminogen into plasmin; c) the resulting plasmin breaks down fibrin and thereby destroys the blood clot.

Some endogenous (urokinase or tissue plasminogen activator of urokinase type, factor XII, kallikrein, kinins) and exogenous factors (bacterial streptokinase and staphylokinase) also have the ability to activate plasminogen.

Plasmin also has antagonists - β2-antiplasmin, whose activity is higher in plasma than in the deep layers of the thrombus, as well as β2-macroglobulin. In turn, there are tPA inhibitors (mainly PAI-1), as well as an exogenous fibrinolysis inhibitor - aminocaproic acid. Thus, the intensity of fibrinolysis is determined by the balance of stimulating and inhibitory influences, both at the action stage and at the activation stage.

Modern fibrinolytic (thrombolytic) agents are based on stimulating the formation of plasmin from endogenous plasminogen, rather than introducing plasmin from the outside. In this case, the systemic effect of the drug will be combined with the local one (on the surface of the blood clot - where fibrin-bound plasminogen is present). Thrombolytics - plasminogen activators include: drugs of a bacterial nature (streptokinase, anistreplase, staphylokinase), tPA drugs (including recombinant and mutant tPA), urokinase and its analogues, and other drugs.

The first generation of thrombolytics (streptokinase, urokinase) does not have fibrin specificity, i.e. activates both fibrin-bound and freely circulating plasminogen. This leads to significant systemic fibrinolysis, depletion of fibrinogen and β2-antiplasmin, which increases the risk of bleeding.

The second generation of thrombolytics (tPA drugs, prourokinase drugs, anistreplase, staphylokinase) is characterized by high specificity for fibrin-bound plasminogen, although it causes moderate systemic fibrinolysis, accompanied by an increased risk of intracranial hemorrhage.

Third generation drugs (mutant forms of tPA - reteplase, tenecteplase, monteplase, lanoteplase; chimeric molecules containing active fragments of tPA or urokinase) along with high selectivity of action have various additional advantages; many of these drugs are still undergoing clinical trials.

The most studied and used thrombolytics are streptokinase and alteplase (tPA drug).

General principles for the use of thrombolytics

1. Thrombolytics should be used as soon as possible after the first symptoms of thrombosis appear. The best results of thrombolysis in ACS with ST elevation are observed within the first 1-4 hours from the onset of clinical symptoms, so thrombolysis begins without waiting for the results of studies on markers of myocardial necrosis, especially since in the first hours of MI the result may be negative. The time from the patient’s admission to the start of thrombolytic administration should not exceed 30 minutes.

2. The main indications for the administration of thrombolytics: MI with ST elevation, massive pulmonary embolism, thrombosis and thromboembolism of peripheral arteries, thrombosis of artificial heart valves, vascular shunts and catheters;

3. The severity of the thrombolytic effect depends on the dose of the administered drug; if the dose is insufficient, the drug is inactivated by β2-antiplasmin; if the dose is excessive, it can cause severe systemic fibrinolysis with dangerous bleeding;

4. Drug-induced fibrinolysis is accompanied by a reactive increase in blood thrombogenicity (mainly due to platelet activation), therefore, to prevent reocclusion in ACS (15-20% of patients), it is necessary to simultaneously prescribe antiplatelet agents (aspirin) and antithrombins (iv heparins) for for several days;

5. The decision to prescribe thrombolytics is made after carefully weighing the possible benefits and risks of such treatment. When there are relative contraindications to thrombolysis, surgical intervention is sometimes preferable if it is possible in a short time;

6. The positive effect of thrombolysis on the prognosis of ACS is significantly stronger in more severe patients; it increases in proportion to the risk of death.

7. In 10-40% of patients with arterial thrombosis, thrombolytics may be ineffective. Possible reasons for the ineffectiveness of thrombolysis in ACS are: non-thrombotic arterial occlusion (plaque hemorrhage, dissection, occlusion with a piece of tissue after PCI, severe spasm due to cocaine poisoning), poor access of thrombolytics (perfusion disorders due to cardiogenic shock or poor collateral blood flow), some features of thrombosis;

8. The main complication of thrombolytic therapy is bleeding, incl. intracranial hemorrhages. Streptokinase and anistreplase (APSAK) are also characterized by allergic reactions and, rarely, anaphylactic shock. If repeated fibrinolysis is necessary within 5 days to 12-24 months after previous use of streptokinase or APSAC, other thrombolytics should be used to prevent resistance and anaphylaxis due to the possible development of antistreptococcal antibodies;

9. Since all thrombolytics are protein drugs, they are administered intravenously (less often intracoronary) without mixing with other drugs. Due to the short half-life, a relatively long or repeated intravenous infusion of the drug is necessary to realize the effect. The exception is drugs with a longer half-life (anistreplas, reteplase, tenecteplase), which can be administered as a single bolus, which is convenient in the prehospital stage;

10. Constant monitoring of the patient is required for at least 3, and preferably 24 hours after the start of thrombolysis to assess its effectiveness and timely recognition of complications.

Indications for prescribing thrombolytics for OK

WITH

1. MI with ST segment elevation within the first 12 hours from the onset of clinical symptoms, provided ST elevation is more than 1 mm in at least 2 adjacent precordial leads or at least 2 adjacent leads from the limbs (adjacent leads in the frontal plane are determined sequence: aVL, I, inverted aVR, II, aVF, III.)

2. MI within the first 12 hours from the onset of clinical symptoms and the occurrence of a “new” or presumably “new” complete block of the left bundle branch

3. Thrombolysis is also advisable for posterior-basal MI within the first 12 hours from the onset of clinical symptoms (posterior-basal or true posterior MI, characterized by the appearance of high R in V1-2, manifests ST depression in V1-3 and/or isolated ST elevation in the posterior leads (V7-8) and often high pointed T-waves in V1-3)

4. Late thrombolysis for ST-segment elevation MI (within 12-24 hours after the onset of symptoms) is justified if ischemic symptoms persist and ST elevation is more than 1 mm in at least 2 adjacent chest leads or at least 2 adjacent leads from the limbs.

Contraindications to the use of thrombolytics

Absolute:

Intracranial hemorrhage of any nature; known structural abnormalities of intracranial vessels (eg arteriovenous malformation); intracranial malignant tumor (primary or metastatic); ischemic stroke within 3 months (excluding acute ischemic stroke less than 3 hours old); suspected aortic dissection; active bleeding (excluding menstruation) or hemorrhagic diathesis; significant closed head injury or facial injury within the previous 3 months.

Relative (considered based on likely benefits and risks)

: history of long-term severe, poorly controlled arterial hypertension (AH); severe uncontrolled hypertension on admission (SBP > 180 mmHg or DBP > 110 mmHg; eliminating hypertension does not reduce risk); history of ischemic stroke more than 3 months ago, dementia, or previously established intracranial pathology not listed above; traumatic or prolonged (>10 minutes) cardiopulmonary resuscitation, trauma, or major surgery, including retinal laser therapy

It should be noted that there is no single list of contraindications to thrombolysis. So, there are recommendations that add acute pancreatitis and thrombocytopenia to absolute contraindications

Complications of thrombolytic therapy

Complications of thrombolytic therapy are associated either with the main mechanism of action of thrombolytics (bleeding, hypotension, chills, reperfusion arrhythmias) or with antigenic properties (anaphylaxis, rash, fever, vasculitis, pneumonitis, etc.)

Therapeutic measures for the most common complications:
1. Bleeding
(a consequence of plasminemia and fibrinogen depletion, noted in 5-15% of patients, in 0.2-1.0% of patients - intracranial hemorrhage)

Clinic:

bleeding from the nose, from the mouth, from the site of venous puncture, vomiting of coffee grounds, melena, persistent hypotension and tachycardia, with intracranial hemorrhage - mental and consciousness disorders, focal symptoms. Risk factors for intracranial hemorrhage include old age (over 75 years), low weight (175 mm Hg or diastolic blood pressure >110 mm Hg during hospitalization.

Activity:

- for minor bleeding: apply pressure, pack the bleeding site for 20-30 minutes, apply local hemostatic agents.

- in case of severe life-threatening bleeding (from the gastrointestinal tract, intracranial):

a) stop administering thrombolytics, heparin, aspirin;

b) urgently assess the level of hemoglobin, hematocrit, platelets, fibrinogen, prothrombin, APTT;

c) consider neurological symptoms that occur within 24 hours after the start of reperfusion to be associated with intracranial hemorrhage until proven otherwise (consultation with a neurologist and neurosurgeon, MRI or CT upon request);

d) protamine sulfate 50 mg IV over 1-3 minutes to neutralize the effects of heparin (1 mg per 100 units of heparin administered over the previous 4 hours); red blood cell transfusion (hypotension or decreased hematocrit

e) administration of 10 doses of cryoprecipitate intravenously (at low levels of fibrinogen, which can persist for 30 hours after administration of stereptokinase, 6-8 hours after administration of tPA);

f) if ineffective, repeat the administration of cryoprecipitate, 2-4 doses of fresh frozen plasma,

g) platelet transfusion if bleeding continues.

h) fibrinolysis inhibitors if the above measures are ineffective: aminocaproic acid 5 g (100 ml of 5% solution) IV for 1 hour, then 1 g/hour (5% solution 20 ml/hour) for 8 hours; or aminomethylbenzoic acid (PAMBA, “gumbix”, “striptosolute”) 1-3 g IV 3-4 times a day; or tranexamic acid (cyclocaprone, frenolysis) 1-1.5 g IV drip 3 times a day; or aprotinin (trasylol, contrical, gordox) 300,000 units intravenously.

2. Hypotension

(10-15% of patients, caused by activation of bradykinin due to high levels of plasmin in the blood; more often occurs during treatment with streptokinase and anistreplase, depends on the rate of drug administration)

Activity:

a) raise the patient’s legs;

b) infusion therapy (saline or 5% glucose);

c) temporarily slow down or stop thrombolytic administration and resume if SBP >90 mmHg;

d) if hypotension persists - vasopressors (dopamine);

e) for initial hypotension, the use of tPA is preferable.

3. Chills

(reaction to plasminogen breakdown)

Activity:

promedol 2% 1 ml i.v.

4. Reperfusion arrhythmias

Activity:

a) Bezold-Jarisch reflex - vagotonia during reperfusion (bradycardia and hypotension): atropine, intravenous infusions, temporary pacemaker, adrenergic agonists for persistent hypotension - norepinephrine 5-30 mcg/min IV;

b) bradycardia, pauses, complete AV block due to ischemia:

atropine, intravenous infusion, rarely - external pacemaker;

c) idioventricular rhythm

(with PCH

d) ventricular tachycardia

-for short runs does not require treatment (observation for 10 minutes);

- for persistent VT, ventricular fibrillation - intravenous lidocaine 60-100 mg bolus (3-5 ml of 2% solution), if necessary, repeat after 10-15 minutes, then intravenous drip 1-4 mg/min or (10 ml of 2% solution per 200 ml of 0.9% NaCl at a speed of 20-80 drops/min)

-cardioversion with synchronization, defibrillation on demand.

5. Anaphylaxis

(0.2% of patients have an allergic reaction when streptokinase is administered)

Clinic:

often shock, loss of consciousness, stridor, bronchospasm, often in combination with urticaria, erythema, Quincke's edema.

Activity:

a) stop administering streptokinase;

b) tracheal intubation (or conicotomy, tracheotomy) for breathing problems;

c) adrenaline 0.1% 1-5 ml IV stream, then 1-4 mcg/min drip (1 ml 0.1% adrenaline per 200 ml 0.9% NaCl (5 mcg/ml) at a rate of 4- 16 drops/min)

d) infusion therapy (up to 1 liter of 0.9% NaCl in a stream, i.e. in 10-15 minutes)

e) IV corticosteroids: hydrocortisone 100-200 mg (prednisolone 60-120 mg) every 4-6 hours for 24 hours (effect after 2-6 hours);

f) antihistamines: H1-histamine blockers IV (diphenhydramine 1% 2.5-5 ml every 6-8 hours) + H2-histamine blockers IV (ranitidine/famotidine) or orally (300/40 mg every 6-8 hours );

g) bronchodilators for bronchospasm through a nebulizer (salbutamol (ventolin nebula, sterineb-salamol) 0.5 ml solution in 2-5 ml 0.9% NaCl or berodual 0.5-1 ml (10-20 drops) as required ( every 15-20 min - 3-6 hours); aminophylline solution (saturating dose 5-6 mg/kg (15-20 ml of 2.4% solution in 100 ml of 0.9% NaCl) IV drip for 20 min, then 0.2-0.9 mg/kg/h (1.0-4.0 ml/h via infusion pump: 10 ml 2.4% aminophylline + 10 ml 0.9% NaCl).

6. Rash

(2-3% of patients with the introduction of streptokinase, immunocomplex allergic reaction)

Activity:

a) stop administration of SA; if the dose is incomplete, administer 50 mg of alteplase;

b) antihistamines intravenously (diphenhydramine 1% 5 ml); or suprastin or tavegil intramuscularly;

c) IV corticosteroids on demand: hydrocortisone 100-125 mg (prednisolone 60 mg) every 6 hours;.

7. Fever

(in 5% of patients with the introduction of streptokinase)

Activity:

aspirin, paracetamol (up to 4 g/day)

Characteristics of the main thrombolytics

Streptokinase

(Avelysin, Cabikinase, Streptase, Celiase)

Release form:

ampoules and bottles containing 100,000, 250,000, 500,000 and 1,500,000 units of sterile powder.

Mechanism of action:

Streptokinase (SK) is an enzyme of β-hemolytic streptococcus C, an indirect plasminogen activator. Activates plasminogen, both associated with a blood clot and circulating in the blood. The action consists of covalent binding to one plasminogen molecule to form the active streptokinase-plasminogen complex, which is involved in the conversion of the second plasminogen molecule to plasmin. The resulting plasmin is partially inactivated by antiplasmins (the degree of neutralization depends on the administered dose), the remaining part causes systemic fibrinolysis, including at the site of thrombus formation. The destruction of circulating fibrinogen and other coagulation factors is accompanied by a decrease in fibrinogen concentration, an increase in the level of fibrin and fibrinogen degradation products (FDP), and an increase in thrombin time (TT) and activated partial thromboplastin time (APTT).

Thus, SC is a nonspecific thrombolytic, because causes pronounced fibrinolysis not only at the site of thrombosis, but also in the plasma, which increases the risk of bleeding.

Pharmacodynamics and pharmacokinetics: After intravenous administration of 1,500,000 units of SC, the effect reaches a maximum after 45 minutes and persists for several hours. In this case, the level of plasma fibrinogen can remain reduced for up to 30 hours. SA has a short half-life (10-23 min), which requires prolonged infusion, but the active streptokinase-plasminogen complex has a half-life of about an hour, which causes a significant prolongation of the effect. SA is metabolized by hydrolysis, clearance slows down with liver damage, but not with renal failure.

Use for myocardial infarction: intravenous infusion of 1.5 million units over 30-60 minutes. First, the SC is diluted in 5 ml of 0.9% NaCl, avoiding shaking and shaking to prevent foaming, then diluted in 0.9% NaCl to a total volume of 100 ml. Sometimes the first 50 ml of the resulting solution (750,000 units) is administered in 10 minutes, then, after a 15-minute break, the remaining 50 ml is also administered in 10 minutes. With faster administration of SA (in 30 minutes), the effectiveness may be slightly higher, but the risk of hypotension increases significantly.

Heparin, due to the pronounced fibrinolytic effect of SA, is not administered or is prescribed intravenously to persons with a high probability of thrombotic complications (extensive or anterior MI, atrial fibrillation, previous thromboembolism, thrombus in the left ventricular cavity). Before the start of the SA infusion and after its completion, sometimes 100 mg of hydrocortisone (or from 30 mg to 180-240 mg of prednisolone) is administered intravenously. Persons at high risk of allergic reactions are additionally prescribed H1-blockers of histamine (2-5 ml of 1% diphenhydramine solution IV). In the absence of contraindications, all patients are prescribed aspirin (160 mg/day).

Contraindications and side effects of SC are common to all thrombolytics.

Advantages:

low cost, no need for concomitant administration of heparin, lower risk of intracranial hemorrhage compared to tPA (especially in people over 75 years of age), relative effectiveness in cardiogenic shock (compared to tPA), good study.

Flaws:

less effective compared to tPA, low selectivity, high risk of bleeding and hypotension during administration due to significant systemic fibrinolysis, allergenicity, inconvenience of use in the prehospital stage, impossibility of re-use more than 5 days after initial use.

Urokinase (Abbokinase)

Release form:

bottles containing 5000, 9000 and 25000 units of UK in powder form.

Mechanism of action:

Urokinase (UK) is a tissue plasminogen activator preparation of the urokinase type, a direct plasminogen activator. The thrombolytic effect is similar to SK. Just like KS, it causes significant plasminemia, accompanied by hypofibrinogenemia, accumulation of PDP, prolongation of TT and APTT.

Pharmacodynamics and pharmacokinetics:

The peak of action after intravenous administration occurs after 15-30 minutes, the effect persists for several hours, but hypofibrinogenemia and an increase in PDP can persist for 24 hours. The drug is destroyed in the liver by hydrolysis, the half-life of UA is 10-20 minutes, it lengthens with liver failure.

Use for MI:

2 million units IV bolus or 1.5 million units bolus followed by 1.5 million units IV infusion over 60 minutes. At the same time, heparin is prescribed intravenously for at least 48 hours (bolus of 60 units/kg, but not more than 4000 units, then infusion of 12 units/kg/hour, but not more than 1000 units/hour) and aspirin (160 mg/day) .

Advantages:

does not cause sensitization; unlike SC, it can be reused.

Flaws:

lower efficiency compared to tPA, low selectivity, high cost.

Anisoylated streptkinase plasminogen activator complex (APSAC)

(APSAC, Anistreplase, Eminase)

Release form:

bottles containing 30 units (30 mg) of sterile powder.

Mechanism of action:

APSAK - streptokinase-acylated human plasminogen complex. In this complex, plasminogen is activated after deacylation, which occurs quite quickly only in the presence of fibrin, i.e. in the area of ​​the thrombus. Thus, partial specificity of the action of APSAC is ensured. The fraction of the drug circulating in the blood undergoes deacylation at a slower rate than in the thrombus area, causing very moderate systemic fibrinolysis.

Pharmacodynamics and pharmacokinetics:

After IV administration, the effect of APSAC occurs immediately, thrombus lysis is observed 45 minutes from the start of the infusion, the duration of action is about 6 hours (half-life - 90-105 minutes), so the drug can be administered as an IV bolus once. Metabolism occurs by hydrolysis. Impaired liver and kidney function do not affect the clearance and elimination of the drug.

Use for MI:

30 units IV over 3-5 minutes. Preparation of the drug: slowly add 5 ml of water for injection to a bottle with 30 units of medication, avoiding foaming. The finished solution should be colorless or have a light yellow tint; it is administered no later than 30 minutes after preparation.

Advantages:

partial selectivity, hypotension rarely occurs, no need for concomitant administration of heparin, ease of use in the prehospital stage (bolus administration).

Flaws:

allergenicity, impossibility of re-use more than 5 days after initial use.

Tissue plasminogen activator

(Alteplase, Activase, Actilyse)

Release form:

sterile powder in bottles of 20 mg, 50 mg and 100 mg of tPA and bottles with sterile water for dilution, respectively, of 20, 50 and 100 ml.

Mechanism of action:

Tissue plasminogen activator (tPA) is a physiological direct plasminogen activator. It has fibrin specificity, because causes the conversion of plasminogen to plasmin mainly in the presence of fibrin - in the area of ​​​​the blood clot. Activation of plasminogen in the systemic circulation occurs much more slowly, and it is quickly neutralized by antiplasmins. However, the administration of large doses of tPA, necessary for complete dissolution of the thrombus, is often accompanied by plasminemia, which can cause complications, including intracranial hemorrhages. Recombinant tPA is used in clinical practice.

Pharmacodynamics and pharmacokinetics.

The action develops immediately after intravenous administration, the peak effect occurs after 90-120 minutes. The half-life of tPA is 4-8 minutes, metabolism occurs in the liver by hydrolysis. Clearance worsens with impaired liver function.

Use for MI:

Accelerated method (recommended): IV bolus of 15 mg, then IV infusion at a dose of 0.75 mg/kg (but not more than 50 mg) over 30 minutes, then 0.5 mg/kg over 60 minutes (but no more than 35 mg). The total dose of tPA should not exceed 100 mg. Alternative dosage regimen (if 6 to 12 hours have passed since the onset of MI symptoms): for persons weighing more than 65 kg - 10 mg IV bolus, then 50 mg over 60 minutes (no more than 60 mg in the first hour), then continue infusion at a rate of 20 mg/h for 2 hours (total 100 mg in 3 hours); for persons weighing less than 65 kg - infusion at a dose of 1.5 mg/kg over 3 hours.

Preparation of the drug:

dissolve the contents of the bottle in the supplied water for injection (the resulting concentration is 1 mg/ml); if necessary, the resulting solution can be diluted with 0.9% NaCL to a minimum concentration of 0.2 mg/ml.

Heparin is prescribed simultaneously with tPA, without combining them in the same solution. Initially (before tPA infusion), heparin is administered intravenously as a bolus at a dose of 60 units/kg, but not more than 4000 units, then the intravenous infusion is continued at a rate of 12 units/kg/hour (but not more than 1000 units/hour) at least 48 hours (aPTT prolongation is no more than 1.5-2 times the initial value; or 50-70 s). Aspirin is prescribed orally before the start of thrombolysis or immediately after the end of tPA administration.

Advantages:

high efficiency (more than SC), high specificity, good tolerability, low antigenicity, reusability.

Flaws:

high cost, increased risk of intracranial hemorrhage compared to SC, inconvenience of use at the prehospital stage (the need for long-term IV infusion).

Reteplase

(Rapilizin, Retavaza)

Release form:

sterile white powder in bottles of 10 units of reteplase, bottles with sterile water for dilution of 10 ml

Mechanism of action:

a mutant form of TAP, created by cleaving off part of the original molecule (3 domains) - a single-chain non-glycosylated mutant of TAP. It has less fibrin specificity than tPA, but a longer half-life, which allows the drug to be administered as a bolus.

Pharmacokinetics.

The half-life of reteplase is about 15 minutes.

Use for MI:

twice 10 units IV bolus (over 2 minutes) with an interval of 30 minutes after the first dose.

Preparation of the solution:

Dissolve the contents of the bottle in 10 ml of the supplied water for injection (concentration 1 U/ml), avoiding shaking.

Advantages:

(see TAP) + ease of use at the prehospital stage

Flaws:

(see tPA) + reteplase is somewhat inferior in effectiveness to tPA when there is a delay in the start of treatment (later than 4 hours from the first symptoms of MI).

Tenecteplase

(TNKase)

Release form:

whitish powder in 50 mg bottles and 10 ml bottles with sterile water for dilution.

Mechanism of action:

a mutant form of tPA created by replacing amino acid residues in three sections of the original molecule. This resulted in increased fibrin specificity, prolonged half-life, and resistance to the effects of plasminogen activator inhibitor type 1 (PAI-1).

Pharmacokinetics.

The half-life of tenecteplase is approximately 20 minutes.

Use for MI:

IV bolus over 5 s at a dose of 0.5 mg/kg (0.1 ml/kg). At a dose of 30 mg (6 ml) per weight

Preparation of the solution:

Dissolve the contents of the bottle in 10 ml of the supplied water for injection (concentration 5 mg/ml), avoiding shaking.

Advantages:

(see reteplase) + perhaps a slightly lower incidence of hemorrhagic complications compared to tPA.

Flaws:

high cost, increased risk of intracranial hemorrhage.

Figure 2

Thrombolysis card option

LITERATURE

1. Basic and clinical pharmacology / Sub. ed. B.G. Katsunga. Per. from English edited by E.E. Zwartau: In 2 volumes. - M.: Binom - St. Petersburg: Nevsky Dialect, 1998. - T.2. — P.26-43.

2. Vavilova T.V., Kadinskaya M.I., Orlovsky P.I., Polezhaev D.A. Laboratory monitoring of anticoagulant therapy in surgical patients. Methodical recommendations / Ed. prof. V.L. Emmanuel and prof. V.V. Gritsenko. - St. Petersburg: St. Petersburg State Medical University Publishing House, 2002. - 56 p.

3. Metelitsa V.I. Handbook of clinical pharmacology of cardiovascular drugs / 2nd ed., revised. and additional - M.: BINOM Publishing House - St. Petersburg: Nevsky Dialect, 2002. - 926 p.

4. Register of Medicines of Russia. Encyclopedia of drugs. M.: RLS, 2004. - 1497 p.

5. VNOK recommendations for the treatment of acute coronary syndrome without persistent ST segment elevation on the ECG. - 2003. - 42 p.

6. Recommendations for the provision of emergency medical care in the Russian Federation / Ed. A.G. Miroshnichenko, V.V. Ruksina / 2nd ed., revised. and additional - St. Petersburg: “Nevsky Dialect” - “BHV-Petersburg”, 2004. - 224 p.

7. Ruksin V.V. Emergency cardiology / 4th ed., revised. and additional St. Petersburg: “Nevsky Dialect”, 2000. - 503 p.

8. Vidal reference book. Medicines in Russia: Directory. M.: AstraPharmServis, 2003. - 1488 p.

9. Alpert JC and Thygesen K., et al. Myocardial Infarction Redefined - A Consensus Document of The Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. The Joint European Society of Cardiology/American College of Cardiology Committee. // JACC. - 2000. - Vol.36, No. 3. - P.959-969.

10. Antman EM et al. ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction-Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction) // JACC. - 2004. - Vol. 44, No. 3. - P. 671-719.

11. Bertrand ME et al. Management of acute coronary syndromes in patients presenting without persistent ST segment elevation. The Task Force on Management of acute coronary syndromes of the European Society of Cardiology. // Eur Heart Journal. - 2002. - Vol.23. — P.1809-1840.

12. Braunwald E. et al. ACC/AHA Guidelines for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina) // Journal of the American College of Cardiology. — 2000. -Vol. 36, no. 3. - P.970-1062.

13. Braunwald E. et al. ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction-Summary Article A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina) // JACC. — 2002. -Vol. 40, no. 7. - P.1366-1374.

14. Management of acute coronary syndromes: acute coronary syndromes without persistent ST segment elevation. Recommendations of the Task Force of the European Society of Cardiology. // Eur Heart Journal. - 2000. - Vol.21. — P.1406-1432.

Is it possible to combine direct and indirect anticoagulants?

As has already become clear, anticoagulants are used for therapeutic and prophylactic purposes for heart attacks, angina pectoris, vascular embolism of various organs, thrombosis, and thrombophlebitis. In acute conditions, direct anticoagulants are usually prescribed, which provide an immediate effect and prevent blood clotting. After 3-4 days (subject to the success of primary treatment), therapy can be enhanced with indirect anticoagulants.

Combined anticoagulant therapy is also carried out before operations on the heart and blood vessels, during blood transfusions, and also for the prevention of thrombosis. Treatment with a combination of different types of anticoagulants should be carried out under the constant supervision of medical professionals. Due to the increased frequency of angina attacks and paroxysmal atrial fibrillation, when treated with two types of drugs simultaneously, the presence of sediment in the urine, the rate of blood clotting and the level of prothrombin in the blood are constantly monitored.

Combined anticoagulant therapy should occur under medical supervision

Treatment with a combination of different anticoagulants is contraindicated in:

• hemorrhagic diathesis;
• diseases accompanied by decreased blood clotting;
• during pregnancy;
• liver and kidney dysfunction;
• malignant neoplasms;
• peptic ulcer disease.

It is also necessary to urgently interrupt combination therapy if blood appears in the urine.

Prescription of medications, indications and contraindications

Medicines are manufactured in tablets, injection solutions, ointments, and gels. Anticoagulants are intended to treat and prevent the formation of blood clots. Active components affect the production of elements of the coagulation system, reduce the rate of formation of blood clots settling on the inner surface of blood vessels.

Anticoagulant medications are prescribed:

• for acute venous thrombosis;
• preventing the occurrence of thromboembolism - when replacing heart valves, supraventricular tachyarrhythmia;
• heart attacks, blockages of arterial vessels in the lungs;
• ischemic strokes;
• atherosclerotic vascular damage;
• injuries, shock, septic lesions;
• varicose veins;
• hemorrhoids with blood clots;
• formation of blood clots in the IVC.

Medications are not used:

• with lactose deficiency, impaired absorption of galactose, glucose;
• gastrointestinal ulcers, aneurysms;
• renal, liver pathologies;
• bleeding, thrombocytopenia.

The simultaneous use of anticoagulants with Aspirin, Penicillin, Dipyridamole, Cimetidine and other representatives of the NSAID group is prohibited.

During therapeutic procedures, adverse reactions may occur, which occur due to incorrectly selected doses of drugs or violation of the treatment regimen. General symptoms include attacks of nausea with vomiting, diarrhea, pain in the abdomen, allergies with nettle fever. Sometimes massive hair loss and necrosis begin.

How to determine the effectiveness of taking anticoagulants?

Indirect coagulants are easy to detect in the blood and even measure their effectiveness. For this purpose, a special indicator called “international normalized ratio” has been developed.

1. A person not taking indirect anticoagulants will have an INR just below 1.
2. A patient taking warfarin will have an INR between 2.0 and 3.0. Seeing such high numbers, doctors will be prepared for the possibility of sudden bleeding.
3. An INR between 1 and 2 will indicate that the patient may be at risk of developing an ischemic stroke.
4. With an INR of 4 or higher, there is the greatest risk of blood non-coagulation and the development of hemorrhagic stroke.

A blood test for INR is indicative of therapy with indirect anticoagulants

But a blood test for INR will not provide objective indicators if the patient is taking direct anticoagulants. The biggest problem with the newer direct anticoagulants is the lack of a reliable way to assess their effectiveness. Doctors can tell when bleeding stops, but there is no indicator that assesses the presence of anticoagulant effects. For example, this is very important when treating patients who are admitted to the emergency room in an unconscious state. If the medical record does not indicate any information about the patient taking direct-acting anticoagulants, it is quite difficult to quickly detect them in the blood.

What to do in case of overdose?

Despite all of the above benefits, doctors are still concerned about the lack of specific antidotes to use in the event of an overdose. To prevent such a serious condition, doctors adhere to the following rules:

• reduce the dose of epobaxan after 7 days of use;
• Xalerto requires a dose reduction after a course of 21 days.

Currently, when life-threatening bleeding occurs, including those caused by indirect anticoagulants, the patient is administered fresh frozen plasma, prothrombin complex concentrate, and Phytonadione.

Phytonadione is one of the few antidotes to anticoagulants

The pharmacology and mechanism of action of each antidote are different. Different anticoagulants will require different doses and strategies for administering antidotes. The duration of the course and dosage of antidotes is calculated depending on how the patient reacts to the drugs already administered (there are cases when some antidotes not only stop bleeding, but also activate platelet aggregation).

Mortality rates with DOACs and VKAs

Patients receiving direct anticoagulants to prevent complications of heart disease had a higher incidence of sudden bleeding, but at the same time lower mortality rates, compared with patients who received vitamin K antagonists. It should not be concluded that the presence of bleeding is what - thus helping to reduce mortality rates.

These conflicting results are due to the fact that most studies are conducted in hospital settings. All bleeding that occurs when the patient is in the hospital and receives direct anticoagulants through an IV is very quickly stopped by qualified medical personnel and does not lead to death. But the patient most often takes indirect anticoagulants without medical supervision, which leads to a higher mortality rate.

Natural blood thinners

Adherents of traditional treatment methods use herbs with a blood-thinning effect to prevent thrombosis. The list of such plants is quite long:

• horse chestnut;
• willow bark;
• mulberry;
• sweet clover;
• wormwood;
• meadowsweet:
• Red clover;
• liquorice root;
• evasive peony;
• chicory and others.

Before using herbs, it is advisable to consult a doctor: not all plants can be beneficial.

Red clover is used in folk medicine as a means to improve blood flow.