Table 2. Intitrombotic therapy in patients with clear arrhythmia (recommendations of ACC / AHA / ESC 2006) .12

Table 3. Rafarin saturation algorithm on heparinotherapy background.14

Table 5. Polurin dose algorithm, providing the therapeutic Range of MN * (tablets, containing 2.5 mg of active substance)19

Table 6. Medications, food and states affecting the metabolism of vitamin antagonists . 20

Table 7. The act of a doctor in case of increasing MNA or the development of bleeding.

Recognition of atherotromability The basis of pathogenesis of most cardiovascular diseases, successes in the study of molecular mechanisms of thrombosis-forming effect on the development of antithrombotic therapy and contributed to the emergence of new products. The modern antithrombotic drugs are in the process of the blood processing process, suppressing the platelet processing function and coagulation cascade, and are able to destroy the formed romboy and restore Patency arteries.

These recommendations are devoted to antithrombotic therapy of stable clinical situations associated with atherotromombosis, and addressed to practical doctors, daily in contact with patients suffering from chronic forms ischemic Disease Hearts, flickering arrhythmias, as well as a constantly increasing contingent of patients subjected to invasive treatment of IBS. The fundamental recommendations are the principles of medicine of evidence, recommendations of the European Society of Cardiologists for the treatment of patients with flickering arrhythmia, arterial hypertension, chronic heart failure and clinical recommendations The American College of Thoracic Doctors on Antithrombotic Treatment and Thrombolytic Therapy ACCP (American Coll Edge of Chest Physicians), published in June 2008. These recommendations are in accordance with the published recommendations of the Patients with acute coronary syndromam and stable angina.

What is atherotrombosis, its clinical manifestations. Antithrombotic therapy as a component of pathogenetic treatment of atherotromability.

The concept of atherotromability was formed as a result of sufficient entraining of the fact that atherosclerosis underlying the development of atherosclerotic plaques, and the thrombosis on its damaged surface is closely connected to each other. Morphologically, atherotromboosis is characterized by the presence of rupture, cracks or erosion on the surface of atherosclerotic plaques, which are "covered" with a thrombus of various sizes, from an entry to a completely occlusive angle of arteries.

Clinical manifestations of atherotromability depend on the localization of the atheroma and the size of the thrombus. In the defeat of the brachiocephalic arteries clinical manifestations correspond to a violation of cerebral circulation various degrees Severity, with the coronary localization of atherotromability - development of ischemic heart disease - from stable forms to acute coronary syndromes (OCS), during localization of the process of arteries, blood supply lower limbs- Symptoms of intermittent chromotype.

Atherotromombosis is not only generalized, but also constantly progressive disease. Stable forms of its manifestations (for example, a stress angina or intermitted chromotype) are associated with an increase in the dimensions of an atherosclerotic plaque, gradually narrowing the clearance of the arteries. While the tire and monolayer endothelius, covering an atherosclerotic plaque, the manifestations of atherotromability are stable, however, when the fracture or breaking of the fibrous tire appears, the defect "covers" a thrombus consisting of platelets and fibrin network filled with erythrocytes. The appearance on the surface of the atheroma thrombus, the dimensions of which can increase, then decrease, creates conditions for the instability of the blood circulation of the organ. In dramatic increment, the thrombus develops an occlusion of the artery, which may end with the development of myocardial infarction, ischemic stroke, the lower limb gangrene.

It has been established that thrombosis is the cause of not only acute states, but also the progression of the disease. This is evidenced by the fact of detection of fibrin and clusters of platelets in the atteroma itself. It holds that the microcracks and other damage to the endothelium monolayer is accompanied by the formation of the primary "thrombocytar tube" and fibrin intended for the cover of the resulting defect to explore the connective tissue.

During the damaged atheroma damaged atters occurs for platelet counting and coagulation cascades. Both processes occur simultaneously, and platelet membrane serves as a phospholipid surface at which the cascade is activated. According to the current presentation, the activation of platelets begins with their adhesion (gluing) to a damaged denendothelized vessel section, then the aggregation (gluing) is happening with the formation of the so-called. Primary plateitarian "plugs". Thrombocyte blood clots are fragile and easily "blurred" blood flow and may cause microvascular obstruction.

The activation of the coagulation cascade is associated with the exposure on the surface of the atheroma of the tissue factor contained, along with cholesterol and its esters, in the macrophages of atherosclerotic plaques. Due to the activation of the coagulation cascade, thrombin is formed - the key enzyme of blood turning.

In connection with the foregoing drugs that inhibit platelet and coagulation cascade, are theoretically substantiated for the prevention and treatment of all manifestations of atherotromability.

Preparations that overwhelming the platelet coagulation cascade

From the standpoints of evidence in patients with stable manifestations of atherotromability, the effectiveness of the following antitrombocytic drugs is proved: aspirin, clopidogrel, tylopidine and combinations of a slowly exempted form of dipyridamole and aspirin, as well as vitamin K antagonist - warfarin.

Aspirin Effective antithrombotic drug, which irreversibly inhibits cyclooxygenase (COX) platelets, as a result of which synthesizerboxane A 2 - inducer of platelet aggregation and vasoconstrictor decreases. The assignment of aspirin allows 15% to reduce the frequency of cardiovascularity and a 30% frequency of non-infamous cardiovascular events.

Platelets are nuclear cells, so they are deprived of the ability to synthesize proteins. The irreversible inhibition of COF-1, the impossibility of its resintez due to the lack of kernel, as well as only 10%, the daily update of platelet pool leads to the fact that the blockade of the synthesis of thrombooxane on aspirin therapy is maintained during the lifestyle of platelets (within 7-10 days).

Cyclookisgenase has two isoforms (COF-1 and COG-2), aspirin blocks both isoforms, but its activity in relation to COF-1 in platelets is 50-100 times higher than the effect on COX-2 in monocytes and other inflammation cells.

The formation of anti-inflammatory (COF-2 dependent) effect requires significantly large doses of aspirin, rather than to inhibit platelet function. This is due to one side with a smaller sensitivity of COG-2 to aspirin, and on the other, with a shorter action of aspirin on COX-2 in leukocytes, due to the possibility of the RESINCE COG-2 during the period of leukocytes in the bloodstream.

The oppression of the COW leads to a decrease in the formation of cyclic endoeries, of which, in the future, not only thromboxane is formed, but also prostacycline is the most important anti-aggress and vasodilator. The oppression of the formation of prostacyclin increases the risk of thrombosis. The thromboxane blockade is carried out mainly due to the effects of aspirin on COX-1 in platelets, while the effects of aspirin on the formation of prostacyclin are carried out at the expense of COF-1 and COF-2.

Small and even medium doses of aspirin, with a sufficient effect on the formation of thromboxane, minimally oppress the synthesis of prostacycline -CU due to the possibility of resintezog-1 in the cells of the endothelium and due to the lower sensitivity of the COF-2 to aspirin.

There is evidence that the reception of drugs - inhibitor-2, in two times increases the risk of vascular episodes, and the purpose of traditional NSAIDs is also associated with an increase in the risk of vascular events, which is associated with a decrease in the formation of prostacyclin.

Aspirin is quickly absorbed in the stomach and thin intestinesHis T 1/2 in Bloodstock is only 15-20 minutes. The concentration of aspirin in the plasma reaches a peak after 30-40 minutes, and the suppression of platelet function in an hour after reception. In the widely used intestinal forms of aspirin, absorption slowly and the peak plasma concentration occurs only after 3-4 hours.

Aspirin reduces myocardial infarction frequency (im) and / or death in patients stable angina, unstable angina, it is with the presence and without a qog, after percutaneous coronary interventions (CCV), after the aorto-coronary shunting (AKS), in patients with cerebrovascular disease, as well as in individuals with multiple risk factors for cardiovascular diseases.

The effectiveness of the combination of aspirin with other antiagregants is proved:

1. Aspirin + dipyridamol in patients with ischemic stroke atherothrombotic nature

2. Small doses of aspirin + heparin in pregnant women with antiphospholipid syndrome

3. Aspirin + clopidogrel - prevention of stent thrombosis in patients subjected to PCV, as well as in patients with unstable angina and myocardial infarction

4. Aspirin + WarfarinProfilakta TE and vascular death in patients with mechanical prostatever heart valves

Aspirin slightly increases the risk of intracranial hemorrhages, but its positive effect on the prevention of ischemic stroke (AI) in patients of high risk undoubtedly prevails.

The effectiveness of aspirin in the treatment and prevention of cardiovascular diseases is for a wide range of doses: from 30-50 mg to 1000-1500 mg and there is no reason to believe that the antithrombotic effect of small doses (50-100 mg per day) is inferior to the effect of large (650-1500 mg / day). When using small doses, the action of aspirin on platelets is optimal: with a sufficient blockade of the synthesis of the thrombox, the synthesis of prostacyclin. In addition, using small doses of aspirin to a lesser extent inhibitory formation of the prostacycline of the stomach, which can weaken its local ulcertogenic effect.

In recent years, a phenomenon has been identified, called "aspiriravisistance", which implies the absence of a decrease in the synthesis of thrombooxane on aspirin therapy. The clinical significance of this phenomenon is not fully studied, a standardized test for identifying "aspiri-sisual" patients, which could be recommended to the broad practice, currently not. Aspirin must be appointed clinical Indications and contraindications.

There is an opinion of experts that when carrying out small surgical interventions (dental, dermatological, cataract removal), it is possible not to cancel AVC for the period of intervention, but this is possible in the case of the use of local hemostatic sponge and confidence in ensuring adequate hemostasis. Nevertheless, in our opinion, the cancellation of warfarin is safer for 2-3 days with the renewal of therapy immediately after the procedure.

In the case of emergency surgical or invasive intervention in a patient hosting an adequate dose of AVC, it is recommended to assign vitamin to 1 (2.5-5mg) to / B or Per OS. If there is a need for more fast decline MNO shows the introduction of freshly frozen plasma or concentrate of the prothrombin complex in combination with / in the introduction of small doses of vitamin K.

Literature

1. ESC Guidelines ON Cardiovascular Disease Prevention in Clinical Practice: Executive Summary. EUR HEART J 2007; 28: 2375-2414.

2. ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008. EUR Heart J 2008; 29: 2388-2442.

3. ESC GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF ACUTE NON-ST-SYNDROME 2008. EUR HEART J 2007; 28: 1598-1660.

4. ESC Guidelines for the Management of Arter Hypertension 2008. EUR Heart J 2007; 28: 1462-1536.

5. Antithrombotic and ThromBolytic Therapy: American College of Cheste Physicians Evidenced-Based Clinical Practice Guidelines (8th Edition). CHEST 2008; 133 (Suppl): 67S-887S.

Applications .

Mandatory Patient Examination Plan before the appointment of warfarin

To verify contraindications and clarify the state of potential sources of bleeding to the appointment of anticoagulant reventiveness of the patient's examination.

1. General blood analysis (signs of anemia).
2. Blood chemistry (Hepatic enzymes, general protein, bilirubin, creatinine).
3. Coagulogram (MNA and Protromine).
4. Hidden blood analysis on hidden blood.
5. General urine analysis / urine analysis in Nechiporenko.
6. Ultrasonic renal research.
7. Inspection of the gynecologist.

Plan of additional examination of the patient before the appointment of warfarin (if there is indications)

1. Ezophagogastrodenoscopy for patients with anamnesis peptic disease Stomach or duodenum / positive result of feces analysis on hidden blood / painful abdominal syndrome.

2. Inspection of the oculistomdl patients with perhaps arterial hypertension to eliminate hemorrhages on the eye day.

3. Computer and / or magnetic resonance imaging in patients undergoing stroke to eliminate the hemorrhagic stroke nature.

Contraindications for the appointment of vitamin K antagonists

Before the appointment of warfarin, the presence of contraindications.

The absolute contraindications of the appointment of warfarin are allergic to the drug, hemorrhagic stroke, active bleeding, thrombocytopenia (the amount of platelets is less than 100 thousand in 1 mm 3).

Contraindications for the appointment of warfarin

All other states are relevant contraindications, and the method is carried out on the basis of an individual assessment of the ratio of benefits and risk of bleeding.

Before the appointment of warfarin, it is necessary to clarify whether the patient has hemorrhagic complications in history, such as bleeding from the gastrointestinal tract, macrohematuria, metrragia in menopause in women. Warfarin can be appointed after the appropriate examination confirming the absence of the risk of bleeding at present.

Selection of dose warfarin

The beginning of warfarin therapy provides for the appointment of a saturable dose of 5-7.5 mg. The completion of the first two days with further dose titration is focused on the reached level of many. Smaller starting doses of warfarin (5 mg and less) are recommended for patients over 70 years, having a low body weight, chronic heart failure or renal failure, as well as in the initial impaired of the liver function, co-administration of amiodarone as well as in patients recently undergone surgery.

During the posting of the individual dose of Warfarin, the monitoring of MNO is carried out once every 2-3 days. Previving consecutive values \u200b\u200bof MNA in the target range, the following measurement should be carried out after 1 week, and in the future the level of MNA is measured once a month. With a change in the dose of warfarin, as well as in the case of appropriate drugs affecting the Metabolism of AVC, it is necessary to control MNO after 3-7 days. Varfarin's dose algorithm is presented in the table. It is not recommended to obtain the results of the currently special randomized research by the Routine use of a pharmacogenetic approach to AVC appointment.

Note: * The therapeutic range of MNA with the use of Warfarin nonsense for patients with clarity arrhythmias of unclap etiology 2.0-3.0, with implantation of artificial heart valves 2.5-3.5, when they combine with one antiagrant 2.0-3.0 , when combined with two antiagregants 2.0-2.5.

Dose Warfarin over the treatment may vary, depending on the indicator of MNO (the multiplicity of measurement of which, on average, is 1 time per month) and other factors (associated diseases, medicinal interactions and etc).

There are concurrents and substances of plant origin that affect the metabolism of AVC. Preference should be given to drugs, the effect of which is insignificant to the anticoagulant effect. Using preparations affecting the metabolism of warfarin, requires a dose correction of the latter and monitoring in 3-5 days.

Notes: * - decrease in the level of albuminazma leads to the fact that bo ¢ the smaller number of Kumarin molecules is in a free state, which increases the sensitivity; ** - to reduce the rate of binding of kumarian with albumin due to quality changes in the last

There are patients, the values \u200b\u200bof many significantly differ from measurement to the measurement. For patients long-term host warfarin, and having significant oscillations of many, which cannot be explained by standard reasons, experts recommend the use of daily diamond doses of vitamin K (100-200mkg), which can contribute to the stabilization of the level of many.

Hemorrhagic complications in the treatment of vitamin antagonists

The main risk of AVC therapy is the possibility of developing bleeding of any localization. Allergic reactions are very rare (itching, rash), gastrointestinal disorders (nausea, vomiting, abdominal pain), transient baldness.

The occurrence of large bleeding (i.e. led to death, violations of cardiac or respiratory activities, other irreversible consequences that required surgical treatment of blood transfusion) always requires urgent hospitalization of the obese Detection and eliminating the cause of bleeding. The target range of many patients undergoing bleeding should be reduced to 2.0-2.5.

The occurrence of small hemorrhagic complications (any internal or outer bleeding, not demanded hospitalization, additional examination and treatment, requires the temporary abolition of AVC to stop bleeding, searching for its possible cause of cliff dose. In case of recurrence of small hemorrhagium level, it is necessary to reduce to 2.0. -2.5.

The most often bleeding occurs in the gastrointestinal and urinary tracts, so during the saturation of AVCs the necessary urine tests to eliminate the microhematuria and the part of the feces on the hidden blood.

In patients with an anamnesis of peptic ulcer of the stomach and duodenum host, taking AVC, it is advisable once a year with a venezopagogastroduodenoscopy (EGDS) and twice a year anti-crushing therapy courses. If complaints are suspicious about the exacerbation of ulcerative disease or gastritis, it is advisable to conduct extraordinary EUGDS.

Appointment of warfarinabolic with arterial hypertension is possible only after adequate arterial pressure. During the period of destabilization of arterial hypertensionVarpharin, it is necessary to cancel and resume treatment only after the correction of hypotensive therapy and the stabilization of blood pressure.

Most frame problem In patients with arterial hypertension, taking AVC are nasal bleeding arising from raising blood pressure. It is necessary to clarify the patient that developed nose bleedFirst of all, it may be due to an increase in blood pressure. Fast additional intake of patients with hypotensive drugs often contributes to the cessation of bleeding at home.

It is necessary to inform the patient that in the event of the development of the Breakthrough, it is necessary to do with the doctor. In the case of the development of minor bleeding (bleeding of gums, nasal bleeding, bruising, darkening of urine color, the appearance of a minor amount of blood in feces during defecation) It is necessary to inform the doctor and skip the reception of warfarin on their own.

The doctor's tactics in the asymptomatic increase of it is determined by the degree of its increase, the presence of potential sources of bleeding and the need for invasive interventions in the near future, and in accordance with the latest recommendations it provides for the abolition of anticoagulants, oral administration (vitamin K 1), intravenous administration of the concentrate of the prothrombin complex, recombinant VII factor Freshly frozen plasma. (see the table). Unfortunately, in our country of the proposed scheme, it is possible to carry out only the abolition of vitamin K antagonists and the introduction of fresh frozen plasma. The concentrate of the prothrombin complex and oral formatitamin to 1 (at a dose of 1-2 mg), the purpose of which allows for a month to reduce many, not registered in Russia and are absent on the domestic pharmaceutical market.

The Vikasol preparation existing in Russia is not an analogue of the oral form of vitamin K 1. Vikasol contributes to the synthesis of vitamin K-dependent coagulation factors DE NOVO due to the effect on processed carboxylation, therefore the effect after its reception occurs slowly and it is useless for the rapid recovery of vitamin variable conversion factors. With the disposal of the doctors of the domestic finish of phytomenadionv capsules of 0.1 g, containing a 10% vitamin oil solution to 1, cannot be used to reduce the level of MNA, so as vitamin K, equal to 10 mg, reserved the presence of AVC for 7-10 days.

The risk of bleeding increases during any invasive interventions - dental ophthalmologic, urological procedures, fibroscopy with biopsy, any operations, angiography, intramuscular injections.

Conducting any invasive interventions against the background of continuing therapy of warfarinous peculiar to the risk of perioperative bleeding. Alternative to Warfarina during the preparation and conduct of surgical intervention is heparin, both unfractionated and low molecular weight.

No big

¯ next dose or skip

additionally me

with little ­ Many, especially if there are reasons, do not change anything, additionally many

\u003e 5.0<9,0

No big

skip 1-2 reception

participate

\u003e 5.0 NO.<9,0

No big

If the high risk of bleeding

skip the next reception

vitamin K (1-2.5 mg per os)

participate

continue therapy with therapeutic MNO in the corrected dose

\u003e 5.0 NO.<9,0

No big

If necessary about. fast¯ MNO (Ekrurg.Shurh.)

vitamin to 5 mg per os

MFO should normalize within 24 hours

if I have not decreased, then 1-2mg vitamin Kper Os.

>9,0

No big

suspend warfarin therapy

vitamin K (2.5 -5.0 mgper OS)

Many should decrease within 24-48 hours (1B)

party MNO, if necessary. Vit.K, resume therapy in the corrected dose when the therapeutic values \u200b\u200bof many

>5,0

Yes big

Interrupt treatment with warfarin

vitamin K 10 mg / in slowly + depending on the emergence of the situation: SPP, PC concentrate, recomb.Viia ,. Repeat vit.k every 12 hours for stability of many

\u003e Therapeutic level

Yes life-in-law

Interrupt treatment with warfarin

vitamin K 10 mg / in Slowly + SZP, PC concentrate, Recomb.VIIA , depending on the emergence of the situation.Repeat if necessary

\u003e 5.0 NO.<9,0

No big

If it is decided to give vitamin k, then betterper os than n / k

Anticoagulants (antithrombinic drugs) are a class of preparations that act in order to prevent coagulation (coagulation) of the blood. Such substances are naturally produced in leeches and bloodsowing insects. A group of pharmaceutical preparations called anticoagulant can be used in the form of injection for humans as a drug during thrombotic diseases. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion containers and hemodialysis equipment.

Application

Anticoagulants reduce blood clotting, which can prevent deep veins thrombosis, lung embolism, myocardial infarction and ischemic stroke. The therapeutic use of anticoagulants includes atrial fibrillation, lung embolism, deep vein thrombosis, venous thromboembolism, stagnant heart failure, stroke, myocardial infarction and genetic or acquired hypercoagulation. The decision to start therapeutic anticoagulation often includes the use of tools for assessing the expected risks of multiple bleeding, doctors use non-invasive preliminary stratification due to the possibility of bleeding together with anticoagulants. Among the data of the tools are the range of risk assessment, ATRIA and the risk assessment scale of thromboembolic complications in patients with atrial fibrillation.

Side effects

Patients at the age of 80 and older can be especially predisposed to hemorrhagic complications with intensity in 13 bleeding per 100 people-years. These oral anticoagulants are widely used as poisons for agricultural pests, especially for rodents. (For details, see Rogeticides and Warfarin). Vitamin K splitting through Cumadin therapy increases the risk of arteries and the heart valve, in particular, if there is too high.

Interaction

Food and nutritional supplements with anticoagulant action include lumbroquain, beer, blueberries, celery, cranberries, green tea, horse chestnut, crook, onions, papaya, red clover, soybeans, drinking and yawa bark. Many plant supplements have anticoagulant properties, such as the sage rednevial \u200b\u200band. Multivitamins that do not interact with blood coagulation are allowed to use patients on anticoagulants. However, some food and additives contribute to coagulation. They include alfalfa, avocado, cat claw, coenzyme Q10 and a temmer colors, such as spinach. Their use should be avoided while taking anticoagulants or, if blood clotting is controlled, their use should be maintained at an approximately constant level so that the dose of anticoagulants can be maintained at a sufficient level to counteract this effect without fluctuations in blood clotting. Grapefruit interacts with some anticoagulants, increasing the duration of the time required by them to excrete from the body, so it should be used with caution in anticoagulant treatment. Anticoagulants are often used to treat acute deep veins thrombosis. People who take anticoagulants for the treatment of this disease should avoid bed regime as an additional treatment, since clinical efficacy depends on constant walking and mobility when using anticoagulants in this way. Bed regime during the reception of anticoagulants can harm the patient in cases where it is not necessary.

Physiochemical properties

The newest oral anticoagulants (NOAC), including Dabigatran, Rivroquaban and Apiksaban, are as effective or better than coumarins (vitamin K antagonists), possessing less serious side effects. The newest anticoagulants (NOAC) are more expensive than traditional anticoagulants, and should be taken with care patients with kidney problems. In addition, they do not have opposing agent, thus, it is difficult to stop their action on the body in cases of extreme necessity (accident, emergency operation). Accurate compliance with the indications relative to this therapy is of paramount importance for optimal action.

Cumarins (vitamin K antagonists)

These oral anticoagulants are obtained from Kumarin, which is found in many plants. The main representative of this class is (Kumadin). It requires at least 48 to 72 hours to render anticoagulant action. If immediate action is required, heparin can be accepted at the same time. These anticoagulants are used to treat patients with deep vein thrombosis (TGV), lung embolism (PE) and to prevent embolism in patients with atrial fibrillation (AF), as well as with mechanical artificial heart valves. Other examples include Acentokumarol and Fenfrokenon, Atrenitin and Phoenindion. Kumarina Bodifakum and DiPhenacum are used as rodenticides, but not used for medical purposes.

Heparin and derivatives

Heparin is a biological substance that is usually obtained from the pork intestine. It acts through the activation of Antitrombin III, which prevents blood coagulation by thrombin. Heparin can be used in natural conditions (by injection), as well as in laboratory conditions to prevent blood coagulation or plasma and in medical equipment. In venopunks, test tubes for blood intake brand Vacuater containing heparin, usually have a green cap.

Low molecular weight heparin

Low molecular weight heparin, the most widely used product is effective because it does not require control of the APTC coagulation indicator (has a more predictable level in plasma) and has less side effects.

Synthetic Pentasaccharide Factor Inhibitors XA

Fondaparinux is a synthetic sugar consisting of five sugars (pentasaccharide) in heparin, which binds to antithrombin. It is a smaller molecule than low molecular weight heparin.

Idraparinux

Direct Factor Inhibitors XA

Such drugs as Rivroxabahn, Apixababan and Edoxababa act by inhibiting the Factor Xa directly (in contrast to heparins and foundation, which act by activating antithrombin). Also include Bethriksaban (LY51717) produced by Portola Pharmaceuticals, Doseksan (YM150) produced by ASTELLAS and more recent TAK-442 Lethaxabah ("Takeda") and Eribaksabah (PD0348292) ("Pfizer"). The development of DosrecSaban was discontinued in September 2011: In the study regarding the prevention of a myocardial infarction relapse at the end of double antitrombocyte therapy, the drug did not show effective, and the risk of bleeding was raised about 300%. Development of lethalxabana with respect to acute coronary syndrome was discontinued in May 2011 due to negative results in phase II of the study.

Direct thrombin inhibitors

Another type of anticoagulant is represented by direct thrombin inhibitors. Current representatives of this class include bivalent drugs of girudine, Lepirudine and Bivalirudin; Monovalent drugs include Argatroban and Dabigatran. The straight oral inhibitor of Thrombin Ximelagatran ("Exanta") was not approved by the Office of Food Control and Medicinal Products (FDA) in September 2004 and was fully removed from the market in February 2006. After reports of severe liver damage and heart Attimes. In November 2010, Dabigatran was approved by the FDA for the treatment of atrial fibrillation.

Antithrombin protein therapeutic agents

An antithrombin protein used as a protein therapeutic agent can be isolated from human plasma or developed artificially (for example, an atrine produced from milk genetically modified goats). The antithrombin is approved by the FDA as an anticoagulant to prevent the formation of blood clots before, during or after a surgical operation or birth in patients with congenital deficiency of the anti-brief.

Other types of anticoagulantov

There are many anticoagulants for use in research and development, diagnostics or as candidates for drugs.

Batroxobin, toxin from the serpentine poison, coagulates the plasma-enriched plasma without affecting platelet functions (dissolves fibrinogen).

Hematin is an anticoagulant protease from the salivary glands of the giant Amazon leech, Haementeria Ghilianii.

Society and culture

Warfarin (Kumadin) is the main agent used in the United States and the UK. Acenokumarol and Fenfrokoumon are more often used outside the United States and the UK.

Laboratory application

Laboratory tools, blood transfusion containers, as well as medical and surgical equipment will be blocked and becoming unsuitable for use if the blood will be able to roll. In addition, chemicals that prevent blood clotting are added to the test tubes used in laboratory blood tests. If you do not count the heparin, most of the data of chemicals acts by binding calcium ions, preventing their use by coagulant proteins.

Ethylenediaminetetrauxous acid (EDTC) strongly and irresistibly chelates (binds) calcium ions to prevent blood clotting.

Adams J, Pepping J (1 Aug 2005). "Vitamin K in the Treatment and Prevention of Osteoporosis and ARTERIAL CALCIFICATION" (PDF). American Journal of Health-System Pharmacy 62 (15): 1574-81. DOI: 10.2146 / AJHP040357. PMID 16030366. Retrieved 2012-10-03.

Wittkowsky AK (September 2001). "Drug Interactions Update: Drugs, Herbs, And Oral Anticoagulation." J. Thromb. Thrombolysis 12 (1): 67-71. DOI: 10.1023 / A: 1012742628628. PMID 11711691.

Steg, PG; MEHTA, SR; JUKEMA, JW; Lip, gy; Gibson, cm; Kovar, f; Kala, p; GARCIA-HERNANDEZ, A; Renfurm, RW; Granger, CB; Ruby-1, Investigators (2011). "Ruby-1: A Randomized, Double-Blind, Placebo-Controlled Tral Of The Safety and Tolerability of The Novel Factor Xa Inhibitor Darexaban (YM150) Following Acute Coronary Syndrome." European Heart Journal 32 (20): 2541-54. DOI: 10.1093 / EURHEARTJ / EHR334. PMC 3295208. PMID 21878434.

anticoagulants.txt · Last Changes: 2019/08/06 11:56 - Nataly

According to statistics, various thromboembolic complications (pulmony artery thromboembolism, deep veins thrombosis) occupy one of the leading places in the mortality structure of the Russian population. In medicine for the treatment of such states, anticoagulants are used - substances that prevent the formation of thin fibrin filaments under the action of coagulation factors, the growth of the already formed thrombus is inhibit and increase the activity of internal fibrinolytic (aimed at resorption) enzymes.

• Show all

  Classification of drugs

  Currently, the classification of anticoagulants is based on points of application of their impact in the body. Preparations:

  • Direct action (for example, heparin). Act quickly, their effect is associated with direct effect on the rolling system of blood through the formation of complexes with different coagulation factors and braking three phases of coagulation.
  • Indirect action (vitamin K antagonists). Act long, but after the latent ("silent") period stop the activation of the enzyme involved in the transformation of vitamin K, thereby stopping the production of vitaminossendable plasma coagulation factors (II, VII, IX, X).

  

  Direct Anticoagulants

  Nefricated heparin (NFG) is a natural substance obtained from pet organs. The mechanism of its action is based on the ability of binding to antithrombin and increasing its ability to deactivate the coagulation factors IIA, IXA, XA, XIA, XIIA. Especially sensitive to the impact of the Heparin -antitrombin complex is thrombin (factor IIa).

  The effect of heparin is carried out exclusively in parenteral administration: after intravenous use, activity is manifested immediately, with subcutaneous administration - after 20-60 minutes with a bioavailability of 10-40% (that is, only this percentage of the substance reaches systemic blood flow). Due to the fact that unfractionated heparin is associated with blood plasma proteins, this drug often manifests an unpredictable anticoagulant effect. To create and maintain the necessary therapeutic concentration of heparin in the blood, it is necessary for its constant intravenous administration or regular subcutaneous injections with respect to bioavailability. To control treatment requires the determination of activated partial thromboplastinetime (AFTT), whose indicators should remain in the range of 1.5-2.3 control values.

  Low molecular weight heparins (NMG) - chemically or enzymatically processed unfractionated heparin. The mechanism of action is similar to NFG, but NMG is significantly more active with respect to the coagulation factor Xa than thrombin. When intravenous administration, the maximum activity is manifested in 5 minutes, with subcutaneous administration - after 3-4 hours with bioavailability of more than 90%, therefore, to maintain the resistant level of anticoagulant plasma activity, it is not necessary to carry out constant intravenous infusion, unlike the NFH. Dosing of the drug is carried out individually under the control of anti-XA blood activity.

  Sodium Fondaparinux is a drug selectively decontaming coagulation factor Xa. The bioavailability of the substance at subcutaneous administration is 100%, and the activity is maintained for 17-21 hours, therefore, to achieve the therapeutic concentration of sufficiently single subcutaneous injection.

  Biblerudine is a substance that directly burning the activity of thrombin, the only drug registered in Russia for parenteral administration. Its action is directed not only to thrombin circulating in the blood, but also on thrombin inside the formed thrombus. The drug is injected exclusively intravenously, and the time of its activity is only 25 minutes. The appointed doses are fixed and do not require control of blood coagulation indicators.

  

  

  New drugs

  New oral anticoagulants (Dabigatatran, Apiksaban, Rivroxabahn) are aimed at selecting any coagulation factor.

  Their efficacy and security are proven by major studies, and when applied, laboratory control is required.

  Dabigatran Etexlate in the body is converted into the active substance Dabigatran, acts on thrombin, is 80% excreted by the kidneys and in 10% of cases causes digestion disorder. Apixababan and Rivroxababan initially belong to active drugs that do not need to be transformed after receipt, act on the XA coagulation factor. The average bioavailability during oral administration is more than 50%, and the reception of rivochasabana on an empty stomach increases its almost to 100%. Preparations do not cause intolerance to the gastrointestinal tract.

  

  Anticoagulants indirect action

  Vitamin K antagonists (AVC) are drugs that block the transition of vitamin K to the active form required for the formation of prothrombin, VII, IX and X of coagulation factors in the liver. The actions of drugs of this group are associated with the removal of a functioning prothrombin from serum. AVK is used inside in tablets, while their bioavailability is more than 90%. Warfarin is a drug selection due to ensuring the most stable anticoagulant effect. Difficulties are possible in the selection of drug dosages: their clear regulation is required by the international normalized ratio (many), and the effect of the first dose is manifested only in 5 days after consumption. AVC overdose is treated with vitamin K - antidote.

  

  Indications, Contraindications and Side Effects

  Indications, contraindications and side effects of direct anticoagulants. Presented in Table:

  List of drugs	Indications	Contraindications	Side effects
  Neficcated heparin	1. The initial treatment of acute coronary syndrome (myocardial infarction, unstable shape of angina). 2. Prevention and therapy of thrombosis of deep veins and tel. 3. Prevention and therapy of complications in the presence of artificial heart valves, intravascular manipulations, hemodialysis, artificial blood circulation. 4. Prevention of thrombing of intravascular catheters	1. Hypersensitivity. 2. Thrombocytopenia less than 100 * 10 9 / l. 3. Immune form of thrombocytopenia, as a complication of heparinotherapy in history. 4. Uncontrolled active bleeding (except associated with internal combustion). 5. Estimated intracranial bleeding	Bleeding; allergic reactions; hypercalemia; headache, fever, chills; peripheral neuropathy; raising Alat, Asat;
  Low molecular weight heparins	The same as the unfractionated heparin	The same as the unfractionated heparin, as well as allergies to pork products	Bleeding; allergic reactions; osteoporosis; hypercalemia; nausea, diarrhea; raising Alat, Asat; local reactions with subcutaneous injections
  Sodium Fondaparinux	1. Early therapy of acute coronary syndrome (myocardial infarction, unstable angina). 2. Prevention and therapy of deep veins thrombosis and pulmonary thromboembolism. 3. Therapy of thrombosis of the subcutaneous veins of the lower extremities	2. Hemorrhagic diathesis. 4. Active bleeding. 5. Bacterial endocarditis	Bleeding; allergic reactions; hypokalemia; stomach ache; raising Alat, Asat; local reactions with subcutaneous injections
  Bivalirudin	1. Percutaneous coronary intervention (CCV), including in the complex of primary procedures with acute coronary syndrome with the lifting of ST segment. 2. Immune thrombocytopenia therapy as complications of heparinotherapy	1. Allergies or hypersensitivity. 2. Hemorrhagic diathesis. 3. Heavy renal failure. 4. Heavy active bleeding. 5. Subighteous bacterial endocarditis. 6. Age up to 18 years. 7. Heavy arterial hypertension	Bleeding; Allergic reactions
  New oral anticoagulants (Dabigatran, Apiksabahn, Rivroxabahn)	1. Prevention of deep vein thrombosis and pulmonary thromboembolism with planned endoprosthetics of hip and knee joints. 2. Prevention of strokes and thromboembolism in atrial fibrillation	1. Hypersensitivity. 2. Continuing bleeding. 2. Hemorrhagic diathesis. 4. Hemorrhagic stroke in history. 5. Heavy renal and liver failure. 6. Pregnancy and lactation. 7. Age up to 18 years	Bleeding; raising Alat and Asat; hyperbilirubinemia; dyspepsia (Dabigatran Etexlate)

  Indications for the appointment of vitamin K antagonists are:

  • prevention and therapy of venous thrombosis and pulmonary thromboembolism;
  • therapy of thromboembolic events in patients of high-risk groups (in the presence of artificial valves, atrial fibrillations);
  • prevention of coronary complications for ischemic heart disease;
  • prevention of thrombotic events with antiphospholipid syndrome (increased lupus anticoagulant).

  

  Contraindications for warfarin:

  Type of AnticoagulantAn example of a trade name (manufacturer) ApiksabahDirect Inhibitor Factor XaElikvis (Bristol-Myers Squibb Company; Pfizer) AcentokumarolVitamin K. antagonistSyankum (ICN POLFA RZESZOW) BivalirudinDirect inhibitor of thrombinAngioches (Ben Venue Laboratories Inc.) WarfarinVitamin K. antagonistWarfarex (Grindex JSC) Heparin sodiumDirect actionThrombress (Nipharam OJSC), Lioton (A. Menarini Industrie Farmaceutiche Riunite S.R. L.), Heparin (Synthesis of JSC) Dabigatran EtexlateDirect inhibitor of thrombinElikvis (Bristol-Myers Squibb Company), Pradaksa (Boehringer Ingelheim Pharma) RivroxabanDirect Inhibitor Factor XaXarelto (Bayer Pharma AG) Phoenindion.Vitamin K. antagonistPhenylin (Tallinn Pharmaceutical Plant) Sodium FondaparinuxDirect Inhibitor Factor XaArikastra (Glaxo Wellcome Production) Eanoxaparin sodiumDirect action, low molecular weight heparinKleksan (Sanofi-WinThrop Industrie)

In the liver contributes to U-carboxylation of glutamic acid residues, which are part of factors II, VII, IX, and X. Carboxyl groups are necessary for Ca 2+-surfactant binding with phospholipid surfaces. There are several vitamin K derivatives with different origins: K 1 (phytomenodion) from chlorophyll-containing plants; K 2 forms intestinal microflora; K 3 synthesize chemically (menadion). All of them are hydrophobic, bile acids are needed for their suction,

but) Oral anticoagulants. Close by the structure with vitamin K 4-hydroxycumarines act as a "false" vitamin K and prevent regeneration of the reduced (active) vitamin to from its epoxide, thereby distinguishing the synthesis of vitamin to-dependent coagulation factors.

Kumarina Well absorbed after taking inside. The duration of their action varies to a large extent. The synthesis of coagulation factors depends on the relationship between the concentrations of kumarins and vitamin K in hepatocytes. The dose required for an adequate anticoagulant effect is determined individually for each patient. To control the dosing in the treatment, the international normalized attitude is used.

Indications. Hydroxycumarines are used for the prevention of thromboembolism, for example, when atrial fibrillation or after prosthetic heart valves.

b) The most significant side effect - bleeding. When using kumarins, it can be avoided by introducing a patient with vitamin K, however, the blood coagulation system returns to its normal state only after hours or days after the liver will resume synthesis and the sufficient level of carboxylated coagulation factors will be restored in the liver. In emergency cases, the missing factors are replenished directly (by transfusion of solid blood or protecrin concentrate).

Other known side effects: hemorrhagic skin necrosis and alopecia at the initial stage of therapy: disorders of the formation of cartilage and bone tissues and the damage to the central nervous system (due to bleeding in the embryonic period; increase in risk of retroplated bleeding.

in) Interaction with other substances. When selecting a dose of hydroxycumarines, it is necessary to ensure a difficult balance between the risk of bleeding (too strong) and thrombosis (too weak action). Even with a successfully selected dosage of these drugs, the process can become uncontrollable if some concomitant factors are not taken into account.

If a a patient Changes its usual diet and begins to use more vegetables, vitamin K can prevail over its antagonists. Some representatives of decorative cabbage, such as Brassica CRISPA, which specialists studying the coagulation system are called a "bomb stuffed with vitamin K", contain a very large amount of vitamin. Vitamin K antagonists can prevail in depression of vitamin K-producing intestinal microflora due to antibacterial therapy.

Drugs activating processes enzymatic biotransformation in the livercan accelerate the removal of hydroxycumarine and thereby reduce its level in the blood. Preparations that depress biotransformation in the liver (H 2-block cimetidine) are enhanced by hydroxycumarines. In addition to pharmacokinetic, pharmacodynamic interactions should be taken into account. Thus, acetylsalicylic acid A) slows the hemostasis due to the oppression of platelet aggregation and b) can cause damage to the stomach mucosa with erosion of blood vessels.

This section of the site contains information about the drug drugs - B01AA vitamin K antagonists. Each drug is described in detail by the EUROLAB portal specialists.

Anatomy-therapeutic-chemical classification (ATC) is an international system of classification of medicines. Latin name - Anatomical Therapeutic Chemical (ATC). Based on this system, all medicines are divided into groups according to their main therapeutic application. ATH-classification has a clear, hierarchical structure, which facilitates the search for the necessary drugs.

Each medicine has its own pharmacological effect. The correct definition of the necessary drugs is the main step for the successful treatment of diseases. In order to avoid unwanted consequences before using those or other drugs, consult with a doctor and read the instructions for use. Pay special attention to commemotion with other medicines, as well as on the terms of use during pregnancy.

ATH B01AA Vitamin K antagonists:

Group Medicines: Vitamin K antagonists

• Acentokumarol (oral pills)
• Valfarex (oral tablets)

• Warfarin Nicomed (Overtal Tablets)
• Marevian (oral pills)

• Syankum (tablets)
• Phenylin (oral tablets)

If you are interested in any other drugs and drugs, their descriptions and instructions for use, synonyms and analogues, information about the composition and form of release, indications for use and side effects, methods of application, dosage and contraindications, notes about the treatment of children's medicine, Newborn and pregnant women, price and reviews about medicines or you have any other questions and suggestions - write to us, we will definitely try to help you.

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Pharmacological group - Anticoagulants

Preparations subgroups are excluded. Enable

Description

Anticoagulants are mainly inhibited by the appearance of fibrin threads; They impede thrombosis, contribute to the cessation of the growth of the already occurred thrombus, enhance the effects of endogenous fibrinolytic enzymes.

Anticoagulants are divided into 2 groups: a) Anticoagulants direct - fast action (sodium heparin, calcium pressure, sodium eneoxaparin et al.), Effective in vitro. and in vivo.; b) Antiacoagulants indirect (vitamin K antagonists) - long-term action (warfarin, phneneone, acenokumarol, etc.), only in vivo. And after the latent period.

The anticoagulant effect of heparin is associated with a direct action on the blood coagulation system due to the formation of complexes with many gemochaguance factors and manifests itself in braking I, II and III phases of coagulation. Heparin itself is activated only in the presence of antithrombin III.

Anticoagulants of indirect effects - derivatives of oxycumarine, indandion, competitively inhibit the reductate of vitamin K, which inhibit the activation of the latter in the body and stop the synthesis of K-vitamin-dependent plasma hemostasis factors - II, VII, IX, X.

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Vitamin K. antagonists

Warfarin refers to vitamin K antagonists (AVC), also called indirect anticoagulants. Two groups of AVK are known: Indandion derivatives (to which Phenylin refers) and Kumarin. Cumarin derivatives include Acenokumarol (Synkumar) and Warfarin (Warfarin Nikomed, Warfarex Grindeks, Marlevan Orion) are registered in our country.

Warfarin is a racemic mixture of two enantiomers: (s) - and (R) - warfarin. The clinical effect of warfarin is more dependent on (s) - warfarin, which is 3-5 times pharmacologically more active than (R) - warfarin. (S) - Warfarine is metabolized by means of the cytochrome of the P-450 2C9 (CYP2C9), R-Warfarin - by CYP3A4, CYP1A1, CYP1A2. Thus, it is CYP2C9 a key enzyme of biotransformation of warfarin. The target molecule for AVC is a subunit of 1 vitamin K-epoxide of the Reductive Complex (vitamin K-epoxyreductase, VKORC1). With the help of vitamin K-epoxydase, the vitamin of K-epoxide is converted to its active form (vitamin K-hydroquinone), which is a cofactor for the carboxylation reaction required for the synthesis of complete vitamin of key-dependent coagulation factors.

After taking inside, the Kumarina derivatives are absorbed in the stomach and a cister, while the change in the intestinal bacterial flora synthesizing vitamin K, both as a result of endogenous causes and when taking drugs, has an antagonistic effect on the anticoagulant Kumarian effect.

After suction, Cumarine derivatives are firmly and reversible associated with plasma albumin. The drug associated with albumin does not fall into the liver, reaches with blood flow and filtered with glomes. On the transformations of vitamin K in the liver, the molecule of free coumarin is influenced.

The beginning of AVK is sharply. The anticoagulant effect is implemented due to the inhibiting epoxy submission of vitamin K and, possibly, the reduction of vitamin K, which leads to a decrease in the formation of vitamin K-dependent factors, coagulation - Protromine (II), VII, IX and X factors. For AVC therapy, blood coagulation factors secreted by hepatocytes contain a reduced amount of residual G-carboxyglutamine amino acid residues (Pivka - proteins formed during vitamin K deficiency). They have a reduced ability to activate in Ca 2+ dependent reactions of the blood coagulation system, which leads to the development of the state of hypocoagulation.

Vitamin K antagonists reduce the formation of proteins in the liver proteins - proteins C and S. The decrease in the level of natural protein anticoagulant with ahead of the decrease in the content of three vitamin to dependent coagulation factors (II, IX and X factors). High starting doses of warfarin (10 mg or more) lead to a rapid decrease in protein C, which can cause thrombotic complications. Warfarine is not a drug to create a rapid anticoagulant effect, parenteral anticoagulants should be used for this purpose. In patients with high risk, thromboembolic complications of Warfarin should be prescribed against the background of heparinotherapy, which during the saturation period by warfarin will create the necessary anticoagulant effect.

Elimination of the unchanged drug is carried out through the liver, and metabolites through the kidneys. For warfarin, the presence of enterprise recycling and the period of its half-life of forges is characterized. The peak of action at Warfarin comes on the 3-6th day, the duration of the effect, as much as possible to 5 days. AVC is saved for some time after the cancellation of the drug.

To date, the only possible way to control the therapy of AVC is a prothrombin test, with the presentation of results in the form of an international normalized relationship (MNO).

Prothrombin test models part of the physiological reactions of the activation of the blood coagulation system. The method of its execution was proposed by Quick A.J. et al. In 1935, and consists in determining the coagulation time of citrate plasma after adding thromboplastin and Ca 2+ ions. The sensitivity of thromboplastins depends on the method of their production and differs from thromboplastins of different firms. The NGO system is approved WHO to standardize the prothrombin test and allows the characteristics of different used thromboplastins, expressed in the so-called international index sensitivity of thromboplastin. The value of MNA is normal equal to 1.0, its values \u200b\u200bincrease on AVC therapy, for most clinical situations therapeutic Dipan meter from 2.0 to 3.0.

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Anticoagulants: Main Preparations

Complications caused by vessel thrombosis are the main cause of death in cardiovascular diseases. Therefore, in modern cardiology, it is very important to prevent the development of thrombosis and embolism (blockage) of vessels. Blood coagulation in the simplest form can be represented as the interaction of two systems: platelets (cells responsible for the formation of blood clots) and dissolved in the blood plasma proteins - coagulation factors, under the action of fibrin. The resulting thrombus consists of a platelet conglomerate, protruded fibrin threads.

Two groups of drugs are used to prevent thrombus formation: antiagregants and anticoagulants. Antiagregants prevent the formation of thrombocyte clots. Anticoagulants block enzyme reactions leading to the formation of fibrin.

In our article, we will look at the main groups of anticoagulants, indications and contraindications to their use, side effects.

Classification

Depending on the point of the application, anticoagulants of direct and indirect action are distinguished. The anticoagulants of direct action depress the synthesis of thrombin, the formation of fibrin fibrin is inhibited. Anticoagulants of indirect action oppress the processes of education in the liver of blood coagulation factors.

Direct coagulants: heparin and its derivatives, direct thrombin inhibitors, as well as selective inhibitors of factor HA (one of the blood coagulation factors). Indirect anticoagulants include vitamin K. antagonists

1. Vitamin antagonists:
   • Phoenindion (phenylin);
   • Warfarin (warfarex);
   • Acentokumarol (Synkumo).
2. Heparin and its derivatives:
   • Heparin;
   • Antrombin III;
   • Dalteparin (Fragmin);
   • Eanoxaparine (Anfira, GEMAPAXAN, KLEXAN, ENICHUM);
   • Obverse (fraxipart);
   • Parnaparin (Fluuxum);
   • Sulodekside (Angaoflyux, Vessel Due F);
   • Bemiparine (Cybor).
3. Direct thrombin inhibitors:
   • Bivalirudin (angiox);
   • Dabigatran Etexlate (Pradaksa).
4. Selective Factor Hay Inhibitors:
   • Apiksabah (Elikvis);
   • Fondaparinux (Arikstra);
   • Rivroxabah (Ksarato).

Vitamin K. antagonists

Anticoagulants of indirect action - the basis for the prevention of thrombotic complications. Their tableted forms can be taken for a long time in an outpatient basis. The use of indirect anticoagulants has provenly reduces the frequency of thromboembolic complications (infarction, stroke) during the atrial fibrillation and the presence of an artificial heart valve.

Phenylin is currently not used due to the high risk of unwanted effects. Syncumar has a long period of action and accumulates in the body, therefore it is used infrequently due to the difficulty of control of therapy. The most common preparation from the vitamin K antagonist group is warfarin.

Warfarin differs from other indirect anticoagulants with an early effect (10 to 12 hours after admission) and the rapid cessation of undesirable effects with a decrease in the dose or cancellation of the drug.

The mechanism of action is associated with the antagonism of this drug and vitamin K. Vitamin K participates in the synthesis of some coagulation factors. Under the action of warfarin, this process is broken.

Warfarin is prescribed for the prevention and growth of venous thrombus. It is used for long-term therapy in atrial fibrillation and in the presence of an intracardiac thrombus. With these states, the risk of heart attacks and strokes associated with the blockage of blood vessels with parties of thromboms is significantly increased. Warfarina helps prevent these heavy complications. This drug is often used after the myocardial infarction suffered in order to prevent the re-coronary catastrophe.

After prosthetizing the heart valves, the reception of warfarin is necessary for at least several years after the operation. This is the only anticoagulant used to prevent the formation of blood clots on artificial heart valves. Constantly take this medicine is needed with some thrombophilia, in particular, antiphospholipid syndrome.

Warfarine is prescribed with dilatation and hypertrophic cardiomyopathy. These diseases are accompanied by the expansion of the cavities of the heart and / or hypertrophy of its walls, which creates prerequisites for the formation of intracardiac thrombov.

In the treatment of warfarin, it is necessary to evaluate its efficiency and safety by controlling the MNA - international normalized relationship. This indicator is estimated every 4 - 8 weeks of reception. Against the background of treatment, MNO should be 2.0 - 3.0. Maintaining the normal value of this indicator is very important for the prevention of bleeding, on the one hand, and increased blood coagulation, on the other.

Some food and medicinal herbs enhance the action of warfarin and increase the risk of bleeding. It is cranberry, grapefruit, garlic, ginger root, pineapple, turmeric and others. Weaken the anticoagulant effect of drugs The substances contained in the leaves of the Kochan, Brussels, Chinese cabbage, beet, parsley, spinach, lettuce latch. Patients hosting warfarin can not be abandoned from these products, but take them regularly in small quantities in order to prevent sharp fluctuations in blood medication.

Side effects include bleeding, anemia, local thrombosis, hematoma. The activity of the nervous system with the development of fatigibility, headaches, violations of taste may be violated. Sometimes nausea and vomiting, abdominal pain, diarrhea, violation of the liver function. In some cases, the skin is affected, the purple painting of the fingers of the foot, paresthesia, vasculitis, the chilleness of the limbs appears. It is possible to develop an allergic reaction in the form of a skin, urticaria, angioedema edema.

Warfarin is contraindicated during pregnancy. It should not be appointed with any states associated with the threat of bleeding (injury, operations, ulcerative lesions of internal organs and skin). It does not apply it for aneurysms, pericardius, infectious endocarditis, severe arterial hypertension. Contraindication is the impossibility of adequate laboratory control due to the inaccessibility of the laboratory or the characteristics of the patient's personality (alcoholism, inorganization, senile psychosis, etc.).

Heparin

One of the main factors that prevent blood coagulation is antithrombin III. The unfractionated heparin binds to it in the blood and increases the activity of its molecules several times. As a result, reactions aimed at the formation of blood clots in vessels is suppressed.

Heparin is applied for over 30 years. It used to be administered subcutaneously. It is now believed that unfractionated heparin should be administered intravenously, which facilitates control over the safety and effectiveness of therapy. For subcutaneous use, low molecular weight heparins are recommended, we will talk about below.

Heparin is used to be most often used for the prevention of thromboembolic complications in acute myocardial infarction, including during thrombolysis.

Laboratory control includes determining activated partial thromboplast coagulation time. Against the background of heparin treatment after 24 - 72 hours, it must be 1.5 - 2 times more source. It is also necessary to control the number of blood platelets in order not to miss the development of thrombocytopenia. Usually, heparinotherapy continues for 3 to 5 days with a gradual reduction in dose and further cancellation.

Heparin can cause hemorrhagic syndrome (bleeding) and thrombocytopenia (reducing the number of blood platelets). With long-term use of it in large doses, the development of alopecia (baldness), osteoporosis, hypoaldosteroneism is likely. In some cases, allergic reactions arise, as well as an increase in the level of alaninotransferase in the blood.

Heparin is contraindicated in hemorrhagic syndrome and thrombocytopenia, ulcerative disease of the stomach and 12-rosewind, bleeding from urinary tract, pericardius and acute aneurysm of the heart.

Low molecular weight heparins

DateParin, ENCHSAPARIN, PARNAPARIN, PARNAPARIN, SOULDEKSID, BEMPARIN is obtained from an unfractionated heparin. From the latter, they differ in the smaller molecule size. This increases the safety of drugs. The action becomes longer and predictable, so the use of low molecular weight heparins does not require laboratory control. It can be carried out using fixed doses - syringes.

The advantage of low molecular weight heparins is their effectiveness at subcutaneous administration. In addition, they have significantly below the risk of side effects. Therefore, at present, derivatives of heparin displaces heparin from clinical practice.

Low molecular weight heparins are used to prevent thromboembolic complications in surgical operations and thrombosis of deep veins. They are used in patients in bed and having a high risk of such complications. In addition, these drugs are widely prescribed at unstable angina and myocardial infarction.

Contraindications and undesirable effects of this group are the same as heparin. However, the severity and frequency of side effects is significantly less.

Direct thrombin inhibitors

Direct thrombin inhibitors, as clearly from the name, directly inactivate thrombin. At the same time, they suppress the activity of platelets. The use of these drugs does not require laboratory control.

Biblerudine is administered intravenously with acute myocardial infarction for the prevention of thromboembolic complications. In Russia, this drug is not yet applied.

Dabigatran (Pradaksa) is a tablet for reducing the risk of thrombosis. Unlike warfarin, it does not interact with food products. Studies of this medication are continuing under the constant form of atrial fibrillation. The drug is allowed for use in Russia.

Selective Factor Factor Inhibitors

Fondaparinux is associated with antithrombin III. Such a complex inactivates the X-factor inactivating, reducing the intensity of the thrombosis. It is prescribed subcutaneously with acute coronary syndrome and venous thrombosis, including pulmonary artery thromboembolism. The medicine does not cause thrombocytopenia and does not lead to osteoporosis. Laboratory control of its safety is not required.

Fondaparinux and Biblerudine are particularly shown in patients with increased risk of bleeding. Reducing the frequency of blood closures in this group of patients, these drugs significantly improve the disease forecast.

Clinical trials are tested inhibitors of the factor ha in the form of tablets.

The most frequent side effects include anemia, bleeding, abdominal pain, headache, skin itching, increasing transaminase activity.

Contraindications - active bleeding, severe renal failure, intolerance to the components of the drug and infectious endocarditis.

Anticoagulants: mechanism of action of drugs, indications and contraindications to use

According to statistics, various thromboembolic complications (pulmony artery thromboembolism, deep veins thrombosis) occupy one of the leading places in the mortality structure of the Russian population. In medicine for the treatment of such states, anticoagulants are used - substances that prevent the formation of thin fibrin filaments under the action of coagulation factors, the growth of the already formed thrombus is inhibit and increase the activity of internal fibrinolytic (aimed at resorption) enzymes.

Currently, the classification of anticoagulants is based on points of application of their impact in the body. Preparations:

• Direct action (for example, heparin). Act quickly, their effect is associated with direct effect on the rolling system of blood through the formation of complexes with different coagulation factors and braking three phases of coagulation.
• Indirect action (vitamin K antagonists). Act long, but after the latent ("silent") period stop the activation of the enzyme involved in the transformation of vitamin K, thereby stopping the production of vitaminossendable plasma coagulation factors (II, VII, IX, X).

Nefricated heparin (NFG) is a natural substance obtained from pet organs. The mechanism of its action is based on the ability of binding to antithrombin and increasing its ability to deactivate the coagulation factors IIA, IXA, XA, XIA, XIIA. Especially sensitive to the impact of the Heparin -antitrombin complex is thrombin (factor IIa).

The effect of heparin is carried out exclusively in parenteral administration: after intravenous use, the activity is manifested immediately, with subcutaneous administration - 6-40% are empty with bioavailability (that is, only this percentage of the substance reaches systemic blood flow). Due to the fact that unfractionated heparin is associated with blood plasma proteins, this drug often manifests an unpredictable anticoagulant effect. To create and maintain the necessary therapeutic concentration of heparin in the blood, it is necessary for its constant intravenous administration or regular subcutaneous injections with respect to bioavailability. To control treatment requires the determination of activated partial thromboplastinetime (AFTT), whose indicators should remain in the range of 1.5-2.3 control values.

Low molecular weight heparins (NMG) - chemically or enzymatically processed unfractionated heparin. The mechanism of action is similar to NFG, but NMG is significantly more active with respect to the coagulation factor Xa than thrombin. When intravenous administration, the maximum activity is manifested in 5 minutes, with subcutaneous administration - after 3-4 hours with bioavailability of more than 90%, therefore, to maintain the resistant level of anticoagulant plasma activity, it is not necessary to carry out constant intravenous infusion, unlike the NFH. Dosing of the drug is carried out individually under the control of anti-XA blood activity.

Sodium Fondaparinux is a drug selectively decontaming coagulation factor Xa. The bioavailability of the substance at subcutaneous administration is 100%, and the activity is supported on the lengths, therefore, to achieve the therapeutic concentration of sufficiently single subcutaneous injection.

Biblerudine is a substance that directly burning the activity of thrombin, the only drug registered in Russia for parenteral administration. Its action is directed not only to thrombin circulating in the blood, but also on thrombin inside the formed thrombus. The drug is injected exclusively intravenously, and the time of its activity is only 25 minutes. The appointed doses are fixed and do not require control of blood coagulation indicators.

New oral anticoagulants (Dabigatatran, Apiksaban, Rivroxabahn) are aimed at selecting any coagulation factor.

Their efficacy and security are proven by major studies, and when applied, laboratory control is required.

Dabigatran Etexlate in the body is converted into the active substance Dabigatran, acts on thrombin, is 80% excreted by the kidneys and in 10% of cases causes digestion disorder. Apixababan and Rivroxababan initially belong to active drugs that do not need to be transformed after receipt, act on the XA coagulation factor. The average bioavailability during oral administration is more than 50%, and the reception of rivochasabana on an empty stomach increases its almost to 100%. Preparations do not cause intolerance to the gastrointestinal tract.

Vitamin K antagonists (AVC) are drugs that block the transition of vitamin K to the active form required for the formation of prothrombin, VII, IX and X of coagulation factors in the liver. The actions of drugs of this group are associated with the removal of a functioning prothrombin from serum. AVK is used inside in tablets, while their bioavailability is more than 90%. Warfarin is a drug selection due to ensuring the most stable anticoagulant effect. Difficulties are possible in the selection of drug dosages: their clear regulation is required by the international normalized ratio (many), and the effect of the first dose is manifested only in 5 days after consumption. AVC overdose is treated with vitamin K - antidote.

Indications, contraindications and side effects of direct anticoagulants. Presented in Table:

1. 1. The initial treatment of acute coronary syndrome (myocardial infarction, unstable shape of angina).
2. 2. Prevention and therapy of thrombosis of deep veins and tel.
3. 3. Prevention and therapy of complications in the presence of artificial heart valves, intravascular manipulations, hemodialysis, artificial blood circulation.
4. 4. Prevention of thrombing of intravascular catheters

1. 1. Hypersensitivity.
2. 2. Thrombocytopenia less than 100 * 10 9 / l.
3. 3. Immune form of thrombocytopenia, as a complication of heparinotherapy in history.
4. 4. Uncontrolled active bleeding (except associated with internal combustion).
5. 5. Estimated intracranial bleeding

headache, fever, chills;

raising Alat, Asat;

raising Alat, Asat;

local reactions with subcutaneous injections

1. 1. Early therapy of acute coronary syndrome (myocardial infarction, unstable angina).
2. 2. Prevention and therapy of deep veins thrombosis and pulmonary thromboembolism.
3. 3. Therapy of thrombosis of the subcutaneous veins of the lower extremities

1. 2. Hemorrhagic diathesis.
2. 4. Active bleeding.
3. 5. Bacterial endocarditis

raising Alat, Asat;

local reactions with subcutaneous injections

1. 1. Percutaneous coronary intervention (CCV), including in the complex of primary procedures with acute coronary syndrome with the lifting of ST segment.
2. 2. Immune thrombocytopenia therapy as complications of heparinotherapy

1. 1. Allergies or hypersensitivity.
2. 2. Hemorrhagic diathesis.
3. 3. Heavy renal failure.
4. 4. Heavy active bleeding.
5. 5. Subighteous bacterial endocarditis.
6. 6. Age up to 18 years.
7. 7. Heavy arterial hypertension

1. 1. Prevention of deep vein thrombosis and pulmonary thromboembolism with planned endoprosthetics of hip and knee joints.
2. 2. Prevention of strokes and thromboembolism in atrial fibrillation

1. 1. Hypersensitivity.
2. 2. Continuing bleeding.
3. 2. Hemorrhagic diathesis.
4. 4. Hemorrhagic stroke in history.
5. 5. Heavy renal and liver failure.
6. 6. Pregnancy and lactation.
7. 7. Age up to 18 years

raising Alat and Asat;

dyspepsia (Dabigatran Etexlate)

Indications for the appointment of vitamin K antagonists are:

• prevention and therapy of venous thrombosis and pulmonary thromboembolism;
• therapy of thromboembolic events in patients of high-risk groups (in the presence of artificial valves, atrial fibrillations);
• prevention of coronary complications for ischemic heart disease;
• prevention of thrombotic events with antiphospholipid syndrome (increased lupus anticoagulant).

Contraindications for warfarin:

• hypersensitivity;
• hemorrhagic diathesis;
• high risk of bleeding;
• intracranial bleeding;
• heavy arterial hypertension;
• the impossibility of monitoring many.

Among the side effects of vitamin antagonists:

• bleeding;
• allergic reactions;
• skin necrosis;
• paresthesia;
• osteoporosis;
• rash;
• dermatitis;
• leukopenia;
• agranulocytosis;
• disorders of liver and kidney functions.

The list of anticoagulants and trading titles of drugs are indicated in the following table:

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Basics of therapy antagonists vitamin K for practitioners doctors

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For citation: Kropacheva E.S., Panchenko E.P. Fundamentals of therapy antagonists Vitamin K for practitioners // RMW. 2009. №8. P. 507.

The time of conducting large randomized studies and to date, Warfarine has no alternative for long-term prevention of thromboembolic complications in patients with flickering arrhythmia without damage to heart valves, patients with artificial valves, as well as persons who have undergone venous thrombosis.

The only proven way to control therapy AVC today is a prothrombin test with the presentation of results in the form of an international normalized relationship (many). The MNA system developed by WHO takes into account the international sensitivity index of thromboplastin used in each specific laboratory, which allows standardizing the test results.

Currently, AVC's effectiveness for the prevention of thromboembolic complications in patients with flicker arrhythmia (MA), after prosthetizing the heart valves, in the secondary prevention of cardiovascular episodes in patients who have undergone acute coronary syndrome, as well as in the treatment and prevention of venous thrombosis are also in patients.

at shimmer arrhythmia

The main cause of death and disability patients without damage to the valves of the heart is ischemic stroke (AI) and systemic thromboembolism. According to large studies, the risk of stroke in patients in patients increases 6 times compared to persons having sinus rhythm, does not depend on the duration of arrhythmia (i.e., comparable in the debut of the disease and during the long existence of arrhythmias) and the same for patients with constant and Paroxysmal forms Ma. Cardioembolic strokes in patients with MA are characterized by an extensive infarction of the brain, leading to a pronounced neurological deficit, which entails in most cases a resistant disability of the patient.

Reducing the risk of AI with warfarin therapy in patients without damage to the heart valves has been proven by major randomized studies and is 61%. Determining in the choice of tactics of antithrombotic therapy in each particular patient MA is the presence of risk factors for thromboembolic complications (Table 1). In the Recommendations for the treatment of MA, published in 2006, when appointing Warfarin, it was proposed to use the CHADS scales, where such factors as insufficient blood circulation, arterial hypertension, age older than 75 years old and diabetes mellitus, and AI / transient brainwater impairment or The systemic embolism in history - 2 points. The risk of stroke is 2.8% per year with a single score and increases to 8.5% per year if there are 4 points on the Chads2 scale.

The effectiveness of acetylsalicylic acid (ASC) in the prevention of stroke in patients with MA is inferior to warfarine. Meta-analysis of 5 randomized studies has established that the appointment of ASC reduces the risk of stroke in patients by 19%. ASK may be an alternative to AVC in patients with low risk of thromboembolism or in patients with contraindications to indirect anticoagulants.

In addition to patients with the chronic atrial fibrillation, the appointment of anticoagulants is required to patients who are planned to restore sinus rhythm. The risk of systemic thromboembolism during cardioversion without using anticoagulants reaches 5%, and the use of 4-week warfarine therapy before and after cardioversion allows you to reduce this risk to 0.5-0.8%.

The duration of warfarin therapy after cardioversion is associated with the ability of the patient to keep sinus rhythm and with the presence of risk factors in thromboembolic complications. At the frequency of paroxysis, more than one per month, patients must follow the recommendations for patients with paroxysmal form of flickering arrhythmia.

The use of percussive echocardiography makes it possible to exclude the thrombus in the left atrium ear - the main source of thromboembolism in patients Ma, which allows closer to carry out cardioversion. In this case, heparin is used (both unfractionated and low molecular weight) or AVC at least 5 days (until the two-time values \u200b\u200bof MNA in the target range of 2.0-3.0). After cardioversion, AVC therapy should be continued at least within 4 or more weeks depending on the rhythm and the presence of risk factors for thromboembolism.

Conducting 4-week warfarine therapy is required in the case of cardioversion without the preliminary assignment of AVC (the duration of paroxysm is less than 48 hours or in the case of an acute paroxysm of Ma, accompanied by unstable hemodynamics).

AVK in patients with artificial heart valves

The main danger to the lifetime of patients with artificial artificial valves is thromboembolic complications, the source of which are blood clots formed on the surface of the valve prosthesis. The risk of thrombosis of an artificial valve - a life-degraded complication in the absence of AVC therapy reaches 8-22% per year. The assignment of warfarin allows to reduce the risk of thromboembolism by 75%, so when installing the mechanical prostheses of the AVC heart valves are required and cannot be replaced by ASK. The exceptions are patients with bioprapists without risk factors for thromboembolic complications, the duration of AVK therapy, which is 3 months. In all other cases, treatment should be lifelong. Risk factors for patients with artificial heart valves are thromboembolism in history, Ma, insufficiency of blood circulation, atriomegaly. The level of anticoagulation in the overwhelming majority of cases must correspond to the Range of MNA 2.5-3.5. The exception is the patients after implantation of the Saint-Jude aortal valve prosthesis, in the absence of other risk factors of thromboembolium (in this case, the target range of MN 2.0-3.0).

AVK in the treatment of venous thrombosis

The duration of treatment with warfarin after the first episode of deep veins thrombosis is at least 3 months. If there is a high risk of thrombosis recurrence (proximal leakage of thrombosis, repeated episodes of venous thrombosis, transferred to the thromboembolism of the pulmonary artery or its branches, the presence of constant reasons for activating the blood coagulation system) - 6 months, and in some cases (the presence of cancer, antiphospholipid syndrome, thrombophilia ) Must be lifelong. The level of anticoagulation to prevent the recurrences of venous thrombosis corresponds to MNA 2.0-3.0.

AVK with secondary

Warfarin's effectiveness In the secondary prevention of IBA studied in ASPECT-2, Apricot-2, Waris-II, Champ studies. These studies differed in design, anticoagulation modes, the presence of concomitant therapy of ASK and dose of the latter. The effectiveness of the combination of warfarin and ASC was higher than the ASC monotherapy, but the risk of hemorrhagic complications was higher in the group of combination therapy. In this regard, in routine clinical practice, the appointment of warfarin patients after acute coronary syndrome has found its use in special cases - in the intolerance of antiagregants, as well as in the presence of thrombophilia or additional readings for AVC therapy.

Practical aspects of AVC therapy

Warfarin therapy must meet two requirements:

1) an effective and safe dose must be selected during the first month of therapy;

2) Supporting dose should be seamless in accordance with possible changes in weight, diet, somatic status and taking into account the sharing of other medicines.

The beginning of warfarin therapy provides for the appointment of a saturable dose of 5-7.5 mg during the first two days with further dose titration, focusing on the reached level of many (Table 2). Smaller starting doses of warfarin (5 mg and less) are recommended for patients over 70 years having a low body weight, chronic heart or renal failure, as well as in the original violation of the liver function, co-administration of amiodarone, and also in patients recently undergone surgery.

The appointment of at once high starting doses of warfarin (10 mg or more) is not recommended, since at the beginning of WCC therapy there is a decrease in the level of the natural anticoagulant of protein C, which can lead to the development of venous thrombosis.

During the selection of the dose, the monitoring of MNO is carried out 1 time in 2-3 days. After receiving the results of many, within the target range, twice dose of warfarin is considered selected, and in the future IMO control is carried out 1 time per month.

The target range of Mons for patients without damage to the valves of the heart and after the transferred venous thrombosis, when using warfarin without antiagregants, is 2.0-3.0, with a combination of one anti-agregant 2.0-3.0, with a combination with two antiagregants 2, 0-2.5. In patients after implantation of artificial heart valves, in most cases, target components are 2.5-3.5.

For patients with antiphospholipid syndrome, which does not have additional risk factors, target components are 2.0-3.0. For patients who suffered thrombotic complications, despite the anticoagulant therapy, it is advisable to increase the average values \u200b\u200bof MNO to 3.0.

Currently, polymorphisms are revealed mainly by the Biotransformation gene of Warfarin CYP2C9 and the target molecule of its action vkorc1. The carriers of mutant alleles require a smaller supporting dose of warfarin, while the frequency of bleeding and episodes of excessive hypocoagulation are higher. Currently, research is carried out, the purpose of which is to determine whether the advantage of a pharmacogenerating approach has the advantage of a standard empirical selection of a dose of warfarin. However, in the recommendations of the 2008 ASSR, it is said that in the absence of currently data from special randomized studies, the use for all patients of the pharmacogenetic approach to the appointment of AVC is not justified.

Before appointment of warfarin, it is necessary to estimate the presence of contraindications. Absolute contraindications to the appointment of warfarin are allergic to the drug, hemorrhagic stroke in history, active bleeding, thrombocytopenia (the number of platelets is less than 100 thousand). All other states are relative contraindications, and the choice is carried out on the basis of the individual benefit ratio and the risk of bleeding.

Before the appointment of warfarin, it is necessary to clarify whether the patient has hemorrhagic complications in history, conduct a survey aimed at clarifying the state of potential sources of bleeding. When confirming the lack of risk of bleeding, Warfarin can be appointed. The plan of the mandatory and additional examinations to determine the contraindications and clarify the state of potential sources of bleeding, is shown in Figure 1.

Warfarin is a medicine for which the dosage response is characterized by a variety of factors such as external (diet, drug interactions) and internal (the somatic state of the patient, age), as well as genetically determined. To eliminate unwanted drug interactions when appointing concomitant therapy, preference should be given to drugs whose action on the anticoagulant effect of warfarin is insignificant (Table 3). The use of drugs affecting the Metabolism of AVC requires the monitoring of the MNO after 3-5 days and, if necessary, the dose correction of warfarin.

Patients taking anticoagulants need a patronage system, which is due to the need to regularly control MNO, correction of the dose of the drug and the assessment of other factors affecting the value of many.

The fluctuation of values \u200b\u200bof MNO may be due to several factors:

Change in vitamin C consumption with food

The impact of changes in the somatic status, reception of drugs and substances of plant origin on the metabolism of warfarin

Lack of commitment to treatment with warfarin.

The most frequent reason explaining the absence of adequate anticoagulation with warfarin therapy is the poor commitment of treatment patients, high vitamin K in food and reception of drugs that increase the activity of the SYP2C9 enzyme (barbiturates, carbamazepine).

To eliminate food interactions, it should be recommended to patients hosting warfarin:

Adhere to the same power mode

Limit the consumption of raw vegetables (no more than 250 μg / day. In terms of the content of vitamin K1)

Taking polyvitamins, choose a drug that does not contain vitamin K1

In the case of alcohol use, it does not exceed it more than 25 g per day in terms of ethanol.

The value of MNA from measurement to the measurement, in the same patient may vary inside the therapeutic range. Fluctuations MNA, slightly leaving the therapeutic range (1.9-3.2), are not grounds for changing the dose of the drug. In order to avoid significant oscillations of the level of anticoagulation, it is advisable to reduce the dosage of warfarin at the values \u200b\u200bof many more than 3.0, but less than 4.0, while not passing the next reception of the drug.

For patients, long-term host warfarin and having significant oscillations of many, which cannot be explained by standard reasons, it is recommended that the use of daily small doses of vitamin K (100-200 μg), which may contribute to the stabilization of the MNA level.

The question of what to consider true resistance to warfarine remains up to the present time. Perhaps it is worth talking about true resistance, if the dose of warfarin, exceeding 20 mg per day, has not led to the achievement of the therapeutic level of anticoagulation. This is the so-called pharmacodynamic (or true) resistance, which can be confirmed by the detection of high concentration of warfarin in the blood plasma in the absence of increasing the values \u200b\u200bof many. The number of such cases among patients, according to specialized studies, does not exceed 1%.

Risk of bleeding with AVK therapy

The development of hemorrhagic complications is the most formidable complication of AVC therapy and the main reason for the unassignment of drugs of this group. Very rarely there are non-immoorgic side effects of warfarin - allergic reactions (itching, rash), gastrointestinal disorders (nausea, vomiting, abdominal pain), transient baldness.

The main risk factors of hemorrhagic complications are the degree of hypocoagulation, elderly age, interaction with other drugs and invasive interventions, as well as the beginning of therapy.

The emergence of large bleeding (i.e. led to death, violations of cardiac / respiratory activities, other irreversible consequences that required surgical treatment or blood transfusion) always requires urgent hospitalization of the patient to search for the causes of bleeding and stopping. The resumption of warfarin therapy after large bleeding is possible only if the cause of bleeding is found and eliminated. The target range of MNO should be reduced to 2.0-2.5.

The occurrence of small hemorrhagic complications (of any internal or external bleeding, not demanding hospitalization, additional examination and treatment) requires temporary cancellation of warfarin until stopping bleeding, search for a possible cause of bleeding and dose correction of warfarin. To resume warfarin therapy after stopping small bleeding with many<3,5. В случае рецидивирования малых геморрагий целевой уровень МНО необходимо снизить до 2,0–2,5.

Excessive anticoagulation is a predictor for the development of bleeding, so the doctor's attention requires any, even asymptomatic increase in the level of MNO above the therapeutic range.

The doctor's tactics in asymptomatic increase and the development of bleeding is determined by the degree of hypocoagulation, the presence of potential sources of bleeding and the need for invasive interventions in the near future, and in accordance with the latest 2008 recommendations, it provides for the abolition of anticoagulants, oral administration of phytomenadion (vitamin K1), intravenous administration of the prothrombin complex concentrate , recombinant VII factor, freshly frozen plasma (Table 5). Unfortunately, in our country from the proposed scheme it is possible to carry out only the abolition of warfarin and the introduction of freshly frozen plasma. The concentrate of the prothrombin complex and the oral shape of the vitamin K1 (at a dose of 1-2 mg), the purpose of which allows to reduce many changes in Russia during the day and are not registered in the domestic pharmaceutical market.

Available in Russia The Vikasol preparation is not an analogue of oral shape vitamin K1. Vikasol contributes to the synthesis of vitamin K-dependent coagulation factors DE NOVO due to the effect on carboxylation processes, so the effect of it occurs slowly and it is useless to quickly restore vitamin to-dependent coagulation factors. Domestic drug phytomenadion in capsules in capsules 0.1 g, containing a 10% solution in vitamin K1 oil, cannot be used to reduce the level of many, because The dose of vitamin K1, equal to 10 mg, causes resistance to AVC action for 7-10 days.

However, it is quite often an increase in Mno is not accompanied by bleeding and requires control of many and correction of the dose of warfarin. It is necessary to clarify the patients with the possible reasons for increasing MNA, as well as monitor the state of potential sources of bleeding.

The risk of bleeding increases during any invasive interventions - dental, ophthalmic, urological procedures, fibroscopy with biopsy, any operations, angiography, intramuscular injections.

A measure that reduces the risk of perioperative bleeding is replacing AVC on heparin therapy (both unfrained and low molecular weight). To make a decision on the temporary cancellation of warfarin or replacing it to heparin, it is necessary to assess the risk of bleeding during intervention and thromboembolic risk.

In patients with low risk of thromboembolism (flickering arrhythmia in the absence of risk factors for thromboembolic complications), warfarin can be canceled for a period of 5-7 days. Invasive intervention can be carried out at the level of many<1,5.

In patients with high risk of thromboembolism (patients with artificial valves of the heart, flickering arrhythmia, in the presence of risk factors, thromboembolism, undergoing deep vein thrombosis or a pulmonary artery thromboembolism), if necessary, the invasive intervention of anticoagulants should be replaced by heparin (unfractionated or low molecular weight) in doses used for the treatment of venous Thrombosis.

Low molecular weight heparin should be canceled 24 hours before surgery, while it is better to use a half-dose as the last injection. In the case of using intravenous administration of the unframeing heparin as a peripheral replacement, warfarin cancel the heparin is necessary, at least 4 hours before intervention.

Patients after small surgical interventions or after invasive procedures, heparin with low molecular weight can be resumed after 24 hours. Patients after a large surgical intervention or having an increased risk of bleeding It is recommended to postpone the resumption of heparinetherapy to 48-72 hours to ensure adequate hemostasis. Based on the individual risk assessment of bleeding, the presence of an adequate hemostasis is the resumption time of heparinotherapy in special cases can be postponed.

Patients before the upcoming dental operations can be continued to receive warfarin in the case of the use of a local hemostatic sponge and ensuring adequate local hemostasis. However, according to the author's opinion, the temporary cancellation of warfarin for 2-3 days with the resumption of therapy immediately after the procedure is more secure for the patient.

For home control currently there are portable devices for measuring the level of many. The meta-analyzing conducted by Heneghan in 2006 showed that self-adjusting MNA improves the outcomes of patients receiving warfarin. But for most patients of our country, the cost of portable coagulometrov is quite high, and they are unlikely to replace stationary and outpatient laboratory control in the near future.

Currently, Warfarin is a major drug for the prevention of thromboembolic complications in patients, after prosthetic heart valves, in persons after transferred venous thrombosis. The vitamin K antagonists are determining in the matter of effectiveness of therapy is the target range of many, which must be achieved in each patient. The frequency of hemorrhagic complications, as well as the need for permanent laboratory control is the main reason for the unassignment or cancellation of warfarin in real clinical practice. However, the rejection of anticoagulant therapy leads to the development of thromboembolic complications, death and diskaling of the patient. Existing algorithms for the selection of an individual supporting dose of warfarin, a system of patronage and regular laboratory monitoring of MFA allow you to improve the safety of anticoagulant therapy.

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Mitral insufficiency (regurgitation) is a state accompanied by overload.

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