What are hemorrhagic complications? Hemorrhagic syndrome caused by heparin Hemorrhagic complications during heparin therapy when used
Of the 5,000 primary or recurrent strokes diagnosed in the Republic of Belarus annually, 80% are cerebral infarctions. The selection of adequate treatment for ischemic cerebrovascular diseases depends on the accuracy of determining the causes of stroke. Heterogeneous structure of cerebral infarction currently implies the following variants of the disease:
- strokes due to stenosis or occlusion of large arterial vessels of the carotid or vertebral basin;
- blockage of small cerebral arteries;
- cardiogenic embolism;
- infarctions of adjacent blood supply zones (so-called hemodynamic);
- vasculopathy of non-atherosclerotic origin (arterial dissection, cerebral vasculitis, fibromuscular dysplasia, Moya-Moya disease, etc.);
- strokes due to hypercoagulable states;
- ischemic strokes of unknown etiology.
In international scientific research distribution of ischemic stroke subtypes carried out according to TOAST criteria: atherothrombotic, cardioembolic, lacunar and mixed/unspecified.
Most patients with cerebral infarction have atherosclerosis of the main and intracerebral arteries and arterial hypertension. Local ischemia of brain tissue develops as a result of atherothrombotic vascular occlusion, arterio-arterial embolism by detached atherosclerotic plaques, or hypoperfusion hemodynamic disorders.
In addition to a clinical neurological examination and a thorough history, the main methods for confirming the diagnosis of ischemic stroke Computer and magnetic resonance imaging of the brain is used, since intracerebral hemorrhages in some cases can give clinical symptoms similar to the symptoms of cerebral infarction. To identify the pathology of extra- and intracranial arteries and clarify the condition of the heart, an ultrasound examination of the heart and blood vessels is performed.
Patients hospitalized in the intensive care unit are basic stroke therapy. After excluding intracranial hemorrhages, differentiated drug therapy begins, the main focus of which is the use antithrombotic agents the following groups: anticoagulants, fibrinolytic agents and antiplatelet agents.
It must be emphasized that, according to modern scientific literature, There are no generally accepted anticoagulant therapy regimens in the acute period of cerebral infarction.. Anticoagulants inactivate thrombin and prevent the formation of fibrin strands of intravascular thrombus.
The most widespread both in our country and in foreign neurological clinics is anticoagulant therapy with heparin.
Heparin is the main representative of direct-acting anticoagulants. This endogenous substance is synthesized in the human body in the liver, lungs, intestinal mucosa, and muscles; is a mixture of heterogeneous fractions of glycosaminoglycans, consisting of sulfated D-glucosamine and D-glucuronic acid residues, with different polymer chain lengths and molecular weights from 2000 to 50,000 daltons. For clinical use, the drug is obtained from the intestinal mucosa of pigs, as well as from the lungs of cattle.
Angioneurologists use the leading effect of heparin, which manifests itself in thrombin inhibition- the main enzyme of blood clotting. To carry out the anticoagulant effect of heparin, its coenzyme is necessary - antithrombin III. Heparin, by changing the conformation of the antithrombin III molecule, significantly accelerates the binding of the coenzyme to the active centers of a number of factors of the blood coagulation system. Inhibition of thrombosis develops as a result of inactivation of blood clotting factors IXa, XIa, XIIa, kallikrein, thrombin and factor Xa. The drug suppresses the aggregation and adhesion of platelets, erythrocytes, leukocytes, reduces the permeability of the vascular wall, thereby improving collateral circulation, inhibits lipoprotein lipase, which is accompanied by a moderate decrease in the level of cholesterol and triglycerides in the blood serum.
The main complications of drug therapy with heparin are bleeding, thrombocytopenia, as well as osteoporosis, alopecia and hyperkalemia with long-term use. It is believed that high blood pressure levels significantly increase the risk of hemorrhage in patients with stroke. The TAIST studies on the treatment of patients with cerebral infarction with heparin showed that the incidence of intracerebral hemorrhage reaches 1-7%. Moreover, the risk of hemorrhagic complications correlates with the size of the infarction.
The second dangerous complication of heparin therapy in 1-2% of patients is heparin-induced thrombocytopenia due to increased platelet aggregation. In this regard, in stroke departments, the administration of heparin to patients should be carried out against a background of systematic (every 2 days) control of platelet count in general blood test. This is due to the fact that in some cases, on the 6-8th day of anticoagulant therapy with heparin, thrombocytopenia of immune origin, caused by IgG and IgM immunoglobulins.
Contraindications to heparin administration include bleeding of any location, hemophilia, hemorrhagic diathesis, increased vascular permeability, bleeding ulcerative lesions of the gastrointestinal tract, subacute bacterial endocarditis, severe liver and kidney dysfunction, acute and chronic leukemia, acute cardiac aneurysm, venous gangrene, allergic reactions.
Requires caution carrying out heparin therapy prescribed for health reasons, with high blood pressure (200/120 mm Hg), pregnancy, varicose veins of the esophagus, in the immediate postpartum and postoperative period.
Heparin solutions are administered intravenously or subcutaneously (into the periumbilical fatty tissue of the abdomen). Doses and methods of use of heparin are selected individually depending on the pathogenetic variant of cerebral infarction, clinical and laboratory parameters, neuroimaging results, and the presence of concomitant diseases.
With the intravenous method of heparin therapy, 5000 units of the drug are administered intravenously, after which they proceed to intravenous injection at a rate of 800-1000 units/hour. With intravenous administration of heparin, the anticoagulant effect develops immediately and lasts 4-5 hours. With subcutaneous injection of heparin, the anticoagulant effect begins after 40-60 minutes and lasts up to 8 hours.
The activity of heparin is expressed in units of action and is determined spectrophotometrically or by its ability to lengthen partial thromboplastin clotting time(aPTT). To achieve a therapeutic effect, aPTT is maintained at a level 1.5-2 times higher than normal values. When titrating the heparin dose, blood sampling to determine the aPTT is carried out every 6 hours, and subsequently daily throughout the entire period of heparin therapy.
Heparin antagonist is protamine sulfate. If hemorrhages develop during heparin therapy, 5 ml of 1% protamine is diluted in 20 ml of physiological sodium chloride solution and administered slowly intravenously. The maximum dose of protamine should not exceed 50 mg over a 10-minute administration time or 200 mg over 2 hours.
In the 1980s developed low molecular weight heparins(LMWH) are special drugs that differ from unfractionated heparin (UFH) by the constant molecular weight (4000-5000 daltons) and have high antithrombotic activity. LMWH inactivate factor Xa to a greater extent than unfractionated heparin, while LMWH inactivate thrombin to a lesser extent than unfractionated heparin, therefore the risk of hemorrhagic complications with their use is reduced. In addition, thrombocytopenia and osteoporosis are not observed. The half-life of LMWH is 1.5-4.5 hours, which allows them to be prescribed 1-2 times a day.
One of the main representatives of NMG is fraxiparine(nadroparin calcium). It is a glycosaminoglycan with an average molecular weight of 4300 daltons and is characterized by high anti-factor Xa activity, which persists for about a day after administration of the drug. Fraxiparine is distinguished by high bioavailability (98%), rapid development of anticoagulant action and its prolonged effect, complex mechanism of action, less binding to blood proteins, endothelium and macrophages.
Currently, the results of international studies TAIST, HAEST, TOPAS have been published, convincingly indicating the effective use of fraxiparine in the acute period of ischemic stroke. The drug can be prescribed within the first 24 hours of the disease. The multicenter randomized trial FISS (Fraxiparine in Ischemic Stroke Study) found that in the group of people treated with fraxiparine for cerebral infarction, the proportion of people with death or severe neurological deficit was 20% less than in the group of patients receiving placebo.
A significant advantage of Fraxiparin and other drugs from the LMWH group (Clexane, Fragmin, etc.) is that they are more selective influence on the process of blood clot formation. Compared to UFH, they have a lesser effect on the content of platelets and thrombin and, accordingly, are less likely to provoke thrombocytopenia and bleeding. Therefore, fraxiparine is currently recommended for use in patients with heparin-induced thrombocytopenia who should receive direct anticoagulant therapy for cerebral infarction. The high bioavailability and long half-life of LMWH compared to UFH have been confirmed in the prevention and treatment of venous thrombosis in patients with stroke.
The results have now been published randomized controlled trial of fraxiparine in acute cerebral infarction. The first point was defined as an unfavorable outcome - overall mortality and inability to self-care within 6 months after randomization. The second end point was defined as an unfavorable outcome over the next 3 months. After 6 months, there was a significant dose-dependent reduction in the incidence of adverse outcomes of ischemic stroke in patients treated with fraxiparine.
In January 2006, the results of the PROTECT trial were reported to the general medical community, in which patients with ischemic stroke were prescribed a new low-molecular-weight heparin, Certoparin, to prevent thrombotic and embolic complications.
When analyzing fatal cases caused by cerebral infarction, it was shown that 20% of patients die within the first 30 days. Moreover, in half of the deaths, the cause of death is potentially curable medical causes. The incidence of pneumonia, deep vein thrombosis and pulmonary embolism is 30%, 10 and 5%, respectively. Studies by foreign neurologists have found that in the treatment of patients with stroke, fraxiparine is significantly better than UFH in preventing the development of deep vein thrombosis and pulmonary embolism.
A multicenter trial of heparinoid Organon 10 172 in cerebral infarction is underway. The results of phases I and II of the studies have been published. During treatment, several patients experienced hemorrhagic complications, but in general the drug was found to be safe; within 3 months, patients showed positive dynamics in the clinical symptoms of stroke.
Large randomized trials have reduced the indications for the treatment of ischemic stroke with UFH. They believe that immediately after diagnosing ischemic stroke, the patient should be prescribed acetylsalicylic acid(aspirin) at a dose of 50-325 mg once a day.
For small or medium-sized cerebral infarction, antithrombotic therapy begins with immediate intravenous administration of heparin or fraxiparin, if there is a threat of a significant increase in the primary neurological deficit. In 2004, recommendations of the VII International Conference on Antithrombotic and Thrombolytic Therapy for the treatment of patients with acute cerebral infarction were published. All patients are proposed to be stratified according to the risk of thromboembolic complications. For prophylactic purposes, at a high risk of embolism (Grade 1A), subcutaneous administration of UFH, LMWH or heparinoid is indicated.
O. D. Wiebers et al. (2005) main indications for the use of direct anticoagulants consider:
- condition after a transient ischemic attack (TIA);
- increased frequency of TIAs, increased duration and severity;
- progressive stroke with stenosis of large arteries;
- the presence of a thrombus in the lumen of the main or intracerebral arteries;
- during operations on the arteries of the head and neck;
- cerebral venous sinus thrombosis;
- strokes due to hypercoagulability.
At cardioembolic ischemic stroke The effectiveness of heparin has not yet been proven. Moreover, in 1994, the American Heart Association Stroke Council recommended avoiding the use of heparin for cardioembolic stroke. At the same time, there is evidence of the relative safety of heparin use in patients with small and medium-sized embolic cerebral infarctions, the main condition of which should be careful monitoring of aPTT. In the case of extensive cardioembolic cerebral infarction (which involves the entire blood supply area of the middle cerebral or internal carotid arteries), intravenous heparin treatment is not used in the first days of the stroke. A few days later, a repeat computed tomography scan of the brain is performed. In the absence of hemorrhagic transformation of the infarction, intravenous administration of heparin is started at a dose of 1000 mg/h, ensuring careful monitoring of the aPTT.
In domestic neurology along with infusion drip administration of heparin, subcutaneous injections of heparin are used at a dose of 5000 units 2-4 times a day or fraxiparin subcutaneously once a day at a dose of 0.3-0.6 ml for 10 days, which corresponds to 2850-5700 IU anti- Ha-factor.
From 10-14 days after a cardioembolic stroke, in the absence of contraindications, treatment with indirect anticoagulants (warfarin) is prescribed. The advisability of pre-prescribing LMWH for 5-7 days before prescribing warfarin is currently the subject of clinical research. Primary and secondary prevention of stroke in patients with atrial fibrillation without valve damage, with rheumatic valvular disease or prosthetic heart valves involves taking direct and indirect anticoagulants. When taking oral anticoagulants in an adult patient, the average dose of warfarin is 5.0-7.5 mg in the first 2 days, then 2.5-5.0 mg per day. Monitored daily international normalized ratio(INR). The recommended INR level for primary or repeated prevention of cerebral infarction is from 2.0 to 3.0 units. At a high risk of repeated cardioembolic stroke in patients with artificial heart valves, repeated cardiogenic embolisms - from 3.0 to 4.5 INR units. Heparin administration is continued for 5-7 days while taking warfarin until therapeutic INR values are achieved. During the first week of warfarin therapy, clotting indicators are monitored daily or every other day, and once the INR has stabilized - once a month. In the case of long-term treatment with anticoagulants, the risk of developing hemorrhagic complications is 0.5-1.5% per year. Exceeding recommended levels of hypocoagulation, advanced age of patients and high blood pressure values increase the risk of hemorrhage with warfarin.
The European Atrial Fibrillation Trial (1994) demonstrated that in patients with small strokes or TIA due to atrial fibrillation anticoagulants are 62% more effective in reducing the risk of recurrent cerebral infarction than aspirin.
Experimental methods for normalizing blood flow in occluded cerebral vessels during ischemic stroke include thrombolysis using urokinase, streptokinase, tissue plasminogen activator, the use of fibrinolytic drugs (ankrod), neutrophil migration/adhesion inhibitors (anti-MMA antibodies), thrombin inhibitors (ximegalatran). Multicenter trials are studying the effectiveness of these drugs in cerebral infarction.
Thus, the question of the advisability of prescribing heparin in the acute period of cerebral infarction is still controversial. At the same time, it is recognized that anticoagulant therapy is one of the few real ways to prevent and treat thromboembolic stroke. Established indications for therapy with direct anticoagulants are cases of cerebral infarction, when there is a threat of increasing neurological deficit. Research in recent years is characterized by the use of LMWH (fraxiparine, etc.) for cerebral infarction due to their more selective effect on the mechanism of the hemocoagulation cascade and a low number of hemorrhagic complications. Particular prospects for the use of fraxiparine may be associated with the prevention and treatment of cardioembolic ischemic strokes in patients with cardiac arrhythmias, acute coronary syndrome and congestive heart failure.
Gonchar I. A., Likhachev S. A., Nedzved G. K. Republican Scientific and Practical Center of Neurology and Neurosurgery of the Ministry of Health of the Republic of Belarus.
Published: Medical Panorama magazine No. 6, December 2006.
Heparin is used to prevent and treat venous thrombosis and pulmonary embolism. It is also used in the treatment of unstable angina and myocardial infarction, to prevent acute reocclusion after angioplasty or stenting, to prevent thrombosis during vascular surgery, and in high doses for hemodialysis or extracorporeal circulation. In patients with DIC, heparin can be used to reduce the activation of hemostasis.
Heparin is used for anticoagulant therapy during pregnancy. In this situation, it is the anticoagulant of choice, since warfarin is contraindicated during pregnancy due to its teratogenic effect. Heparin does not cross the placenta and does not cause any anticoagulant effect in the fetus. However, it may increase the risk of bleeding during labor, so its administration is discontinued shortly before the onset of labor or planned surgical delivery.
To prevent thromboembolic complications, heparin is used subcutaneously at a dose of 5000 units. every 8-12 hours; in patients at higher risk, an 8-hour dosing regimen is more appropriate. For the treatment of venous thromboembolism, heparin is used according to the following regimen (level of evidence – I): 5000 units IV bolus followed by IV infusion of 1680 units/hour. For unstable angina or acute myocardial infarction without thrombolytic therapy, heparin is administered 5000 units. IV bolus and then 32,000 units. within 24 hours by infusion (level of evidence – I). If thrombolytic therapy is performed during myocardial infarction, then heparin is administered 5000 units. IV bolus and then 24,000 units. within 24 hours by infusion (level of evidence – I).
Complications of heparin therapy
The main complications of heparin therapy are presented in Table 3.2.
Table 3.2. Complications of heparin therapy
Heparin-associated bleeding. On average, they develop in 5% of patients receiving therapeutic doses of heparin. The development of bleeding depends more on the total daily dose, and not on the method of administration of heparin. The risk of hemorrhage increases with the simultaneous administration of antiplatelet drugs, thrombolytics and other drugs that potentiate the anticoagulant effect of heparin. The risk of hemorrhagic complications increases with renal failure, peptic ulcer, open wound surface (after surgery), advanced age or concomitant hemostatic defect.
Heparin - induced osteoporosis. A decrease in bone density is observed in 30% of patients receiving heparin for 1 month or more. Heparin leads to osteoporosis by decreasing osteogenesis and increasing bone resorption. Heparin-induced osteoporosis takes a long time to resolve (possibly because heparin binds to bone tissue).
Heparin-induced thrombocytopenia (HIT). Develops during heparin therapy in 1-5% of patients. Type I HIT is caused by the direct proaggregation effect of heparin. It is characterized by moderate thrombocytopenia (platelet count > 100 thousand/μl) and does not require specific therapy.
Type II HIT develops 4-14 days after the start of heparin administration and has an immune pathogenesis - the development of autoantibodies against the complex of platelet factor 4 and heparin. Antibodies activate platelets, the complement system, cause damage to endothelial cells with exposure to tissue factor and collagen, thereby promoting the development of thrombosis. Thrombocytopenia in this case is significant (often< 100 тыс/мкл). Необходима немедленная отмена гепарина и продолжение антикоагулянтной терапии рекомбинантным гирудином, данапароидом или фондапарином.
Low molecular weight heparins
The presence of clinical problems with heparin therapy (unpredictable absorption and bioavailability during subcutaneous administration, complications) led to the development and introduction into practice of low molecular weight heparins (LMWH). Low molecular weight heparins are produced by chemical or enzymatic processing of heparin to reduce the size of the polysaccharide chains, resulting in substances with low molecular weight (on average approximately 4000–5000 kDa) (Table 3.3).
Table 3.3. LMWH group drugs
Like unfractionated heparin (UFH), the anticoagulant effect of LMWHs occurs through their interaction with antithrombin III. In the presence of LMWH, antithrombin III inactivates factor Xa, like unfractionated heparin, but is less able to inactivate thrombin due to the shorter length of the polysaccharide. A comparison of the important clinical properties of heparin and LMWH is shown in Table 3.4.
Table 3.4. Comparative characteristics of LMWH and UFH
| NFG | NMG | |
| Molecular mass | 15-20 thousand kDa | Average 5000 kDa |
| Bioavailability | 30% | 100% |
| Half life | 1-2 hours | 3-5 h |
| Elimination from the body | Cellular saturation | Mainly kidneys |
| Dose-dependent clearance | + | - |
| Ability to bind to endothelial cells | + | - |
| The antithrombotic effect is due to | Mainly antithrombin activity | 30% anti-Xa activity, 70% via ITP release |
| APTT prolongation | expressed | minimum |
| Rebound thromboses | causes | don't call |
| Autoimmune thrombocytopenia | + | not significant |
| The need for laboratory control | + | - |
| Transplacental transition | + | - |
| Increased permeability of the vascular wall | + | - |
| Complications of use: hemorrhages, alopecia, osteoporosis | + | - |
LMWHs can be used intravenously, but are usually administered subcutaneously due to their almost complete absorption and the apparent convenience of this route of administration. In addition, unlike heparin, LMWHs bind much less to plasma proteins and blood cells. Consequently, their plasma concentrations and effects are more predictable. LMWH also has a longer half-life than unfractionated heparin. Based on this, it is possible to administer LMWH subcutaneously once or twice a day. LMWHs are excreted primarily through the kidneys, so in patients with impaired renal function, monitoring the level of anti-Xa activity and dose adjustment are necessary. Obese patients also present certain difficulties in selecting the required dose.
The use of LMWH is increasing, covering more and more areas where UFH was previously traditionally used. Many clinical studies have been conducted on the use of LMWH for the prevention and treatment of thromboembolic complications. Dosage regimens for LMWH drugs approved for use in Russia are presented in Table 3.5.
| General surgery - moderate risk of venous thromboembolism (VTE) | |
| Dalteparin (Fragmin) | 2500 units subcutaneously 1-2 hours before surgery and 1 time per day after surgery |
| Enoxyparine (Clexane) | 20 mg subcutaneously 1-2 hours before surgery and 1 time per day after surgery |
| Nadroparin (Fraxiparin) | |
| General surgery - high risk of VTE | |
| Dalteparin (Fragmin) | 5000 units subcutaneously 8-12 hours before surgery and once a day after surgery |
| Enoxyparine (Clexane) | 40 mg subcutaneously 1-2 hours before surgery and 1 time per day after surgery |
| Nadroparin (Fraxiparin) | 2850 units subcutaneously 2-4 hours before surgery and 1 time per day after surgery |
| Traumatology and orthopedics | |
| Dalteparin (Fragmin) | 5000 units subcutaneously 8-12 hours before surgery, 12-24 hours after surgery and then once a day |
| Enoxyparine (Clexane) | 40 mg subcutaneously 10-12 hours before surgery and 1 time per day after surgery |
| Nadroparin (Fraxiparin) | 54 units/kg subcutaneously 12 hours before surgery and 1 time per day after surgery |
The pharmacokinetic properties of LMWH drugs allow them to be administered subcutaneously for the treatment of acute venous thrombosis and pulmonary embolism; the effectiveness and safety of this method of administration have been clinically established (level of evidence – I):
Enoxaparin – 1 mg\kg (100 units\kg) after 12 hours subcutaneously;
Nadroparin –90 units/kg after 12 hours subcutaneously;
Dalteparin – 100 units/kg every 12 hours subcutaneously.
Similar doses are used in the treatment of acute coronary syndromes; Clinical studies have shown a higher effectiveness of LMWH compared to UFH in patients with unstable angina and acute myocardial infarction.
The main complication of LMWH use is bleeding. Major bleeding occurs at approximately the same rate as with UFH treatment in similar patient groups. Heparin-induced thrombocytopenia is much less common with LMWH treatment (approximately 10%-15%) than with heparin treatment, however, due to the presence of cross-reactivity to antibodies, LMWH are not optimal drugs for long-term anticoagulant therapy in patients treated with heparin -induced thrombocytopenia. Osteoporosis with the use of LMWH is observed much less frequently than with the use of UFH, but there is not yet enough clinical data on this.
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Release form: Liquid dosage forms. Injection.
General characteristics. Compound:
Active ingredient: 5000 units of heparin in 1 ml of solution.
Pharmacological properties:
Pharmacodynamics. Heparin is a direct-acting anticoagulant. Binds to antithrombin III, causes conformational changes in its molecule and accelerates the complexation of antithrombin III with serine proteases of the coagulation system; as a result, thrombin and the enzymatic activity of factors IX, X, XI, XII, plasmin and kallikrein are blocked. Heparin does not have a thrombolytic effect. Introduction of the drug into the blood in small doses is accompanied by a slight and inconsistent increase in the fibrinolytic activity of the blood; Large doses of heparin usually cause inhibition of fibrinolysis.
Heparin reduces blood viscosity and prevents the development of stasis. Heparin is able to adsorb on the surface of endothelial membranes and blood cells, increasing their negative charge, which prevents the adhesion and aggregation of platelets, erythrocytes, and leukocytes. Heparin molecules, which have a low affinity for antithrombin III, cause inhibition of smooth muscle hyperplasia and also suppress the activation of lipoprotein lipase, which prevents the development. Heparin has an antiallergic effect: it binds some components of the complement system, reducing its activity, prevents the cooperation of lymphocytes and the formation of immunoglobulins, binds histamine and serotonin. Inhibits the activity of hyaluronidase. Has a weak vasodilator effect.
In patients with coronary artery disease (in combination with acetylsalicylic acid) it reduces the risk of developing acute thrombosis of the coronary arteries, myocardial infarction and sudden death. Reduces the frequency of recurrent infarctions and mortality in patients who have had myocardial infarction. In high doses it is effective for pulmonary embolism and venous thrombosis, in small doses - for the prevention of venous thromboembolism, incl. after surgical operations.
Heparin acts quickly, but is relatively short-lived. With intravenous administration, blood coagulation slows down almost immediately, with intramuscular administration - after 15-30 minutes, with subcutaneous administration - after 40-60 minutes, after inhalation the maximum effect is observed within a day; The duration of the anticoagulation effect, respectively, is 4-5 hours, 6 hours, 8 hours, 1-2 weeks, the therapeutic effect (prevention of thrombosis) lasts much longer. I in plasma or site may limit the antithrombotic effect of heparin.
Pharmacokinetics. When administered subcutaneously, bioavailability is low, Cmax is achieved after 2 - 4 hours; T1/2 is 1 - 2 hours. In plasma, heparin is mainly in a protein-bound state; intensively captured by endothelial cells of the mononuclear-macrophage system, concentrated in the liver and spleen; when administered by inhalation, it is absorbed by alveolar macrophages, endothelium of capillaries, large blood and lymphatic vessels.
Subject to desulfation under the influence of N-desulfamidase and platelet heparinase. Desulfated molecules are converted into low molecular weight fragments under the influence of kidney endoglycosidase. It is excreted by the kidneys in the form of metabolites, and only with the administration of high doses is excretion possible in unchanged form. Heparin penetrates the placenta poorly due to its high molecular weight. Not excreted in breast milk.
Indications for use:
Directions for use and dosage:
Heparin is administered intravenously or intramuscularly (every 4 hours), subcutaneously (every 8-12 hours) and as an intra-arterial infusion, as well as by electrophoresis. In case of acute myocardial infarction, on the first day, the first dose (10,000-15,000 units) is administered intravenously, then fractional intravenous or intramuscular administration of the drug is continued at a dose of 40,000 units per day, so that the blood clotting time is 2.5-3 times higher than normal quantities. Starting from the 2nd day, the daily dose is 600 units/kg of patient weight (30,000-60,000 units), so that the blood clotting time is 1.5-2 times higher than normal. Treatment with heparin is continued for 4-8 days. 1-2 days before discontinuation of heparin, the daily dose is gradually reduced (daily by 5000-2500 units for each injection without increasing the intervals between them) until the drug is completely discontinued, after which treatment is carried out only with indirect anticoagulants (neodicoumarin, phenylin, etc.), which are prescribed from 3-4 days of treatment.
When using heparin in complex conservative therapy of acute venous or arterial obstruction, they begin with a continuous intravenous drip infusion of the drug for 3-5 days. The daily dose of heparin (400-450 units/kg) is diluted in 1200 ml of isotonic sodium chloride solution or Ringer-Locke solution and poured at a rate of 20 drops per minute. Then heparin is administered in fractional doses at a dose of 600 units/kg per day (100 units/kg per injection). If intravenous administration of heparin is not possible, it is used intramuscularly or subcutaneously at a dose of 600 units/kg per day. Heparin therapy is continued for 14-16 days. 3-4 days before discontinuation of heparin, the daily dose is reduced daily by 2500-1250 units for each injection without increasing the intervals between them. After discontinuation of the drug, treatment is carried out with indirect anticoagulants, which are prescribed one day before the first reduction in the dose of heparin.
In the surgical treatment of these diseases during surgery immediately before thrombectomy from the main veins or immediately after embolthrombectomy from the arteries, heparin is administered at a dose of 100 U/kg intravenously or intraarterially. Then, during the first 3-5 days of the postoperative period, heparin is administered intravenously at a rate of 20 drops per minute regionally into the vein from which the thrombus was removed, at a dose of 200-250 units/kg per day or intravenously into the general bloodstream at a dose of 300- 400 units/kg per day. Starting from 4-6 days after surgery, heparin therapy is carried out in the same way as with conservative treatment. After operations performed for acute arterial obstruction, heparin therapy is continued for 10-12 days, and a reduction in the dose of heparin begins on the 6-7th day of treatment.
In ophthalmological practice, heparin is used for all types of vascular occlusion of the retina, as well as for all angiosclerotic and dystrophic processes of the vascular tract and retina. In case of acute obstruction of retinal vessels, the first dose of heparin (5000-10000 units) is administered intravenously. Next, heparin is used in fractional intramuscular doses of 20,000-40,000 units per day. Treatment is carried out in accordance with the clinical picture of the disease for 2-7 days. On the second or third day, it is possible to use heparin in combination with indirect anticoagulants.
For direct blood transfusion, heparin is administered to the donor in a dose of 7500-10000 units intravenously.
Features of application:
Treatment with heparin must be carried out under careful monitoring of the state of hemocoagulation. Studies of the state of blood coagulation are carried out: in the first 7 days of treatment - at least 1 time in 2 days, then 1 time in 3 days; on the first day at least 2 times a day, on the 2nd and 3rd days - at least 1 time a day. With fractional administration of heparin, blood samples for analysis are taken immediately before injection of the drug.
Sudden cessation of heparin therapy can lead to rapid activation of the thrombotic process, so the dose of heparin should be reduced gradually while prescribing indirect anticoagulants. Exceptions are cases of severe hemorrhagic complications and individual intolerance to heparin.
Hemorrhagic complications can occur in any condition, including a hypercoagulable state of blood coagulation. Measures to prevent hemorrhagic complications include: the use of heparin only in a hospital setting; limiting the number of injections (subcutaneous and intramuscular), with the exception of injections of heparin itself; careful monitoring of blood coagulation status; if threatening hypocoagulation is detected, immediately reduce the dose of heparin without increasing the intervals between injections. To avoid the formation of hematomas at injection sites, it is better to use the intravenous method of administering heparin.
Side effects:
When using heparin, headaches, early (2-4 days of treatment) and late (autoimmune), hemorrhagic complications - in the gastrointestinal tract or in the urinary tract, retroperitoneal hemorrhages in the ovaries, adrenal glands (with the development of acute adrenal insufficiency), soft tissue calcification can be observed. , inhibition of aldosterone synthesis, increased levels of transaminases in the blood, allergic reactions (fever, rashes, bronchial asthma, anaphylactoid reaction), local irritation, pain upon administration).
In case of individual intolerance and the appearance of allergic complications, heparin is discontinued immediately and desensitizing agents are prescribed. If it is necessary to continue anticoagulant therapy, indirect anticoagulants are used.
Depending on the severity of the hemorrhagic complication, you should either reduce the dose of heparin or discontinue it. If bleeding continues after discontinuation of heparin, a heparin antagonist, protamine sulfate (5 ml of 1% solution), is administered intravenously. If necessary, the administration of protamine sulfate can be repeated.
Interaction with other drugs:
The effects of heparin are enhanced by acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, warfarin, dicoumarin (increases the risk of bleeding), weakened by cardiac glycosides, tetracyclines, antihistamines, nicotinic acid, ethacrynic acid.
Contraindications:
The use of heparin is contraindicated in case of individual intolerance and the following conditions: bleeding of any location, with the exception of hemorrhage caused by embolic (hemoptysis) or kidney (hematuria); hemorrhagic diathesis and other diseases accompanied by slow blood clotting; increased vascular permeability, for example, with Werlhof's disease; history of repeated bleeding, regardless of location; subacute bacterial endocarditis; severe impairment of liver and kidney function; acute and chronic leukemia, aplastic and hypoplastic anemia; acutely developed cardiac aneurysm; venous gangrene.
The drug should be used with caution in the following cases: with ulcerative and tumor lesions of the gastrointestinal tract, regardless of its etiology, high blood pressure (above 180/90 mmHg), in the immediate postoperative and postpartum period during the first 3-8 days (except for operations on blood vessels and in cases where heparin therapy is necessary for health reasons).
The risk of adverse effects in pregnant women when using heparin ranges from 10.4% to 21%. During a normal pregnancy, it is 3.6%. When using heparin, the risk of death is 2.5% and 6.8% and is similar to the risk in the natural population. The consequences of heparin use during pregnancy may include: bleeding, thrombocytopenia, osteoporosis. The risk of developing thromboembolic complications during pregnancy, which can be eliminated by the use of heparin, is more life-threatening, so the use of heparin during pregnancy is possible, but only according to strict indications, under close medical supervision. Heparin does not cross the placenta and side effects on the fetus are unlikely. Possible use during lactation (breastfeeding) according to indications.
Vacation conditions:
On prescription
Package:
Solution for injection 5000 U/ml in 5 ml bottles in package No. 5
Typical injection sites: outer upper arm. Outer surface of the thigh. Subscapular region. Anterior abdominal wall.
Possible complications:
Infiltration is the most common complication of subcutaneous and intramuscular injections. It is characterized by the formation of a compaction at the injection site, which is easily determined by palpation.
An allergic reaction is an increased sensitivity of the body to the administration of a particular drug. It manifests itself as a rash, swelling, itching, and increased body temperature.
An abscess is a purulent inflammation of soft tissues with the formation of a cavity filled with pus.
Anaphylactic shock - (allergic reaction) develops within a few seconds or minutes from the moment of administration of the drug.
Hematoma.
Drug embolism (Greek Embolia - throwing in) is a blockage of a vessel with a medicinal solution, for example, when administering oil solutions.
Features of the use of heparin.
Heparin is a direct anticoagulant: it inhibits the formation of thrombin and prevents blood clotting.
Doses are set individually: 5,000 units are administered intravenously or intramuscularly after 4-6 hours, or subcutaneously deep, in the epigastric region - to stimulate the production of endogenous heparin.
Complications. When using heparin, hemorrhagic complications may occur:
* hematuria (blood in
* hemorrhages in the joints,
gastrointestinal bleeding,
* hematomas at the site of subcutaneous and intramuscular injection.
Possible allergic reactions:
* urticaria,
* lacrimation.
In case of an overdose of heparin, 5 ml of a 1% solution of protamine sulfate, 1-2 ml of dicinone are administered intravenously or intramuscularly as its antagonist.
1-2 ml syringe for single use; needle 20 mm, cross-section 0.4 mm.
Complications of antithrombotic therapy for acute coronary syndrome.
Honored Doctor of the Russian Federation, anesthesiologist-resuscitator of the ICU State Budgetary Healthcare Institution "Bryansk Regional Cardiological Dispensary"
The basis of treatment for ACS (acute coronary syndrome) without ST segment elevation is active antithrombotic therapy, which consists of the use of antiplatelet agents aspirin and clopidogrel in combination with an anticoagulant - heparin (unfractionated or low molecular weight) or a synthetic factor Xa inhibitor (fondaparinux). The most important component of antithrombotic therapy in the treatment of ST-segment elevation ACS is thrombolytic therapy. Complications of antithrombotic therapy will be presented next.
The main complications of thrombolysis:
1. Bleeding(including the most severe - intracranial) - develop due to inhibition of blood coagulation processes and lysis of blood clots. The incidence of serious bleeding is no more than 3%. The risk of stroke during systemic thrombolysis is 0.5-1.5% of cases; stroke usually develops on the first day after thrombolysis. The patient's age over 65 years, body weight less than 70 kg, a history of arterial hypertension, as well as the use of tPA (tissue plasminogen activator) as a thrombolytic can be considered as risk factors for hemorrhagic stroke. Undoubtedly, an important issue in the prevention of hemorrhagic complications is the adequate implementation of concomitant anticoagulant and antiplatelet therapy. This is especially true for the prescription of heparin, since a prolongation of APTT (activated partial thromboplastin time) of more than 90 s correlates with an increased risk of cerebral hemorrhages. To stop minor bleeding (from the puncture site, from the mouth, nose), pressing the bleeding area is sufficient.
For more significant bleeding (gastrointestinal, intracranial), an intravenous infusion of aminocaproic acid is necessary - 100 ml of a 5% solution is administered over 30 minutes and then 1 g/hour until the bleeding stops, or tranexamic acid 1-1.5 g 3-4 once a day intravenously, in addition, transfusion of fresh frozen plasma is effective. It should be remembered that when using antifibrinolytic drugs, the risk of coronary artery reocclusion and reinfarction increases, so they should be used only for life-threatening bleeding.
2. Arrhythmias, occurring after restoration of coronary circulation (reperfusion) are “potentially benign” and do not require intensive care.
This applies to a slow nodal or ventricular rhythm (with a heart rate less than 120 per minute and stable hemodynamics); supraventricular and ventricular extrasystole (including allorhythmic); atrioventricular block I and II (Mobitz type I) degree.
Emergency treatment is required: - ventricular fibrillation (defibrillation and a set of standard resuscitation measures are required); - bidirectional fusiform ventricular tachycardia of the “pirouette” type (defibrillation, intravenous bolus administration of magnesium sulfate are indicated); - other types of ventricular tachycardia (use lidocaine administration or perform cardioversion); - persistent supraventricular tachycardia (stopped by intravenous jet administration of verapamil or novocainamide); - atrioventricular block II (Mobitz type II) and III degree, sinoatrial block (atropine is injected intravenously in a dose of up to 2.5 mg, if necessary, emergency cardiac pacing is performed).
3. Allergic reactions.
The incidence of anaphylactic shock when using tPA is less than 0.1%. Rash, itching, periorbital edema occur in 4.4% of cases, severe reactions (Quincke's edema, anaphylactic shock) - in 1.7% of cases. If an anaphylactoid reaction is suspected, the streptokinase infusion should be immediately stopped and a bolus of 150 mg prednisolone administered intravenously. In case of severe hemodynamic depression and signs of anaphylactic shock, 0.5 - 1 ml of a 1% solution of adrenaline is administered intravenously, continuing the administration of steroid hormones intravenously. For fever, aspirin or paracetamol is prescribed.
4. Recurrence of pain after thrombolysis is relieved by intravenous fractional administration of narcotic analgesics. If ischemic changes on the ECG increase, intravenous drip administration of nitroglycerin is indicated, or if the infusion has already been established, an increase in the rate of its administration.
5. For arterial hypotension in most cases, it is sufficient to temporarily stop the thrombolytic infusion and elevate the patient's legs; if necessary, the blood pressure level is adjusted by administering fluids, vasopressors (dopamine or norepinephrine intravenously until systolic blood pressure stabilizes at 90-100 mm Hg).
Thrombolytic drugs are not used for ACS without ST segment elevations on the ECG. Data from large studies and meta-analyses did not reveal the benefits of thrombolysis in patients with unstable angina and non-Q wave MI; on the contrary, the administration of thrombolytic drugs was associated with an increased risk of death and myocardial infarction.
Complications of heparin therapy:
- bleeding, including hemorrhagic stroke, especially in the elderly (from 0.5 to 2.8%); hemorrhages at injection sites; thrombocytopenia; allergic reactions; osteoporosis (rare, only with long-term use).
If complications develop, it is necessary to administer a heparin antidote - protamine sulfate, which neutralizes the anti-IIa activity of unfractionated heparin at a dose of 1 mg of the drug per 100 units of heparin. At the same time, discontinuation of heparin and use of protamine sulfate increase the risk of thrombosis. The development of complications when using heparin is largely associated with the characteristics of its pharmacokinetics. Heparin is eliminated from the body in two phases: a rapid elimination phase, as a result of the drug binding to membrane receptors of blood cells, endothelium and macrophages, and a slow elimination phase, mainly through the kidneys. The unpredictability of receptor uptake activity, and therefore the binding of heparin to proteins and the rate of its depolymerization, determines the second “side of the coin” - the impossibility of predicting therapeutic (antithrombotic) and side (hemorrhagic) effects. Therefore, if it is not possible to control the aPTT, it is impossible to talk about the required dose of the drug, and therefore about the usefulness and safety of heparin therapy. Even if the aPTT is determined, the dose of heparin can only be controlled with intravenous administration, since with subcutaneous administration there is too much variability in the bioavailability of the drug.
In addition, it should be noted that bleeding caused by the administration of heparin is associated not only with the effect of the drug on the blood coagulation system, but also on platelets. Thrombocytopenia is a fairly common complication of heparin administration. The drug should be immediately discontinued if the patient detects red blood cells in the urine, petechial rashes on the skin, unusual bleeding of the gums, nasal, intestinal or other bleeding, as well as if the number of platelets in the hemogram drops by half compared to the initial value. After 5-7 days from the start of heparin therapy, the activity of aminotransferases (especially alanine) sharply increases in a number of patients, which is most often mistakenly interpreted as a sign of current hepatitis. Using heparin for more than 10-15 days increases the risk of possible development of osteoporosis. Low molecular weight heparin derivatives cause thrombocytopenia much less frequently. Longer inhibition of thrombin activity and higher, compared with heparin, bioavailability of these anticoagulants allow them to be prescribed in low doses and it is easier to control the therapeutic effect.
Combination of clopidogrel with aspirin, complications.
Based on the data from the CURE study, the combination of clopidogrel with aspirin is recommended for all patients with ACS without ST segment elevation on the ECG, both in the case of CBA (coronary balloon angioplasty) and without planned intervention on the coronary arteries. The dose of aspirin when combined with clopidogrel should not exceed 100 mg/day. The recommended duration of administration of clopidogrel in patients who have undergone ACS is up to 9 months if the drug is well tolerated and there is no risk of bleeding. In the case of coronary artery bypass surgery, clopidogrel is discontinued 5–7 days before surgery.
Combination therapy was associated with an increase in the number of serious bleeding complications: 3.7% versus 2.7%, p = 0.001, but there was no statistical difference in life-threatening bleeding complications (2.2% versus 1.8%). A relationship was noted between the increase in bleeding and the dose of aspirin when combined with clopidogrel. The risk of bleeding was almost 2 times higher when taking aspirin >200 mg/day than when taking<100 мг/сут.
Platelet receptor IIb/IIIa inhibitors, complications.
Inhibitors of IIb/IIIa platelet receptors are essentially universal antiplatelet drugs that block the final stage of platelet aggregation, namely the interaction between activated receptors and adhesive proteins (fibrinogen, von Willebrand factor, fibronectin).
The most common complications with the use of platelet receptor IIb/IIIa inhibitors are bleeding and thrombocytopenia. Thrombocytopenia is rare, and stopping the infusion of IIb/IIIa receptor inhibitors usually results in normalization of platelet counts. Less commonly, platelet transfusions may be required when using absiximab. There are reports of a reduced risk of complications when low molecular weight heparins are used in combination with platelet receptor IIb/IIIa inhibitors instead of unfractionated heparins.
Literature
2. Kirichenko angina. Tutorial. Moscow, 1998.
3. Kryzhanovsky and treatment of myocardial infarction. Kyiv: Phoenix, 2 pages.
4. Acute coronary syndrome without persistent ST segment elevation on the ECG. Recommendations of the working group of the European Society of Cardiology (ESC). Supplement to the journal "Cardiology", 2001, No. 4. -28s.
5. Federal guidance for doctors on the use of medicines (formulary system) Issue III. - M.: "ECHO", 20 p.
6. Yavelov of acute coronary syndrome without ST segment elevation. Heart: a magazine for medical practitioners. 2002, vol. 1, no. 6, pp. 269-274.
7. Yavelov aspects of thrombolytic therapy for acute myocardial infarction. Pharmateka. 2003; No. 6: 14-24
Anesthesiologist-resuscitator, ICU
Chief Physician Honored Doctor of the Russian Federation
