- Anticoagulants (anticoagulants): indications
- Anticoagulants: contraindications
- Mechanism (cascade) of blood coagulation
- Anticoagulants (anticoagulants): types
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VERIFIED CONTENTAuthor: lek. Piotr PodwysockiAnticoagulants, or anticoagulants, are a large group of drugs whose main task is to slow down the blood clotting process. It is a process that prevents blood loss with tissue damage and vessel disruption. Check what are the indications and contraindications for the use of anticoagulants and what side effects they can cause. Learn about the variety of anticoagulants.
Anticoagulants( anticoagulants ), whose task is to inhibit blood clotting, are mainly used to prevent and treat thromboembolism complications that may develop in the course of atrial fibrillation, as well as in the treatment of congenital blood coagulation disorders.
Anticoagulants (anticoagulants): indications
Among the main indications for the use of drugs that inhibit blood clotting are:
- prophylaxis of venous thromboembolism (pulmonary embolism, deep vein thrombosis) and its complications in hospitalized, long-term immobilized patients (e.g. elderly, unconscious patients in severe clinical condition, patients wearing a plaster cast), after extensive surgical procedures and those suffering from neoplastic disease
- prevention of ischemic stroke and thrombosis in patients with atrial fibrillation, as well as during cardiac surgery, including implantation of artificial heart valves
- thrombophilia, a congenital disorder of the coagulation system characterized by an increased tendency to form blood clots. It occurs in people with, among others, an inherited increase in the concentration of coagulation factors and co-factors, hyperhomocysteinemia, congenital deficiency of antithrombin and proteins C and S (which are natural anticoagulants in the human body), as well as a genetic mutation of Leiden factor V of blood clotting
- therapy of the antiphospholipid syndrome (also known as the anticardiolipin syndrome). Antiphospholipid syndrome is an autoimmune disease of unknown etiology characterized by the presence of antiphospholipid antibodies. The disease is more common in women than in men. In its coursethere is a vascular thrombosis and obstetric complications in the form of recurrent miscarriages and difficulties in maintaining the pregnancy.
Anticoagulants: contraindications
Drugs that inhibit blood clotting should be taken under strict medical supervision. There are 2 groups of contraindications, absolute and relative, which must be taken into account by a doctor before issuing a prescription and starting therapy.
Absolute contraindications
- active clinically significant bleeding
- fresh intracranial bleeding
- spontaneous or traumatic subarachnoid bleeding
- haemorrhagic diathesis, congenital or acquired
- drug hypersensitivity
Relative contraindications
- gastrointestinal diseases associated with a high risk of bleeding (especially peptic ulcers of the duodenum and stomach) and symptoms of gastrointestinal bleeding
- symptomatic portal hypertension
- advanced liver failure and kidney failure
- poorly controlled hypertension (>200 / 110mmHg)
- brain tumor
- condition immediately after surgery on the brain, spinal cord and eyes
- aortic dissection
- up to 24 hours after surgery, organ biopsy or arterial puncture
- diagnostic or therapeutic lumbar puncture (within 24h)
- diabetic retinopathy
- acute pericarditis
- Heparin-dependent immune thrombocytopenia (HIT)
- pregnancy (oral vitamin K inhibitors are teratogenic!)
Mechanism (cascade) of blood coagulation
The blood clotting process takes place as a result of the activation of platelets (under the influence of stimulation of various receptors on their surface), plasma factors and vascular factors.
There are two basic mechanisms that initiate the process of blood coagulation: extravascular and intravascular.
With the participation of many coagulation factors, which take part in a series of cascade protelitic reactions and transform from an inactive form into an active protease (e.g. inactive factor VIII into active factor VIIIa), prothrombin is finally converted into thrombin (under the influence of active factor Xa).
The resulting thrombin is an enzyme that plays a key role in blood clotting. It causes that not only soluble fibrinogen produces insoluble fibrin (i.e. fibrin) and forms a clot, but also activates many clotting factors. The action of thrombin inhibits endogenousanticoagulant which is antithrombin.
Anticoagulants (anticoagulants): types
There are many ways to classify anti-clotting drugs. They are most often divided according to the route of administration (oral, intravenous and subcutaneous preparations), the mechanism of action, and the purpose for which they are used.
There are 4 main groups of drugs that inhibit blood clotting: vitamin K antagonists, drugs indirectly inhibiting thrombin activity, drugs directly inhibiting thrombin activity and drugs directly inhibiting the activity of coagulation factor Xa.
1. Vitamin K antagonists
Among the drugs belonging to the group of vitamin K antagonists, acenocoumarol and warfarin are distinguished. It is worth mentioning that warfarin is one of the most commonly used anticoagulants by patients worldwide.
- vitamin K antagonists - mechanism of action
Vitamin K is necessary for the synthesis of blood clotting factors in the liver. When vitamin K antagonists are used, the resulting blood coagulation factors (factor II, VII, IX, X and proteins C and S) are not of full value and do not activate the clotting process.
- vitamin K antagonists - route of administration
Both acenocoumarol and warfarin are medications that are administered orally.
- vitamin K antagonists - main differences between acenocoumarol and warfarin
The basic differences between acenocoumarol and warfarin include the time after which drugs reach their maximum concentration in the blood (acenocoumarol 2-3h, warfarin 1.5h) and their biological half-life (acenocoumarol 8-10h, warfarin 36-42h) .
- vitamin K antagonists - indications for administration
Vitamin K antagonists are the basic drugs used prophylactically in patients with an increased predisposition to develop thromboembolism, suffering from atrial fibrillation (prophylaxis of arterial embolism), with implanted artificial heart valves, as well as secondary prevention of myocardial infarction.
However, in the treatment of thromboembolic conditions, patients are initially given heparin due to the rapid onset of action, and vitamin K antagonists are used only after a few days as a continuation of treatment.
- vitamin K antagonists - monitoring of blood coagulation parameters
Frequent blood laboratory tests and monitoring of coagulation parameters (exactly prothrombin time (PT) expressed as INR, the international normalized ratio, are very important.(INR, international normalized ratio).
Choosing the right dose of the drug is not a simple task and requires an individual approach to each patient.
Depending on the patient's he alth and clinical situation, the recommended INR value in the prevention and treatment of thrombotic diseases is 2-3.
Maintaining a higher INR value (in the range of 2.5-3.5) is recommended in patients with risk factors for thrombosis (e.g. with implanted artificial heart valves).
It should also be noted that the action of warfarin is modified by numerous drugs and foods. It is then necessary to change the dosage of the drug, frequent monitoring of laboratory parameters and careful monitoring of blood clotting time.
The substances that do not change the action of warfarin include paracetamol, ethanol, benzodiazepines, opioids and most antibiotics.
| FACTORS AFFECTING PROTROMBIN TIME (i.e. intensifying the anticoagulant effect of warfarin, thus prolonging blood clotting time and increasing the risk of bleeding) | FACTORS AFFECTING THE SHORTENING PROTROMBIN TIME (i.e. they reduce the anticoagulant effect of warfarin, thus shortening the blood clotting time) |
| Amiodaron | Barbiturates |
| Diltiazem | Carbamazepina |
| Klofibrat | Cholestyramine |
| Metronidazole | Rifampicin |
| Ciprofloxacin | Rybavirin |
| Erythromycin | Mesalazine |
| Fluconazole | Diuretics (e.g. chlorthalidone, spironolactone) |
| Disulfiram | Vitamin K |
| Phenytoin | Oral contraceptives |
| Omeprazole | |
| Anabolic steroids |
- vitamin K antagonists - side effects
The complications observed in patients using vitamin K antagonists include bleeding, allergic reactions, gastrointestinal complaints, skin necrosis, ischemic heart necrosis, purple feet syndrome, hair loss, and priapism (i.e. prolonged, painful erection penis).
It is worth remembering that both warfarin and acenocoumarol should not be taken by pregnant women under any circumstances, because they show teratogenic effects. These are drugs that cross the placenta and can cause bleeding in the fetus, as well as serious birth defects related to the structure of the baby's bones!
- antagonistsvitamin K - overdose
In the case of using too much of the drug without bleeding, it is usually enough to reduce the dose of the drug or temporarily stop taking it.
However, in the event of bleeding, not only the use of the preparation should be discontinued, but also sometimes oral or intravenous administration of vitamin K preparations, fresh-frozen plasma (rich in blood coagulation factors), prothrombin complex concentrates or recombinant coagulation factor VIIa.
2.Drugs indirectly inhibiting thrombin activity
Anticoagulants that inhibit thrombin activity include unfractionated heparin, low molecular weight heparins and fondaparinux.
A) Unfractionated heparin
- Unfractionated heparin - mechanism of action
Heparin is a drug that works by increasing the action of antithrombin (it is a natural coagulation inhibitor that inactivates thrombin and coagulation factor Xa). Together they form the heparin-antithrombin complex, which not only neutralizes the procoagulant effect of thrombin, but also other coagulation factors (factor IXa, Xa, XIa and XIIa).
- unfractionated heparin - route of administration
Heparin is administered subcutaneously, intravenously or topically (in the form of ointments, gels and creams). Due to the risk of hematoma, it must not be administered intramuscularly.
- unfractionated heparin - monitoring of blood coagulation parameters
The anticoagulant effect of heparin is assessed on the basis of the results of laboratory blood tests, namely the activated partial thromboplastin time (APTT).
The doctor selects the dose of the drug individually for each patient and depending on his clinical condition. APTT reference values in patients taking heparin should be in the range 1.5-2.5.
- unfractionated heparin - indications
Due to its strong anticoagulant effect, unfractionated heparin is used to prevent the formation of blood clots in arteries and veins during replacement blood transfusion or plasmapheresis, in artificial kidney dialysis therapy, in patients undergoing percutaneous coronary interventions (PCI). . percutaneous coronary intervensions), as well as in the acute phase of myocardial infarction.
Heparin in the form of ointments and creams is used for topical application in the case of thrombophlebitissuperficial, in the treatment of varicose veins of the lower limbs and soft tissue injuries.
- unfractionated heparin - side effects
The complications observed in patients using unfractionated heparin include bleeding, allergic reactions, hair loss (and even reversible alopecia), skin necrosis and osteoporosis. One of the side effects of unfractionated heparin is heparin-induced thrombocytopenia (HIT), there are two types of disease:
- HIT type 1 is diagnosed in approximately 15% of patients taking heparin. It develops within the first 2-4 days of use and is most often associated with a slight decrease in the amount of thrombocytes in the blood (less than 25%). In such a case, it is not necessary to discontinue anticoagulant treatment with heparin and the platelet count spontaneously returns to normal. There are no clinical sequelae.
- HIT type 2 is diagnosed in approximately 3% of patients taking heparin and usually develops after 4-10 days of using it. The disease is caused by antibodies against the factor released from platelets. The platelet aggregates that form are quickly removed from the blood, leading to transient thrombocytopenia. HIT type 2, on the other hand, is associated with an increased risk of venous or arterial thrombosis due to increased thrombin formation. These consequences develop in as many as 30-75% of patients with HIT!
For this reason, all patients taking heparin should have frequent monitoring of thrombocyte (or platelet) counts. In the event of HIT, the administration of unfractionated heparin should be immediately stopped and anticoagulants should be started, the mechanism of action of which is to directly neutralize thrombin.
- unfractionated heparin - contraindications
Unfractionated heparin should not be used in patients with known post-heparin thrombocytopenia (HIT), drug hypersensitivity, active bleeding, blood coagulation disorders (haemophilia, severe thrombocytopenia, purpura), severe hypertension, intracranial hematoma, infective endocarditis , active tuberculosis, gastrointestinal diseases at risk of bleeding (especially peptic ulcers of the stomach and duodenum).
Unfractionated heparin should not be administered to people with renal or hepatic insufficiency, as well as to pregnant women, unless clearly indicated and the patient's he alth condition allows it.
People who are taking heparin and have recently had surgery should be vigilant and frequently check their clotting timessurgery (especially of the central nervous system) or eyesight, organ biopsy, as well as lumbar puncture.
- unfractionated heparin - overdose
In the case of taking too much of the drug and bleeding occurs, the use of the preparation should be discontinued and the patient should be given a specific unfractionated heparin antagonist, i.e. protamine sulphate. It combines with heparin to form a complex that is devoid of anticoagulant activity.
B) Low molecular weight heparins
Low-molecular-weight heparins are among the drugs that inhibit blood clotting, which act by neutralizing factor Xa. Among them, there are enoxaparin, nadroparin and d alteparin.
- Low molecular weight heparins - mechanism of action
Low-molecular-weight heparins show a similar mechanism of action to unfractionated heparin, i.e. they bind to the antithrombin molecule, but they inhibit factor Xa much more strongly and inactivate thrombin less. Moreover, low-molecular-weight heparins have a longer duration of action than low-molecular-weight heparin.
- Low molecular weight heparins - route of administration
Low molecular weight heparins are administered subcutaneously.
- Low molecular weight heparins - monitoring of blood coagulation parameters
In the case of using low molecular weight heparins in patients with normal kidney function, control of blood coagulation parameters as well as dose adjustment are not necessary (except for patients with renal insufficiency, obese people with BMI over 35 kg / m² and pregnant women ).
- Low molecular weight heparins - side effects
The complications observed in patients using low molecular weight heparin include bleeding, thrombocytopenia and osteoporosis.
- Low molecular weight heparins - contraindications
Low molecular weight heparins should be used with caution in patients with diagnosed renal insufficiency and in obese people whose body weight exceeds 150 kg, because the dose of the drug is determined per kilogram of the patient's body weight.
- Low molecular weight heparins - overdose
It is worth noting that, unlike unfractionated heparin, low molecular weight heparins are not efficiently and completely inactivated by protamine.
C) Fondaparinux
- Fondaparinux - mechanism of action
Fondaparinux is a drug which has a similar mechanism of action to low molecular weight heparin.It binds strongly and specifically to antithrombin, which results in effective inactivation of factor Xa.
- Fondaparinux - administration route
Fondaparinux is administered subcutaneously once daily.
- Fondaparinux - indications
Fondaparinux is mainly used in the prevention of venous thrombosis in people undergoing orthopedic surgery (e.g. hip or knee arthroplasty), prevention and treatment of venous thromboembolism, and in the course of myocardial infarction.
- Fondaparinux - overdose
Unfortunately, no fondaparinux neutralizing agent is available at the moment, protamine sulphate does not inhibit its anticoagulant properties.
3. Oral Direct Factor Xa Inhibitors
A) Rywaroksaban
Rivaroxaban is a relatively new drug on the pharmaceutical market.
- Rivaroksaban - mechanism of action
The mechanism of action of rivaroxaban is based on the direct neutralization of coagulation factor Xa, the drug molecule binds to the active site of factor Xa and thus inactivates it.
By inhibiting the activity of factor Xa, they prevent the production of thrombin, and thus the formation of a blood clot (it should be emphasized that they do not inhibit the already produced and active thrombin). It is also worth noting that it is characterized by a quick onset and end of action.
- Rywaroksaban - route of administration
It is worth noting that this is the first orally administered factor Xa inhibitor, which makes its use very convenient for the patient, but unfortunately it is associated with a high price of the drug.
- Rivaroxaban - monitoring of blood coagulation parameters
When rivaroxaban is used at the recommended doses in patients with normal renal function, monitoring of blood coagulation parameters as well as dose adjustment are not necessary. In people diagnosed with renal insufficiency, dosage adjustment is necessary.
- Rywaroksaban - indications
Rivaroxaban is used in patients to prevent venous thromboembolism and its life-threatening complications (especially in people undergoing major orthopedic surgery - hip or knee replacement) as well as in people diagnosed with atrial fibrillation. In this situation, it reduces the risk of stroke, pulmonary embolism and deep vein thrombosis.
- Rivaroxaban - side effects
Among the side effects of rivaroxaban, fatigue and feeling stand outbreathlessness, pale skin, nausea, and increased liver transaminases. It is worth noting that bleeding is not a common complication observed in patients taking rivaroxaban, but the risk of its occurrence increases significantly with the concomitant use of other drugs, e.g. non-steroidal anti-inflammatory drugs.
- Rivaroksaban - overdose
Unfortunately, there is currently no agent available to counteract the effects of rivaroxaban and other oral factor Xa inhibitors.
B) Apiksaban
A drug similar to rivaroxaban.
4. Drugs that directly inhibit thrombin activity
Direct thrombin inhibitors include hirudin, recombinant hirudins (lepirudin and disrudin), and synthetic analogues (bivalirudin and argatroban).
- Drugs that directly inhibit thrombin activity - mechanism of action
The action of direct thrombin inhibitors is based on binding to the thrombin active site, so that they form a complex (they do not act through antithrombin like fractionated heparin or low molecular weight heparins). Bound thrombin loses its anticoagulant properties because it cannot bind to fibrinogen.
- Drugs directly inhibiting thrombin activity - route of administration
The route of administration of direct thrombin inhibitors differs depending on the active ingredient in the drug. Lepirudin and bivalirudin are used only parenterally, while dabigatran is used orally.
- Drugs directly inhibiting thrombin activity - monitoring of blood coagulation parameters
The anticoagulant effect of hirudin and its analogues is assessed on the basis of the results of blood laboratory tests, namely the activated partial thromboplastin time (APTT). The doctor selects the dose of the drug individually for each patient and depending on his clinical condition. It is worth mentioning that dabigatran does not require monitoring of blood coagulation parameters, therefore its use is convenient and comfortable for patients.
- Drugs directly inhibiting thrombin activity - indications
Direct thrombin inhibitors, especially argatroban, are used in the treatment of heparin thrombocytopenia (HIT). In interventional cardiology, they are anticoagulant therapy during percutaneous coronary interventions (PCI). In addition, dabigatran is a recommended drug reducing the risk of VTE and its life-threatening disease.complications. It should also be used by patients with atrial fibrillation to prevent ischemic stroke and systemic embolism.
- Drugs that directly inhibit thrombin activity - side effects
The complications observed in patients using direct thrombin inhibitors include, first of all, bleeding (especially from the gastrointestinal tract), as well as life-threatening anaphylactic reactions (mainly after lepirudin). Medicines from this group should not be taken by pregnant and breastfeeding women.
- Drugs that directly inhibit thrombin activity - contraindications
Lepirudin should be used with caution in patients diagnosed with renal insufficiency, as well as in people who have taken it before. It has been shown that approximately half of the patients receiving intravenous lepirudin develop antibodies against the lepirudin-thrombin complex, which may enhance the anticoagulant effect.
It is worth noting that kidney diseases do not make it necessary to change the dosage of argatroban, but it should not be used in people with hepatic insufficiency.
Dabigatran is a drug excreted by the kidneys, therefore in patients with impaired kidney function, the doctor should remember to exercise caution and change the dosage based on blood laboratory results (the doctor takes into account the values of creatinine clearance and GFR). Dabigatran is contraindicated in renal or hepatic insufficiency.
- Drugs that directly inhibit thrombin activity - overdose
Unfortunately, at the moment there is no effective agent available to neutralize the effects of direct thrombin inhibitors.