Anticoagulants

Anticoagulants represent extremely important and diverse class of drugs that are extensively used in internal medicine. Before introducing the drugs, it is necessary to briefly explain the principle of blood clotting, which in different ways affected by the anticoagulation drugs.

 

The process of blood clotting is in fact absolutely necessary and prevents fatal hemorrhages in case of injury. The process of coagulation has three main levels.

 

The first level is measured by local contraction of smooth muscles in the arterial wall to improve the subsequent formation of the blood clot. Second level is facilitated by platelets. Platelets accumulate around the tear of arterial wall and help to plug it. This is referred to as the primary thrombus. Third level is the coagulation cascade, which is a complex process involving many proteins. These proteins activate each other and the result is activated substance known as fibrin. The fibrin forms a solid net, which stabilizes the primary thrombus. This whole process is regulated by competing mechanisms that ensure degradation of fibrin and counteract the blood clotting. An important compound capable of fibrin degradation is s substance called plasmin.

 

Drugs used to suppress the blood clotting either affect the platelets and formation of the primary thrombus (antiplatelet drugs), or affect the coagulation cascade. In certain acute conditions, it is also possible to use drugs that directly help to dissolve the thrombus. However, these may have extremely serious side effects and therefore, they have to be cautiously indicated.

 

Note: Due to the large numbers of used substances, it is not possible to name their complete list, but just to mention the most commonly used and clinically significant medications.

Indications

The particular types of medications have their special indications. The situations requiring administration of anticoagulant drugs include atrial fibrillation, chronic narrowing of arteries by atherosclerosis (narrowing of carotid artery, chronic ischemic heart disease including angina pectoris, peripheral artery disease, myocardial infarction, etc.), conditions after ischemic stroke, situations after coronary angiography with stenting, presence of mechanical artificial heart valve, prevention and therapy of deep vein thrombosis, pulmonary embolism and others.

Complications

Major complication of anticoagulant drugs is obviously undesirable bleeding, which can occur both in overdose and even in the right dose. This can manifest with bruising, nosebleeds, blood in stool, blood in urine and dangerous internal bleeding, including dangerous brain hemorrhage.

Types of drugs

I. Antiplatelet drugs

This group includes compounds that inhibit the ability of platelets to cluster together (so-called platelet aggregation). This includes particularly the acetylsalicylic acid (ASA), which belongs among the non-steroidal anti-inflammatory drugs (NSAID). Acetylsalicylic acid used in a small dose of 100 mg daily has a satisfactory effect in reduction of blood clotting, without any significant side effects. The effect of the drugs persists for several days and therefore, they should be discontinued few days before any planned surgical intervention.

 

Preparations with acetylsalicylic acid are administered mainly in oral form in chronic complications of atherosclerosis. However, there are intravenous preparations, which may be administered as part of first aid in acute myocardial infarction.

 

Clopidogrel is another substance suppressing platelet functions. It is a more modern and expensive compound than the acetylsalicylic acid and it is used either in allergy to ASA, or after introduction of artificial material into a blood vessel (e.g. stenting during angiography). Clopidogrel has a very good effect to prevent occlusion of the synthetic material by blood clots.

 

Even more modern compound is known as ticagrelor. It has similar effect and indications as clopidogrel, but it is evaluated more effective with less side effects. The only limiting factor is a far higher price. 

II. Drugs acting against coagulation factors

 

a) Warfarin

Warfarin inhibits one of the pathways of the coagulation cascade by blocking the formation of certain coagulation factors in the liver. It is a widely used drug. Its advantage is low price and the possibility of administration in oral tablets. However, it has also many disadvantages, including slow onset and offset of action (usually several days) and certain dietary restrictions. Many foods are unfriendly to warfarin and significantly decrease its effects. These foods include mainly vegetables rich on vitamin K such as spinach, broccoli, cabbage, green beans, green peas, etc.

 

The effect of warfarin can be measured by so-called INR test. The INR value is in international units and it tells us, how many times slower the blood coagulation is in the particular patient when compared to a norm. This means that INR value 1.7 means that the blood clots 1.7 times slower. As effective but safe level of warfarin we consider INR 2-3, i.e. blood clotting 2-3 times slower than normal.

 

Overdose by warfarin is relatively common. If necessary, the rapid reduction of INR may be performed by administration of an antidote, which is the aforementioned vitamin K. Vitamin K suppresses the effects of warfarin and brings the coagulation back to normal.

 

Due to strong teratogenic effect of warfarin (damage of human fetuses), the drugs containing this substance shall never be prescribed to pregnant women and when we prescribe it to a fertile woman, she must be warned to avoid pregnancy at all cost!

 

b) Heparin

Heparin also blocks the coagulation cascade, but in a slightly different mechanism than warfarin. It is applied in an injection form, especially in acute conditions including sudden arterial closure, or pulmonary embolism. Main benefits include a very short half-life of heparin and the possibility to administer an antidote in case of heparin overdose. The antidote is a substance known as protamine. The effect of heparin can be measured from a sample of venous blood using the APTT test. When we administer the heparin continuously, it is very advisable to check the APTT more times a day, because unintentional overdose is very easy.

 

c) Low molecular weight heparins (LMWH)

These substances inhibit one of the coagulation factors and thereby disrupt the coagulation cascade. They are usually administered in small doses daily in hospitalized immobilized patients as prevention of deep vein thrombosis. In large doses, LMWH are used in indications similar to warfarin. Low molecular weight heparins are usually administered in form of subcutaneous injections (only very rarely intravenously) that may cause local bruising. The main advantage is a very little risk of overdose and very rapid onset and offset of their action (the effect lasts from approximately 12 to 24 hours after application). The main disadvantage is only zero chance of blocking their effect in a patient treated by LMWH, who suffers from sudden acute bleeding. The most commonly used LMWH substances are enoxaparin, nadroparin and bemiparin. The effectiveness of low molecular weight heparins can be checked by a special blood test, which evaluates the so-called of Anti-Xa. The test requires only a sample of peripheral venous blood.

 

d) Dabigatran

Dabigatran is a modern anticoagulant. Again, it blocks the coagulation cascade. It is administered in form of oral tablets with a minimal risk of overdose compared to warfarin. It is used for example in prevention of deep vein thrombosis and pulmonary embolism and in case of atrial fibrillation.

 

e) Rivaroxaban

This is another modern anticoagulation drug. It blocks the anticoagulation factor Xa and it has similar advantages as dabigatran. It is also used in prevention of deep vein thrombosis and pulmonary embolism and in atrial fibrillation.

III. Thrombolytics

There are special drugs that are administered intravenously. They are very effective, because they can directly and rapidly dissolve already formed thrombus. Modern drugs of this group are able to activate the compound plasmin (mentioned in the beginning of this text), which dissolves the blood clot. It may be used in acute extensive life-threatening pulmonary embolism and in certain types of ischemic stroke. The application, however, must always be very cautiously considered, because the thrombolytics can cause life-threatening hemorrhagic complications.

Practical examples

Examples from clinical praxis should show specific situations when we use anticoagulant medications and solve potential problems.

 

The first patient chronically uses warfarin due to atrial fibrillation.  Now he has a term of elective surgery. However, warfarin could cause bleeding during or after the surgical intervention. Therefore, warfarin is discontinued and when patient!s INR decreases below 2, we begin to administer a LMWH. The LMWH is administered in the perioperative period with the exception of time period right before the surgery. Few days after the surgery, the warfarin returns to medication and patient uses both the LMWH with warfarin. When the INR increases above 2, LMWH is discontinued and the patient uses again only warfarin.

 

The second patient comes into internal ambulance with chest pain and we diagnose acute heart attack. We administer intravenous form acetylsalicylic acid + heparin and send the patient to urgent coronary angiography. LMWH would not be a suitable choice in this time. If the narrowing or closure of coronary artery is unsolvable by angioplasty and stenting, the patient may be sent for acute aortocoronary bypass. LMWH could cause bleeding during this procedure, while heparin has only a short period of effect and in addition, it can be quickly countered by the protamine antidote.

 

The third patient has recently overcome a heart attack with subsequent coronary angiography, which solved the situation with angioplasty and stenting. This patient receives combined medication of acetylsalicylic acid and clopidogrel. Clopidogrel is used only temporarily depending on the exact type of the stent.

 

The fourth patient has a very interesting combination. It is a person with mechanical artificial heart valve, who takes warfarin. This patient has a large heart attack, which is solved by angioplasty with introduction of the stent. The patient is therefore indicated for simultaneous administration of acetylsalicylic acid with clopidogrel, which means a total triple therapy of acetylsalicylic acid + clopidogrel + warfarin. However, such triple therapy is really dangerous of bleeding combinations and its indications change in time and are different in different countries.