Antithrombotic therapy is summarily the administration of drugs that reduce the formation of thrombi (blood clots). These drugs are widely used both for therapeutic and preventive purposes.
Antithrombotics are commonly divided into three basic categories (Antiplatelet therapy, Anticoagulation therapy and Thrombolytics).
1. Antiplatelet therapy
Antiplatelet drugs inhibit the aggregation of blood platelets and thus the formation of thrombi, a process known as thrombosis. They play a major role in preventing the formation of arterial thrombosis where anticoagulation therapy is less effective. Therefore, they are widely used in the prevention of various cardiovascular and cerebrovascular diseases (so-called primary prevention), and in patients who have suffered these diseases in the past, are therefore in increased risk of experiencing them again (secondary prevention) and have been treated with invasive intravascular techniques. These conditions include myocardial infarction (heart attack), coronary intervention, STENT implantation (insertion of a plastic or metal tube into a blood vessel, to preserve its patency) stroke or advanced atherosclerosis (narrowing of arteries due to deposition of lipid-rich substances in the arterial wall).
Antiplatelet therapy (most commonly Aspirin, see below) is also used as a part of the treatment of Antiphospholipid syndrome. Antiphospholipid syndrome is an autoimmune disease, in which "antiphospholipid antibodies” react against proteins that bind to anionic phospholipids on plasma membranes. Antiphospholipid syndrome causes thrombosis in both arteries and veins, and is associated with various adverse pregnancy outcomes, such as such as miscarriage, stillbirth, preterm delivery, and severe preeclampsia (combination of oedemas, high blood pressure, and presence of protein in the urine during pregnancy, with potentially life-threatening complications). Antiphospholipid syndrome often requires antithrombotic therapy with both antiplatelet and anticoagulant medications to improve the outcomes of the pregnancy.
The most commonly used antiplatelet medications include:
In high-risk patients, so-called dual antiplatelet therapy is used, which consist of simultaneous administration of Aspirin and one of ADP receptor antagonists, most commonly Clopidogrel.
2. Anticoagulation therapy
Anticoagulants are drugs used to prevent mainly venous thrombosis, where the process is usually initiated by abnormal activation of the coagulation cascade (the process of forming a blood clot by a chain reaction of a number of blood proteins). The formation of thrombi inside veins is also associated with the risk of embolism – dislocation of the thrombus and its migration into the pulmonary circulation, causing a condition known as pulmonary embolism (Pic. 1). These conditions characterised by the presence of venous thrombi are therefore know sumarily as thromboembolic disease. The main treatment goal for anticoagulation therapy is to reduce the risk of thromboembolic disease in patients with atrial fibrillation (AF), mechanical heart valves, deep vein thrombosis (DVT) and pulmonary embolism, while at the same time minimising the risk of bleeding as a result of toxicity.
Anticoagulants can be administered either orally (oral anticoagulants), or by subcutaneous or intravenous injections (heparins). Oral anticoagulants are represented by the drug warfarin (Pic. 2), and a group known as novel oral anticoagulants (NOACs), including dabigatran, apixaban and rivaroxaban. Heparins are administered parenterally (by injection) and are classified based on their molecular weight. The most commonly used group are so-called low-molecular weight heparins (LMWH, Pic. 3).
Pregnant women are generally in an increased risk of thrombosis due to the pro-thrombogenic effect of pregnancy. Some women with an added risk of thrombosis (with a history of DVT, pulmonary embolism, with mechanical heart valves or with genetic predispositions for thromboembolic disease) may need anticoagulation therapy during the whole course of pregnancy to ensure the safety of the fetus. The main issue with anticoagulation in pregnancy is that warfarin, the most commonly used anticoagulant in chronic administration, is known to have teratogenic effects on the fetus if administered in early pregnancy. There is no consensus opinion on the correct anticoagulation regimen during pregnancy. Treatment is tailored to the particular individual based on their risk of complications. Pregnant women in need of anticoagulation therapy during pregnancy are, however, usually converted from warfarin to heparin or LMWH for the duration of the pregnancy.
Thrombolytic agents act by actively dissolving thrombi that have already been formed. They are most commonly used in the treatment of stroke and pulmonary embolism. The most commonly used thrombolytic drug is the analog of tissue plasminogen activator (TPA).
Different subgroups of antithrombotic medications have the most significant benefit in different situations, and their use must be carefully considered with respect to possible adverse effects.
The use of warfarin is indicated in the prevention and treatment of venous thromboembolism, in treatment of systemic embolism and cerebrovascular accidents (CVA) in patients with valve prostheses and atrial fibrillation, in the primary prevention of myocardial infarct, and in follow-up of patients who presented with myocardial infarct to prevent stroke, insidious infarction, and death.
Oral anticoagulants are contraindicated in the presence of blood dyscrasia (abnormalities of blood cells formation) associated with hemorrhage or thrombocytopenia, cerebral or dissecting aneurisms, confirmed or suspected cerebral hemorrhage, uncontrolled arterial hypertension, ulcerations or active lesions of the gastrointestinal or urinary tracts, recent neurological, ophthalmic and urological surgery, recent trauma, chronic alcoholism, and hepatic insufficiency. Age in and of itself, is not a contraindication, but it requires additional care because of the possibility of associated conditions that predispose towards bleeding. For the same dose of warfarin, the International Normalized Ratio (INR), an indicator of the efficacy of anticoagulation, is usually higher in the elderly, due to potential difficulties of adequate compliance with treatment, risk of accidental falls, CVA, or other comorbidities. During the entire gestation (pregnancy), the use of warfarin should be avoided since it crosses the placental barrier and may cause fetal abnormalities.
In an acute coronary syndrome (such as myocardial infarction), thrombus formation occurs under conditions of high shear stress and is principally driven by platelet aggregation. This dominance of platelet aggregation during intracoronary thrombus formation reflects the dramatic effects that antiplatelet therapies have on clinical outcomes. Aspirin was the first antiplatelet therapy which induced a halving in event rates in patients with acute coronary syndrome. Subsequently, the benefit of dual antiplatelet therapy following an acute coronary syndrome was established by many clinical trials. Combined aspirin and clopidogrel therapy reduced the 1-year incidence of cardiovascular events by approximately 20% compared with aspirin alone. More potent and consistent ADP receptor inhibition with either prasugrel or ticagrelor was superior to clopidogrel in the subsequent trials.
Antithrombotic medications work by inhibiting the blood’s ability to clot – therefore, their use is associated with a significantly higher risk of haemorrhage.
The most important and frequent complications that may occur with the use of antithrombotic medications, especially warfarin, are hemorrhages, which may be related to the value of the INR (0.4 to 12% in retrospective studies). Other adverse reactions include hypersensitivity reactions, cholestatic jaundice, hepatitis, vasculitis, nausea and vomiting, diarrhea, alopecia, etc. Also counted as a complication is the development of new thrombosis or rethrombosis in the presence of treatment, which can occur in cases of venous thromboembolism at a frequency of 3 to 15%.
Oral anticoagulants are also among the drugs with greatest number of drug-drug interactions. During the period of one year, in a retrospective study on prescriptions of medicines, at least one medication that interacted with warfarin was prescribed for more than 81.6% patients who already used it. Drugs that interact accentuating their anticoagulant effect, contributing to increased morbidity and mortality, were prescribed more frequently. The drugs reported most often are those that contain acetaminophen, thyroid hormones, simvastatin, and ciprofloxacin.
Both antiplatelet and anticoagulation therapies are a major advancement in the treatment of thrombosis-related condition and in the secondary prevention of these events. They significantly reduce the morbidity (existence of the disease) and mortality (number of deaths due to the disease) associated with cardiovascular and cerebrovascular diseases. They also enhance the effect of invasive procedures used in cardiovascular medicine, such as coronary stenting or artificial heart valve implantation, by greatly reducing the incidence of adverse thrombosis-related events following these procedures. In women with an increased risk of thromboembolic disease, anticoagulation therapy lowers the risk of adverse events during pregnancy.