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These are the objectives for this section.
After you finish this section, you should be able to:
There are three main classes of antithrombotic drugs:
Check your current understanding by dragging the category titles to their correct location. You will learn more about each of these drugs throughout this module. Click continue when you are ready.
Anticoagulant and antiplatelet drugs inhibit the coagulation process and can therefore be administered acutely to prevent the initial formation of blood clots, or thrombi , in patients with recognised risk factors (primary prevention), and chronically to treat and prevent recurrence of thrombi and their associated complications (secondary prevention). Thrombolytic or fibrinolytic drugs act by dissolving existing thrombi or emboli and therefore only play a role in the acute treatment of thrombosis.
The principal indications of antithrombotic drugs are the prevention and treatment of venous thromboembolism ( VTE ), the prevention of stroke in patients with atrial fibrillation and the prevention and treatment of acute coronary syndrome ( ACS ). Thus, antithrombotic drugs benefit a wide range of patients. Antithrombotic therapy is required over a long period in some of these patients. There is therefore a great need for effective and safe antithrombotic drugs. Roll over each category to learn more. Click continue when you are ready.
The three categories of antithrombotics are used differently due to their differing properties. Roll your cursor over each box to learn more. Indicate whether each statement is true or false.
There are three principal classes of anticoagulants:
Check your current understanding by dragging the category titles to their correct location. You will learn more about each of these drugs throughout this section. Click continue when you are ready.
The main indications for anticoagulant therapies are prevention and treatment of venous thromboembolism ( VTE ), prevention of stroke in patients with atrial fibrillation and treatment and secondary prevention of ACS . Roll your cursor over each section to view the current recommendations for each. Click continue when you are ready.
Shown here is a timeline summarising the historical development of anticoagulants. Use the slider bar to view all time point.
Heparin was discovered early in the 20th century, and has been used extensively in the prevention and treatment of thrombosis in the last 50 years.
Heparin is a polymer composed of heterogenous polysaccharide units. It has now been established that the region of heparins responsible for its activity is a glucosamine unit within a unique pentasaccharide sequence.
Several derivatives of heparin exist, which differ in their size and activity. Roll your cursor over the highlighted labels to learn more about unfractionated heparin, low molecular weight heparin and the synthetic drug, fondaparinux. Click continue when you are ready.
All heparins inhibit the coagulation process by enhancing the activity of the endogenous anticoagulant , antithrombin . The binding of antithrombin to heparin induces a conformational change in the endogenous anticoagulant, increasing its affinity for thrombin . Unfractionated heparin binds to both antithrombin and thrombin to form a ternary complex and then dissociates leaving the enzyme bound to its inhibitor. Once dissociated, the heparin is free to bind to another antithrombin molecule and subsequently inhibit more thrombin. In addition to thrombin, the heparin-antithrombin complex also inhibits factors Xa, IXa and XIa. Thrombin and Factor Xa are most sensitive to inhibition. Click continue when you are ready.
Inhibition of Factor Xa, which results in inhibition of thrombin generation, does not require binding of the enzyme to heparin to but only to antithrombin and is the principal mechanism by which LMWH and fondaparinux inhibit the coagulation cascade. Click continue when you are ready.
Shown here is a table summarising the other properties of unfractionated heparin, low molecular weight heparin and fondaparinux. Click on the headings to view more information. Click continue when you are ready. Match the statement to the correct type of heparin.The anticoagulant effect of this class of compounds first became apparent during investigation of severe, spontaneous bleeding in cattle fed sweet clover hay. It was discovered that the disease was due to dicumarol, derived from oxidation of coumarin in the hay by fungi. Initially the principal interest in this compound was for the development of rat poison. Patent rights were assigned to Wisconsin Alumni Research Foundation and the compound was subsequently named warfarin. The therapeutic potential of warfarin was then realized and the first clinical study was conducted in the 1950s.
Coagulation factors are functionally activated in the liver. For this process vitamin K is required. The anticoagulant effect of vitamin K antagonists is due to inhibition of the synthesis of vitamin K dependent functional clotting factors prothrombin, VII, IX and X as well as anticoagulant protein C in the liver.
This indirect blocking of clotting factors does not affect circulating functional clotting factors and therefore the onset of action starts after approximately three days.
Prothrombin, factors VII, IX and X are all vitamin K dependent. Click continue when you are ready.
Click on the sections to learn more about vitamin K antagonists. Click continue when you are ready.
Which of the following statements are true?This is a chemically diverse group of compounds. The first direct thrombin inhibitor (or, ‘DTI') to be developed was hirudin, which was isolated from the saliva of the leech, Hirudo medicinalis.
Hirudin consists of a single, polypeptide chain of 65 amino acids and has a molecular weight of approximately 7000 Da. The failure of leech breeding trials, however, meant that isolation of hirudin from leeches became more difficult. Due to the significant potential of this novel therapy, recombinant hirudin, which could be manufactured in large quantities, was subsequently developed. In addition to recombinant hirudin, currently available direct thrombin inhibitors include bivalirudin, another recombinant protein based on hirudin with a molecular weight of 2178 Da, and the smaller molecule argatroban, which has a molecular weight of just 527 Da. Ximelagatran will be the first oral member of this drug class and offers several advantages over current direct thrombin inhibitors. Click continue when you are ready.
Direct thrombin inhibitors bind reversibly to the active site of thrombin, thereby directly inhibiting thrombin mediated catalysis of fibrinogen into fibrin . This direct effect is rapid and potent. Click on the direct thrombin inhibitor icon to continue.
Direct thrombin inhibitors (argatroban and melagatran) bind to the active site but do not block the fibrin-binding site of thrombin. In contrast both hirudin and Bivalirudin bind to the active site as well as to Exosite 1 also known as the fibrin binding site.
Roll your cursor over each section to learn more about direct thrombin inhibitors. Click continue when you are ready.
Match the appropriate statement to the most appropriate direct thrombin inhibitor.