Antithrombotic agents are characterized separately as anticoagulants (including vitamin K antagonists, heparin or heparin derivatives, and directly acting thrombin or factor Xa inhibitors), antiplatelet agents, or fibrinolytic drugs (see Chap. 86), depending on their primary mechanism, although there is overlap in their activities.
Anticoagulant therapy acts to decrease fibrin formation by inhibiting the formation and action of thrombin. Its most common use is in preventing systemic embolization in patients with atrial fibrillation, treatment of acute arterial thrombosis (eg, myocardial infarction or peripheral arterial thrombosis) and for treatment or (secondary) prevention of venous thromboembolism.
Anticoagulant therapy is often monitored using coagulation testing because of marked biologic variation in effect.
Antiplatelet agents act to inhibit platelet function, and their primary uses are in preventing thrombotic complications of cerebrovascular and coronary artery disease. They also have a role in treatment of acute myocardial infarction. They have no effect in preventing or treating venous thromboembolism.
For many agents, the risk-to-benefit ratio is narrow, with the result that bleeding complications occur.
Bleeding is the most common adverse effect of anticoagulation (Table 87–1). Consequently, the clinician should carefully weigh the risks and benefits for each patient when selecting treatment.
The most common oral anticoagulants are vitamin K antagonists (coumarins). However, recently, new oral anticoagulants with specific antithrombin activity or anti–factor Xa activity have become available and are currently evaluated in clinical trials (see section, “Oral Antithrombin and Anti–factor Xa Agents” below).
TABLE 87–1RISK FACTORS FOR HEMORRHAGIC COMPLICATIONS |Favorite Table|Download (.pdf) TABLE 87–1 RISK FACTORS FOR HEMORRHAGIC COMPLICATIONS
|Too high intensity of anticoagulation |
|Simultaneous use of anticoagulants and antiplatelet agents |
|Old age |
|Initial phase of anticoagulation |
|Cerebrovascular disease |
|History of alcohol abuse |
|Renal insufficiency |
|Liver failure |
|Use of nonsteroidal anti-inflammatory drugs (gastrointestinal bleeding) |
|Polymorphisms in cytochrome 450 CYP2C9 gene |
Coumarins act by inhibiting vitamin K–dependent posttranslational γ-carboxylation of glutamic acid residues in the Gla domains of coagulation factors II, VII, IX, and X, and the anticoagulant proteins C and S.
γ-Carboxylation requires the reduced form of vitamin K as a cofactor. During γ-carboxylation, vitamin K is oxidized. The enzymes vitamin K epoxide reductase and vitamin K reductase are required to recycle vitamin K back to its reduced form. Coumarins inhibit these reductases, thus depleting reduced vitamin K.
A decrease in the number of γ-carboxyglutamate residues results in coagulation factors with impaired activity because they are unable to bind calcium and undergo necessary conformation changes.
The production of affected coagulation factors stops promptly, but the anticoagulant effect is delayed until the previously formed coagulation factors are removed from the circulation. Factor VII has the shortest half-life at 6 hours, while the others range from 24 to 72 hours.
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