Ch 23 pp. 424-426

Anticoagulant and Thrombolytic Agents: Key Points

• Apixaban and Rivaroxaban are used for different indications including prevention of thromboembolism and treatment of deep vein thrombosis and pulmonary embolism.
• Both drugs have shared adverse effects such as hematoma, hemorrhage, and severe hypersensitivity reactions.
• Apixaban is administered twice daily, while rivaroxaban is administered once daily.
• Direct thrombin inhibitors include lepirudin, desirudin, and bivalirudin, and are used for prophylaxis against deep vein thrombosis and anticoagulation in patients undergoing coronary angiography and angioplasty.
• These inhibitors have adverse effects like hemorrhage, cerebral ischemia, and peripheral nerve paralysis.
• Argatroban is used for coronary artery thrombosis and prophylaxis in percutaneous coronary intervention, and can cause gastrointestinal, intracranial, and genitourinary tract hemorrhage.
• Dabigatran is used for prevention of thromboembolism in non-valvular atrial fibrillation and treatment of deep vein thrombosis and pulmonary embolism.
• Recombinant activated protein C (r-APC) is used for severe sepsis with organ dysfunction and high risk of death, but is associated with hemorrhage and contraindications such as intracranial mass and recent intracranial surgery.
• Streptokinase is used for ST elevation myocardial infarction and deep vein thrombosis, but can cause major bleeding and intracranial hemorrhage.
• Recombinant tissue plasminogen activator (t-PA) (Alteplase) is used for acute myocardial infarction, acute cerebrovascular thrombosis, and pulmonary embolism, and can cause intracranial hemorrhage and sepsis.
• Tenecteplase and reteplase are genetically engineered variants of t-PA with increased specificity for fibrin and cause adverse effects such as gastrointestinal and intracranial hemorrhage.
• These thrombolytic agents have potential contraindications and adverse effects, including anaphylactoid reactions and stroke.

Pharmacology of Hemostasis and Thrombosis

• Protamine is effective against large unfractionated heparin molecules and can partially reverse the anticoagulant effects of low-molecular-weight heparins, but it is inactive against fondaparinux.
• Aprotinin inhibits serine proteases plasmin, t-PA, and thrombin, promoting clot stabilization, but may increase the risk of postoperative acute renal failure and fatal anaphylactic reactions.
• Aminocaproic acid and tranexamic acid are lysine analogues that inhibit plasminogen and plasmin, used to reduce perioperative bleeding during coronary artery bypass grafting without increasing the risk of postoperative acute renal failure.
• Hemostasis regulates blood fluidity and forms stable fibrin-based clots in response to vascular injury, while pathologic thrombosis results from endothelial injury, abnormal blood flow, and hypercoagulability.
• Antiplatelet agents interfere with platelet adhesion, release reaction, and aggregation, providing prophylaxis against thrombosis in susceptible individuals.
• Anticoagulants primarily target plasma coagulation factors and disrupt the coagulation cascade by inhibiting crucial intermediates.
• Thrombolytic agents mediate clot dissolution by promoting the conversion of plasminogen to plasmin.
• Effective, orally bioavailable, and inexpensive therapeutic agents like aspirin and warfarin are already available for many clinical indications in this field.
• Virtually every antithrombotic and thrombolytic agent is associated with the mechanism-based toxicity of bleeding, which is likely to plague new agents under development.
• Pharmacogenomic techniques may identify individuals with an increased genetic risk of thrombosis who may benefit from long-term antithrombotic treatment.
• Opportunities remain for the development of safer and more effective antiplatelet, anticoagulant, and thrombolytic therapies, including new agents targeting unexploited components of hemostasis.
• Carefully designed clinical trials will be critical to optimize the indications, dose, and duration of treatment for new drugs and drug combinations.

Platelet Inhibitors: Mechanisms and Clinical Considerations

• Phosphodiesterase inhibitors like dipyridamole inhibit platelet cAMP degradation, used for prophylaxis against thromboembolic disorders and as an alternative in thallium myocardial perfusion imaging.
• Dipyridamole adverse effects include exacerbation of angina, liver failure, stroke, and rare bronchospasm.
• Ticlopidine, clopidogrel, prasugrel, and ticagrelor are ADP receptor pathway inhibitors with varying clinical uses and adverse effects.
• Ticlopidine adverse effects include aplastic anemia, neutropenia, and thrombotic thrombocytopenic purpura.
• Clopidogrel is used for secondary prevention of atherosclerotic events and acute coronary syndromes, with less myelotoxicity than ticlopidine.
• Prasugrel is used for acute coronary syndromes with percutaneous coronary intervention and has a more efficient platelet inhibition but increased bleeding risk compared to clopidogrel.
• Ticagrelor is a reversible inhibitor of the P2Y12 ADP receptor, used for acute coronary syndromes and percutaneous coronary intervention.
• GPIIb-IIIa antagonists like eptifibatide, abciximab, and tirofiban prevent binding of fibrinogen and other adhesion ligands.
• Eptifibatide is used for acute coronary syndromes and percutaneous coronary intervention, with major bleeding and thrombocytopenia as adverse effects.
• Abciximab is used as an adjunct to percutaneous coronary intervention to prevent acute cardiac ischemic complications, with thrombocytopenia and stroke as adverse effects.
• Tirofiban is used for acute coronary syndromes and has similar therapeutic considerations as eptifibatide, but is a nonpeptide tyrosine analogue.
• GPIIb-IIIa antagonists have specific contraindications and considerations, such as avoiding co-administration with a second antagonist and minimizing use in certain medical conditions.

Test your knowledge of anticoagulant and thrombolytic agents with this quiz. Explore indications, administration, adverse effects, and contraindications of drugs such as Apixaban, Rivaroxaban, Direct Thrombin Inhibitors, Argatroban, Dabigatran, Recombinant Activated Protein C, Streptokinase, and Recombinant Tissue Plasminogen Activator.