(4.4) ANTICOAGULANTS (HARD QUIZ)

Lecture #27: Anticoagulant Pharmacology

• Lecture presented by Brian Skinner, PharmD, BCPS, Associate Professor of Internal Medicine at Marian University – College of Osteopathic Medicine. The lecture covered BMS 551 Med Phys Pharm in Fall 2024.

Objectives

• Define hemostasis, its clinical manifestations, and general therapeutic strategies for treatment.
• Recall the three components of Virchow's Triad and recognize examples of each.
• Diagram the clotting cascade and correlate how anticoagulants disrupt the cascade.
• Describe the roles of Antithrombin III, Protein C, and Protein S in the clotting cascade.
• Relate how changes in aPTT, PT, and INR are reflected in the clotting cascade, and how they are utilized for therapeutic drug monitoring.
• Identify the mechanism of action, dosage form, adverse events, and contraindications of anticoagulants and thrombolytics discussed in the lecture.
• Recall the drug of choice for treatment and prophylaxis of blood clots in pregnant patients.
• Identify the antidotes associated with warfarin, heparin products, factor Xa inhibitors, and directed thrombin inhibitors, and how they work.
• Predict the impact of Antithrombin III deficiency on pharmacotherapeutic selection.
• Given a simplified patient case, recommend the most appropriate pharmacotherapeutic strategy.
• Lecture notes include figures from Principles of Pharmacology by Baca, Golan (Chapter 22) and Lippincott Illustrated Reviews: Pharmacology 6e Yellepeddi (Chapter 22).

Drug List

• A table listing various drugs (e.g., Heparin, Enoxaparin, Apixaban, Rivaroxaban, Fondaparinux, Argatroban, Bivalirudin, Dabigatran, Warfarin, Alteplase) with their mechanism of action, how they are supplied (oral or injectable), adverse effects, contraindications (including pregnancy), therapeutic indications, and reversal agents. Important note: some entries are listed as having "NONE" in the reversal agent column.

Hemostasis and Thrombosis

• Hemostasis is the process of stopping blood flow.
• Thrombosis, the most common abnormality of hemostasis, involves the formation of blood clots.
  • Platelet-rich clots (white thrombus) are associated with myocardial infarction (MI) and transient ischemic attacks (TIAs).
  • Fibrin-rich clots (red thrombus) are related to cardioembolic strokes, deep vein thrombosis (DVT), and pulmonary embolism (PE). Peripheral clots are also discussed.

Virchow's Triad

• The Virchow's Triad consists of three factors contributing to thrombus formation: circulatory stasis, endothelial injury, and hypercoagulability.
  • Examples of circulatory stasis: immobility, venous obstruction (from obesity or tumor), pregnancy, varicose veins, and atrial fibrillation.
  • Examples of endothelial injury: trauma, cellulitis, atherosclerosis, and venepuncture
  • Hypercoagulability is also listed

Clotting Cascade

• Simplified diagrams of the intrinsic and extrinsic pathways of the clotting cascade, highlighting the common pathway and the interaction with anticoagulants like antithrombin.
• The relationship between the clotting cascade, aPTT, PT, and INR and therapeutic drug monitoring is also covered

Understanding Bleeding Times

• Discusses activated partial thromboplastin time (aPTT), prothrombin time (PT), and the calculation of INR. Normal values and uses of the tests are highlighted. Unfractionated Heparin Efficacy and warfarin efficacy (using PT/INR*) are both noted.

Comprehension Check #1

• A patient case study presents a scenario where a patient undergoes a motor vehicle accident.
• Blood results (aPTT and PT) are cited, and the goal is to determine which clotting factor is most likely affected.

Anticoagulants

• Anticoagulants are used therapeutically and prophylactically (to treat and prevent) thrombotic disease.
• Key classes of anticoagulants covered include Vitamin K Antagonists (like Warfarin), Factor Xa Inhibitors, Direct Thrombin Inhibitors, and their mechanisms.

Vitamin K Antagonists: Warfarin

• Mechanism of Action: Warfarin inhibits vitamin K-dependent clotting factors. The lecture includes the inhibition complex breakdown and discussion of vitamin K as a cofactor.
• Therapeutic Uses: treatment and prevention of DVT, PE, cardioembolic stroke, and those with prosthetic heart valves.
• Adverse Effects: bleeding and skin necrosis.
• Monitoring: Goal INR usually between 2 and 3.
• Reversal Agent: Includes vitamin K1, 4F-PCC, and FFP options for different patient needs and complexities

Heparin Products: Unfractionated Heparin and LMWHs (enoxaparin)

• Antithrombin III; Unfractionated heparin mechanism and formulation specifics. Anticoagulant properties. Clinical uses; prophylaxis and regular treatment.
• Adverse effects include bleeding and heparin-induced thrombocytopenia (HIT).
• Reversal agent: Protamine Sulfate; limitations for LMWHs.

Fondaparinux

• A synthetically derived pentasaccharide anticoagulant. Injectable formulations only. Mechanism of action and in relation to antithrombin III and factors Xa.
• Indications often include prevention and treatment for DVT & PE.
• Side effects and contraindications are noted.
• No established reversal agent.

"Direct" Factor Xa Inhibitors: Rivaroxaban and Apixaban

• Mechanism of action: Inhibiting factor Xa independent of antithrombin activity.
• Indications include treatment & prevention of venous thromboembolism (VTE) and stroke from atrial fibrillation.
• Side effects include increased bleeding risk or treatment failure when taken with an empty stomach; caution for patients with renal disease.
• Reversal agent: Andexanet alfa is mentioned. Mechanism of action is described.

Direct Thrombin Inhibitors: Dabigatran

• Dabigatran inhibits thrombin independently of antithrombin.
• Oral tablets; used for treatment and prevention of DVT, PE, and cardioembolic stroke.
• Side effects include high bleeding risk; contraindicated in patients with renal disease.
• Reversal agent: Idarucizumab. Action and use are described

Direct Thrombin Inhibitors: Bivalirudin and Argatroban

• Mechanisms involving inhibition of thrombin; these are IV-only anticoagulants.
• Indications include specific clinical uses (e.g., PCI, DVT, HIT).
• Side effects involve bleeding.
• No available reversal agent.

Thrombolytics - Alteplase

• Treatment goal: acutely eliminating formed clots.
• Reserved for high-risk patients (including ischemic strokes, high-risk PE, STEMI), and catheter clearance.
• Given intravenously.
• Highly increased bleeding risk is a major concern.
• Contraindications to IV tPA use for acute ischemic stroke are listed.

Comprehension Checks #1 and #2

• Comprehension check questions involving patient cases and appropriate anticoagulant choices for patients with specific conditions (including CKD).

Additional Notes

• Several slides include diagrams illustrating the mechanisms of action of various anticoagulants, relationships, and therapeutic strategies.

This quiz covers key concepts from Lecture #27 on Anticoagulant Pharmacology, presented by Brian Skinner. It explores hemostasis, Virchow's Triad, the clotting cascade, and the roles of Antithrombin III, Protein C, and Protein S. Furthermore, it discusses anticoagulants, their mechanisms, and therapeutic drug monitoring.