(4.4) ANTICOAGULATION PHARMACOLOGY

Lecture 27: Anticoagulant Pharmacology

• Instructor: Brian Skinner, PharmD, BCPS, Associate Professor of Internal Medicine, Marian University – College of Osteopathic Medicine, BMS 551 Med Phys Pharm
• Course: Fall 2024

Objectives

• Define hemostasis, clinical manifestations, and general therapeutic strategies for treatment
• Recall the three components of Virchow's Triad, and examples of each
• Diagram the clotting cascade and 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 reflect in the clotting cascade, and how these are utilized for therapeutic drug monitoring
• Identify the mechanism of action, dosage form, adverse events, and contraindications for various anticoagulants and thrombolytics
• Recall the drug of choice for treatment and prophylaxis of blood clots in pregnant patients
• Identify the antidotes associated with warfarin, heparin, factor Xa inhibitors, and directed thrombin inhibitors, and how they work
• Predict the impact of Antithrombin III deficiency on pharmacotherapeutic selection
• Recommend the most appropriate pharmacotherapeutic strategy given a simplified patient case

Drug List

• Information listed in a table format regarding drug name, mechanism of action, how supplied, adverse effects/contraindications, therapeutic indications, and reversal agent(s) for several medications (Heparin, Enoxaparin, Apixaban, Rivaroxaban, Fondaparinux, Argatroban, Bivalirudin, Dabigatran, Warfarin, Alteplase). Note: information regarding Contraindications, and Safety in Pregnancy provided in table.

Hemostasis and Thrombosis

• Hemostasis: The stopping of blood flow
• Thrombosis: The most common abnormality of hemostasis
• Platelet-rich clots (white thrombus): Myocardial Infarction (MI), Transient Ischemic Attacks (TIAs), Peripheral Arterial Clots
• Fibrin-rich clots (red thrombus): Cardioembolic strokes from atrial fibrillation, Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE)

Virchow's Triad

• Circulatory Stasis: Immobility, venous obstruction (obesity, pregnancy, tumor), varicose veins, atrial fibrillation, Cellulitis, Atherosclerosis, Venepuncture
• Endothelial Injury: Trauma
• Hypercoagulability: Surgery, malignancy, pregnancy, estrogen therapy, inherited thrombophilia

Clotting Cascade: Simplified

• Diagram of the intrinsic pathway (aPTT), extrinsic pathway (PT), and common pathway, and how different factors interconnect, leading to fibrin clot formation. Separate diagrams demonstrating inclusion of Antithrombin III and Protein C & S

Understanding Bleeding Times

• Activated Partial Thromboplastin Time (aPTT): Pathways measured, normal values (30-40 seconds), pharmacological uses
• Prothrombin Time (PT): Pathways measured, normal values (11-13.5 seconds), pharmacological uses

Comprehension Check #1

• A patient with a prolonged aPTT and a PT within normal range is likely to have an Antithrombin III deficiency or a deficiency of other particular clotting factors involved in the pathway (dependent on testing).

Anticoagulants

• Used for treating and preventing thrombotic disease
• Four main classes: Vitamin K antagonists, heparin and heparin-derived products, Factor Xa inhibitors, Direct Thrombin inhibitors
• Goal of Therapy: Prevent clot formation and allow the body to naturally break down clots over 3-6 months

Vitamin K Antagonists: Warfarin

• Inhibition of vitamin K-dependent clotting factors (II, VII, IX, X along with Protein C & S)
• Mnemonic: 2+7=9, not 10 (regarding vitamin K dependent factors)
• Reduces clotting factor production by 10-40% (due to lack of y-carboxyglutamyl side chains)
• Therapeutic Use: Treatment and prevention of DVT, PE, and cardioembolic stroke from atrial fibrillation and/or prosthetic heart valves
• Monitoring: Goal INR, is between 2 and 3 for most patients
• Adverse effects: Bleeding and Warfarin-induced skin necrosis
• Teratogenic, contraindicated in pregnancy
• Mechanism of Action: Warfarin inhibits vitamin K-dependent clotting factors, and reduces clotting factor production by 10–40% due to lack of y-carboxyglutamyl side chains.
• Reversal agent: Vitamin K1 (phytonadione), 4F-PCC, FFP (Fresh frozen plasma)

Heparin Products: Unfractionated Heparin & LMWHs (enoxaparin)

• Antithrombin III: Responsible for inactivating Factor IIa and Xa, along with IXa, XIa, and XIIa

• Unfractionated Heparin: Mixture of sulfated, variable length glycosaminoglycans. Acidic, Injectable ONLY

• Prophylaxis: Subcutaneous every 8-12 hours; Lab monitoring not required

• Used in Treatment: IV infusion to maintain aPTT 1.5-2x normal

• LMWHs (Enoxaparin): Smaller than heparin (~4,500 daltons), available ONLY as subcutaneous injection.

• Mechanism of action: Binding via pentasaccharide complex to antithrombin III (minimal effect on thrombin.)

• Adverse events: Bleeding, Heparin-induced thrombocytopenia (HIT)

Fondaparinux

• Synthetically derived pentasaccharide
• Injectable formulation (subcutaneous) only
• Mechanism: Prevents activation of Factor Xa and possibly thrombin indirectly.
• Contraindicated in End Stage Renal Disease.

"Indirect" Factor Xa Inhibitors: Fondaparinux

• Mechanism: Inhibition of factor Xa via antithrombin III binding
• Indications: Treatment and prevention of DVT and PE
• Side effects: Bleeding, but NO risk for HIT. Substance renal elimination
• Contraindicated in patients with severe renal impairment
• Reversal Agent: No available agent approved for fondaparinux reversal

"Direct" Factor Xa Inhibitors: Rivaroxaban and Apixaban

• Mechanism of Action: Inhibition of factor Xa independent of antithrombin III activity
• How Supplied: Oral tablets
• Indications: Treatment and prevention of DVT, PE, and cardioembolic stroke from atrial fibrillation
• Side effects: Bleeding (risk greater with rivaroxaban), Increased risk of treatment failure in patients with empty stomach (Rivaroxaban only)

Reversal Agent: Andexanet alfa

• Dosing based on the factor Xa inhibitor dose and last dose timing
• Andexanet alfa is a truncated, inactive form of human factor Xa, with serine 149 replaced with alanine
• Removal of membrane-binding domains (y-carboxyglutamic acid)
• Binds to and sequesters factor Xa inhibitors

Direct Thrombin Inhibitors: Dabigatran etexilate

• Mechanism: Prodrug converted to dabigatran in the bloodstream
• How Supplied: Oral tablets
• Indications: Treatment and prevention of DVT, PE, and cardioembolic stroke from atrial fibrillation
• Side effects: Bleeding (higher risk than rivaroxaban and apixaban)
• Contraindicated in patients with renal dysfunction

Reversal agent: Idarucizumab

• Humanized monoclonal antibody fragment (Fab)
• Binds to and sequesters dabigatran in minutes.

Thrombolytics – Alteplase

• Treatment goal: Acutely eliminate an already-formed clot
• Reserved for high-risk patients: Acute ischemic stroke, high-risk pulmonary embolism, STEMI
• Low-dose also used for catheter clearance
• Available as an IV formulation only
• Mechanism: Initiates fibrinolysis by binding to fibrin and converting plasminogen to plasmin
• Adverse effects: INCREDIBLY HIGH risk of bleeding
• Contraindications listed

Comprehension Check #2

• Best initial treatment for a patient with CKD and atrial fibrillation should be a drug with minimal renal impact

Additional Questions

• Specific Questions Regarding Treatment Options for Patients with History of HIT.

Dive into the world of anticoagulant pharmacology with this quiz based on Lecture 27. Explore key concepts such as hemostasis, Virchow's Triad, and the clotting cascade while detailing the roles of various anticoagulants and their therapeutic monitoring. Test your understanding of mechanisms, dosage forms, and clinical applications for effective treatment and prevention of blood clots.