Antiplatelet-Anticoagulant Pharmacology-1

Page 1: Introduction

• Subject Matter: Thrombosis Pharmacology

• References: Handout and Presentation as guidance; Required reading from Basic & Clinical Pharmacology, 15th edition, Katzung, Chapter 34.

• Instructor: Parto Khansari, Ph.D.

• Date: 3/12/2025

Page 2: Learning Outcomes of Thrombosis Pharmacology

• Differentiation:

  • Primary vs. Secondary Hemostasis

• Platelet Structure and Function:

  • Describe characteristics related to thrombosis.

• Events in Platelet Processes:

  • Adhesion, Activation, and Aggregation.

• Pharmacological Classes of Antiplatelets:

  • Classifications and their specifics.

• Mechanisms of Action for Antiplatelets:

  • COX inhibitors, Phosphodiesterase inhibitors.

  • ADP receptor inhibitors, GPIIb/IIIa antagonists.

  • Adverse effects associated with these classes.

• Coagulation Cascade:

  • Overview of events including intrinsic and extrinsic pathways, description of the common pathway.

• Endogenous Anticoagulants:

  • Mechanisms of action.

• Anticoagulants Classification:

  • Warfarin, Heparin, Direct Thrombin Inhibitors, Factor Xa inhibitors.

• Laboratory Tests:

  • International Normalized Ratio and activated partial thromboplastin time.

• Fibrinolytics:

  • Physiological process and major side effects.

Page 3: Hemostasis vs. Thrombosis

• Hemostasis:

  • Physiological process preventing bleeding.

  • Blocks bleeding site and maintains blood fluidity.

• Thrombosis:

  • Pathological state resulting from endothelial cell damage (e.g. atherosclerosis).

  • Inappropriate activation of hemostatic processes.

Page 4: Endothelial Injury Process

• Key Steps in Thrombosis:

  • Endothelial Injury →

  • Exposure of Tissue Factors →

  • Activation of the Common Pathway →

  • Thrombin Formation →

  • Fibrin Formation →

  • Platelet Aggregation and Activation →

  • Platelet Recruitment →

  • Clot Formation

Page 5: Pharmacology of Thrombosis

• Antiplatelet Agents:

  • COX inhibitors

  • Phosphodiesterase inhibitors

  • ADP receptor inhibitors

  • GPIIb/IIIa receptor antagonists

  • Thrombin receptor antagonists

• Anticoagulant Agents:

  • Heparin (Unfractionated and Low Molecular Weight)

  • Direct thrombin inhibitors

  • Factor Xa inhibitors

  • Warfarin (Coumadin)

• Thrombolytic Agents:

  • Recombinant tissue plasminogen activator (r-tPA)

Page 6: Sequence of Events in Hemostasis

• A. Transient Localized Vasoconstriction

• B. Primary Hemostasis:

  • Platelet adhesion, activation, aggregation upon exposure to ECM.

• C. Secondary Hemostasis:

  • Tissue factor exposure leads to coagulation cascade activation.

• D. Limitation:

  • Confinement of hemostatic process to vascular injury site.

Page 7: Primary Hemostasis

• Goal: Formation of a platelet plug to stabilize vascular injury.

• Components:

  • Platelet Adhesion

  • Platelet Activation

  • Platelet Aggregation

Page 8: Platelet Adhesion Mechanism

• Key Components:

  • Exposure of von Willebrand factor (vWF) and collagen.

• Role of von Willebrand Factor:

  • Protein secreted by activated platelets/injured endothelium, mediates adhesion.

  • Binds to collagen and GPIb on platelets.

  • GPVI directly contacts collagen.

Page 9: Platelet Activation Process

• Conformational Changes in Platelets:

  • Protein phosphorylation cascade activated.

• Synthesis and Release Compounds:

  • Thromboxane A2 (TxA2)

  • Serotonin (5-HT)

  • Adenosine diphosphate (ADP)

  • Calcium

  • vWF

  • Platelet factor IV

Page 10: Thromboxane A2 Generation

• Mechanism:

  • Arachidonic acid → Cyclooxygenase 2 → Thromboxane A2 (TxA2) → ↑ Ca2+ concentration → Activation of platelet processes.

Page 11: Platelet Aggregation

• Factors Involved:

  • Endothelial cells, Platelets, Collagen, fibrinogen, vWF.

• Mediators:

  • ADP, TxA2, and thrombin, which facilitate platelet aggregation and granule release.

Page 12: Site of Action for Antiplatelet Agents

• Key Areas: Wall defect, Degranulation, ADP receptors.

• Antiplatelet Agents Include:

  • Aspirin, Clopidogrel, Abciximab, Tirofiban,

  • Mechanisms targeting various processes in platelet activity.

Page 13: Antiplatelet Agents Overview

• Types of Agents:

  • Aspirin: Irreversible COX inhibitor.

  • Thienopyridines: Irreversible ADP receptor antagonists (Clopidogrel, Ticlopidine, Prasugrel).

  • Dipyridamole: Phosphodiesterase inhibitor.

  • GPIIb/IIIa Receptor Antagonists: Abciximab, Eptifibatide, Tirofiban.

Page 14: Action Sites of Antiplatelet Agents

• Mechanisms: Impact on tissue factors, platelet activation, and aggregation processes, and drugs' roles in modulating these mechanisms.

Page 15: Anticoagulant Agents

• Classifications: E.g. Heparin (unfractionated and low molecular weight), Direct Thrombin Inhibitors, Vitamin K antagonists.

Page 16: Learning Outcomes for Coagulation Cascade

• Events: Understanding the coagulation cascade steps and comparison of pathways.

• Key Points:

  • Anticoagulants' mechanisms and characterization of laboratory tests.

Page 17: Overview of Thrombosis Pharmacology

• Reiterate pharmacological agents for antiplatelets, anticoagulants, and thrombolytics.

Page 18: Coagulation Cascade Overview

• Enzymatic Sequence: Activating proenzymes, the role of calcium, and the origins of intrinsic and extrinsic pathways with emphasis on the injuries.

Page 19: Coagulation Cascade Pathways

• Intrinsic Pathway: Activated by surface contact.

• Extrinsic Pathway: Tied to tissue damage.

Page 20: Role of Thrombin in Coagulation

• Functions:

  • Amplifies activation of coagulation factors, converts fibrinogen to fibrin, and serves roles in platelet activation.

Page 21: Anticoagulant Classifications

• Categories: Listing various anticoagulant types, including Heparins, Direct Thrombin Inhibitors, etc.

Page 22: Heparin Mechanisms

• Mechanism of Action: Explain how heparin interacts with antithrombin and inactivates various coagulation factors.

Page 23: Vitamin K Dependent Pathway

• Mechanism: Role of Vitamin K in carboxylation of factors II, VII, IX, X, and proteins C and S.

  • Importance of vitamin K cycles in regulating coagulant activity.

Page 24: Overview of Thrombosis Pharmacology

• Summation of antiplatelet, anticoagulant, and thrombolytic agents previously described.

Page 25: Regulation of Hemostasis

• Mechanisms: Several endogenous processes that prevent excessive clotting, including NO release, Protein C & S, and tissue plasminogen activator.

Page 26: Fibrinolysis Process

• Key Role of Plasminogen: Conversion of plasminogen to plasmin by t-PA.

  • The regulation of this process is crucial for maintaining balance in hemostasis.

Page 27: Endogenous Anticoagulants

• Types: Protein C & S, Tissue factor pathway inhibitor, and their mechanisms in hemostasis regulation.

Page 28: Endogenous Anticoagulants Continued

• Roles of Protein C and TFPI in inhibiting specific factors to maintain hemostatic balance.

Page 29: Thrombolytic Agents Overview

• Types of Thrombolytics: r-tPA, Streptokinase, Alteplase, and their mechanisms and side effects.