Hemostasis and Blood Clotting Overview

Hemostasis (Blood Clotting)

• Hemostasis is a process that maintains circulatory integrity after blood vessel damage, balancing clotting and bleeding.
• Hemostatic clots remain localized to the vessel wall and do not impair blood flow significantly.
• These clots are considered "good" and prevent unwanted bleeding.
• Pathologic clots, also called thrombosis, result in blood flow impairment and often cause complete vessel occlusion.
• These clots are considered "bad".
• Two main types of pathologic clots are venous thrombosis (blood clot blocking a vein) and arterial thrombosis (blood clot blocking an artery).
• Venous thrombosis typically starts from endothelial damage, contains mostly fibrin, and occurs in deep veins, often in the lower leg.
• Deep vein thrombosis (DVT) can lead to pulmonary embolism (PE) when a DVT travels to the lungs.
• Venous thrombosis and PE are collectively called venous thromboembolism (VTE).
• Arterial thrombosis is associated with atherosclerosis, involves platelets and fibrin, often starts with endothelial damage, and occurs in arteries carrying oxygenated blood away from the heart.
• Coronary thrombosis can lead to heart attacks, while thrombosis in brain arteries can lead to strokes.
• Hemostasis involves four processes: vascular constriction, platelet plug formation, fibrin formation, and fibrinolysis.
• Drugs altering blood clot formation and degradation include inhibitors of clot formation (antiplatelets and anticoagulants) and enhancers of clot degradation (thrombolytics).
• Antiplatelet drugs inhibit or prevent platelet activation and/or aggregation, thus inhibiting clot formation.
• Anticoagulants inhibit fibrin formation, inhibiting clot formation.
• Thrombolytics enhance blood clot degradation.
• Specific antiplatelet drugs mentioned include aspirin, abciximab, tirofiban, eptifibatide, ticagrelor, cangrelor, clopidogrel, and prasugrel.

Platelet Activation and Aggregation

• Platelet activation and aggregation are fundamental mechanisms for blood clot formation.
• Platelets initially aggregate, and fibrin subsequently forms around the aggregated platelets.
• This process, platelet aggregation plus fibrin, forms a thrombus.

Drugs Altering Blood Clot Formation and Degradation

• Antiplatelets:
  • Aspirin (COX inhibitor, irreversible)
  • Glycoprotein IIb/IIIa inhibitors (abciximab, tirofiban, eptifibatide)
  • Purinergic receptor inhibitors (e.g., clopidogrel, prasugrel, ticagrelor, cangrelor)
  • Phosphodiesterase 3 inhibitors (cilostazol)
  • Adenosine reuptake inhibitors and PDE inhibitors (dipyridamole)
  • Protease-activated receptor-1 inhibitor (vorapaxar)
• Anticoagulants (inhibit fibrin formation) – next slide pack
• Direct Factor Xa inhibitors (apixaban, rivaroxaban, edoxaban), Direct Thrombin inhibitors, Antithrombin enhancers (unfractionated heparin, low MW heparin, fondaparinux [Arixtra]), and γ-glutamate carboxylation inhibitors(Warfarin)

Major Antiplatelet Drugs

• Aspirin: Inhibits cyclooxygenase, preventing thromboxane A2 synthesis.
• Glycoprotein IIb/IIIa Inhibitors: Block the interaction between platelets and fibrinogen.
• P2Y12 Inhibitors: Block ADP receptors on platelets. (clopidogrel, prasugrel, ticagrelor, cangrelor)
• Cilostazol: Inhibits phosphodiesterase, increasing intracellular cGMP.
• Dipyridamole: Inhibits phosphodiesterase, increasing intracellular cAMP.
• Vorapaxar: Inhibits protease-activated receptor-1 (PAR-1).

P2Y12 Receptor Antagonists

• Clopidogrel and prasugrel are prodrugs; ticagrelor is not.
• Clopidogrel and prasugrel require metabolism to their active forms, leading to variability in response.
• Ticagrelor activation is not dependent on cytochrome P450 activity and hence more reliable.

CYP2C19 and Hemostasis

• Clopidogrel activation requires CYP2C19, a variable enzyme.
• Prasugrel activation relies on multiple CYPs, which reduces variability.
• CYP2C19 inhibitors, like omeprazole, reduce clopidogrel's effectiveness.

Reversible ADP/Purinergic Receptor Antagonist (P2Y12)

• Ticagrelor is a nucleoside analog.
• It does not require hepatic activation and is reversible, unlike clopidogrel and prasugrel.

Cangrelor

• Not a prodrug, reversible, IV injection only
• Approved 2015, structural mimic of ADP

Other Details

• Cilostazol and dipyridamole, also platelet aggregation inhibitors.
• Vorapaxar, a PAR-1 inhibitor, is FDA-approved.