Chapter 39  ·  Module 1

Coagulation Physiology and Pharmacological Targets

Hemostasis, the cascade, natural anticoagulants, fibrinolysis, and drug targets

Primary Hemostasis — Platelet Pharmacological Targets

Aspirin Target

Cyclooxygenase-1

  • Converts arachidonic acid to thromboxane A2
  • Aspirin irreversibly acetylates cyclooxygenase-1
  • Thromboxane A2 blockade lasts full platelet lifetime (8–10 days)

P2Y12 Inhibitor Target

P2Y12 Receptor

  • Adenosine diphosphate receptor sustaining platelet activation
  • Clopidogrel, prasugrel: irreversible prodrugs
  • Ticagrelor, cangrelor: reversible, direct-acting

GPIIb/IIIa Inhibitor Target

Glycoprotein IIb/IIIa

  • Final common pathway of platelet aggregation
  • Binds fibrinogen and von Willebrand factor
  • Abciximab, eptifibatide, tirofiban: intravenous use

Coagulation Cascade — Drug Target Map

Cascade Node Physiological Role Drug Class Agents
Vitamin K factors Synthesis of factors II, VII, IX, X; proteins C, S Vitamin K antagonist Warfarin
Factor Xa Convergence of extrinsic and intrinsic pathways; generates thrombin Indirect (via antithrombin III) or direct Heparins, fondaparinux; rivaroxaban, apixaban, edoxaban
Thrombin (factor IIa) Cleaves fibrinogen; activates factors V, VIII, XIII; activates platelets Indirect or direct thrombin inhibitor Unfractionated heparin; dabigatran, bivalirudin, argatroban
Fibrinolysis Plasmin dissolves fibrin clot Thrombolytics / antifibrinolytics Alteplase, tenecteplase; tranexamic acid, epsilon-aminocaproic acid

Natural Anticoagulant Systems

Serpin

Antithrombin III

  • Inhibits thrombin and factor Xa (slow alone)
  • Heparin accelerates inhibition ~1,000-fold
  • Deficiency: heparin resistance; antithrombin III concentrate needed

Vitamin K-Dependent Pathway

Protein C / Protein S

  • Thrombomodulin activates protein C when bound to thrombin
  • Activated protein C + protein S inactivate factors Va and VIIIa
  • Factor V Leiden: activated protein C resistance; 3–8× venous thromboembolism risk
  • Warfarin start without bridging in protein C deficiency: skin necrosis risk

Extrinsic Pathway Brake

Tissue Factor Pathway Inhibitor

  • Inhibits factor Xa first, then the tissue factor-factor VIIa complex
  • Limits duration of extrinsic pathway activation
  • Released from endothelium by heparin

Arterial vs. Venous Thrombosis — Drug Selection Rule

Arterial thrombosis is platelet-rich (high shear, plaque rupture): antiplatelet therapy is primary. Venous thrombosis is fibrin-rich (low shear, stasis): anticoagulant therapy is primary. Direct oral anticoagulants are first-line for most venous thromboembolism. Warfarin remains required for mechanical heart valves.