Blood Disorders: Hemostasis and Thrombosis

Hemostasis and Thrombosis

• Hemostasis: the process of forming a blood clot to prevent blood loss and promote healing
• Thrombosis: the unwanted formation of blood clots, which can lead to life-threatening conditions
• Types of thrombosis:
  • Venous thrombosis: associated with stasis of blood, high risk of pulmonary embolism, and typically managed with anticoagulants
  • Arterial thrombosis: formed at an atherosclerotic site, leading to myocardial infarction, ischemia, and infarction, and typically managed with antiplatelet agents
  • Atrial fibrillation induced thrombosis: associated with stasis of blood and formation of thrombi in the left atria, leading to embolism of cerebral vessels

Phases of Blood Clot Formation

• 1. Localized vasoconstriction: secretion of endothelin
• 2. Primary hemostasis: formation of a primary hemostatic plug
  • Platelet adhesion: enhanced by factor VIII and von Willebrand factor
  • Release reaction: release of stored substances (ADP, 5-HT, fibrinogen) and newly synthesized substances (TXA2, PAF)
  • Platelet aggregation: binding of fibrinogen to GPIIb–IIIa receptors on platelet membranes
• 3. Secondary hemostasis (coagulation cascade): activation of thrombin and formation of a stable, permanent plug
  • Endothelium and nearby cells express tissue factor, initiating the coagulation cascade
  • Thrombin converts soluble fibrinogen to insoluble fibrin polymer, inducing platelet recruitment and activation

Natural Antithrombotic Mechanisms

• Antithrombin III: inactivates thrombin and other coagulation factors
• Protein C and protein S: slow the coagulation cascade by inactivating coagulation factors
• Plasmin: proteolytically cleaves fibrin into fibrin degradation products
• Tissue plasminogen activator (t-PA): activates the fibrinolytic system
• Prostacyclin (PGI2): inhibits platelet activation and vasoconstriction
• Surface heparin-like molecules: catalyze the inactivation of coagulation factors

Anticoagulants

• Interfere with coagulation factors and thrombus formation
• Examples: heparin, warfarin, fondaparinux

Heparin

• Indirect thrombin inhibitor
• Mechanism of action:
  • Combines with antithrombin III, causing conformational changes that inactivate thrombin and other coagulation factors
• Pharmacological actions:
  • Anticoagulant action: effective both in vitro and in vivo
  • Plasma-clearing effect: stimulates lipoprotein lipase enzyme, decreasing serum triglycerides
• Pharmacokinetics:
  • Immediate onset of action after IV injection, short duration (4-6 hours)
  • 80% metabolized in the liver by heparinase enzyme, 20% excreted unchanged by the kidney
• Uses and routes of administration:
  • Treatment of established thromboembolic disease
  • Prophylaxis against thrombosis
• Adverse effects:
  • Hemorrhage
  • Hair loss (alopecia)
  • Hematoma (if given by IM)
  • Hypersensitivity
  • Osteoporosis (on long-term use, especially in pregnancy)
  • Hyperkalemia
  • Heparin-induced thrombocytopenia (HIT)