Hemostasis Lecture Notes

Introduction to Hemostasis

• Definition: Hemostasis = Hemo (blood) + Stasis (stop) => Localized blood stoppage.
• Context: Occurs when blood vessels are damaged, with the goal of stopping blood loss.
• Steps: Hemostasis involves five key steps.
  1. Vascular spasm
  2. Platelet plug formation
  3. Coagulation
  4. Clot retraction and repair
  5. Fibrinolysis

Natural Inhibitors of Blood Clotting

• Endothelial Cells: Secrete Nitric Oxide (NO) and PGI2 (Prostacyclin) to inhibit platelets.
• Heparin Sulfate: Binds and activates antithrombin 3, degrading clotting factors 2, 9, and 10.
• Thrombomodulin: Binds thrombin leading to activation of Protein C which degrades factors 5 and 8.

Vascular Spasm

• Definition: Contraction of blood vessels to reduce blood loss.
• Mechanisms:
  1. Endothelin: Secreted by injured endothelial cells, causes smooth muscle contraction.
  2. Myogenic Mechanism: Direct injury to smooth muscle prompts contraction.
  3. Nociceptor Activation: Inflammatory chemicals cause pain reflex leading to vasoconstriction.

Platelet Plug Formation

• Von Wildebrand Factor (vWF): Protein that binds platelets to sites of injury.
• Platelet Activation:
  • Inhibited NO and PGI2 -> Platelet binds to vWF using glycoprotein 1B.
  • Activated platelets release ADP, Thromboxane A2, and Serotonin.
• Aggregations: Platelets bind together using glycoprotein 2B/3A and fibrinogen.
• Vasoconstriction: Enhanced by thromboxane A2 and serotonin binding to smooth muscles.

Coagulation (Beast Mode)

• Intrinsic Pathway:
  1. Factor 12 -> Factor 11 -> Factor 9 (with Factor 8) -> Common Pathway (Factor 10).
• Extrinsic Pathway:
  • Tissue factor (Factor 3) + Factor 7 -> Either Factor 9 activation or direct pathway to Factor 10.
• Common Pathway:
  • Factor 10 (with Factor 5) -> Prothrombin activator converts Prothrombin to Thrombin.
  • Thrombin converts Fibrinogen to Fibrin -> Fibrin mesh created and stabilizes clot (Factor 13 cross-links).

Clot Retraction and Repair

• Platelet Contraction: Actin and myosin in platelets pull edges of blood vessel together.
• Secretions:
  • PDGF (Platelet-derived growth factor): Smooth muscle proliferation, collagen repair.
  • VEGF (Vascular endothelial growth factor): Regenerates endothelial lining.

Fibrinolysis

• Tissue Plasminogen Activator (TPA): Converts Plasminogen to Plasmin.
• Plasmin: Degrades fibrin mesh and releases D-dimer (diagnostic marker).
• Clinical Applications: TPA in strokes to dissolve blood clots.

Recap with Drug Info

• Natural Anticoagulants: Nitric oxide, prostacyclin, heparin sulfate, thrombomodulin, antithrombin 3.
• Drugs:
  • Heparin: Enhances activity of antithrombin 3.
  • Clopidogrel: Inhibits ADP for platelet aggregation.
  • Aspirin: COX-2 inhibitor, prevents Thromboxane A2 formation.
  • Abciximab: Blocks glycoprotein 2B/3A.
  • Dabigatran: Direct thrombin inhibitor.
  • Warfarin: Vitamin K oxide reductase inhibitor, prevents activation of clotting factors.

Tricks to Remember Coagulation Cascade

• Intrinsic Pathway: X marks the spot -> 12 -> 11 -> 9 -> 8 -> 10
• Extrinsic Pathway: 3 + 7 = 10
• Common Pathway Formation: 5x2x1 = 10