Hemostasis and Blood Clotting

Hemostasis

• Hemostasis is the process of stopping bleeding.
• It involves three key steps:
  • Vascular spasm: Narrowing of the blood vessel to reduce blood flow.
  • Platelet plug formation: Platelets adhere to the damaged vessel wall, forming a temporary plug.
  • Coagulation cascade: A complex series of reactions leading to the formation of a stable blood clot.

Platelet Plug Formation

• ADP and Thromboxane A2 are important in platelet activation.
• Platelets adhere to exposed collagen and other proteins (like von Willebrand factor).
• Platelets release granules containing substances that activate more platelets.
• Activated platelets cross-link, forming a plug.

Blood Clot Formation

• Prothrombin activator converts prothrombin to thrombin.
• Thrombin converts soluble fibrinogen to insoluble fibrin.
• Fibrin threads form a mesh, trapping blood cells and platelets.
• Factor XIII stabilizes fibrin.

Intrinsic and Extrinsic Pathways

• The intrinsic pathway is activated by damage to the inside of the blood vessel.
• The extrinsic pathway is activated by damage outside the blood vessel.
• Both pathways converge to activate Factor X, which is a key step in the common pathway.

Fate and Course of the Clot

• Fibroblasts invade the clot, converting it into a fibrous tissue.
• The clot is usually completely organized within 1 to 2 weeks.
• Clots form in response to damage to the small holes in the blood vessels.
• The clot ultimately dissolves through a process of fibrinolysis (breakdown).

Natural Anti-clotting Mechanism

• Blood fluidity is maintained by endothelial surface factors.
  • Smoothness of endothelial surface prevents activation of the intrinsic pathway.
  • Glycocalyx (mucopolysaccharide layer) repels clotting factors and platelets.
  • Thrombodulin on endothelial membranes activates protein C, which inactivates factors V and VIII.
• Blood factors:
  • Adsorption: 85-90% of thrombin is adsorbed to fibrin threads, preventing clot spread.
  • Fibrinolytic system: Continuously removes small clots.
  • Antithrombin III: Combines with unbound thrombin and inactivates it.

Heparin

• Produced by mast cells and basophils in tissues surrounding the lungs and liver.
• Co-factor for antithrombin III.
• When combined, Heparin and antithrombin III greatly increase the activity of antithrombin III (100-1000 times).
• Heparin-antithrombin complex removes several activated factors (XII, XI, IX, X).

Fibrinolytic System (Plasmin System)

• Plasminogen (profibrinolysin): Inactive plasma protein.
• Plasmin: Active enzyme that digests fibrin and other clotting factors (V, VIII, prothrombin, XII).
• Plasminogen activation converts plasminogen to plasmin.

Mechanism of Plasminogen Activation

• Tissue plasminogen activator (t-PA) and Urokinase.

  • t-PA is released by injured tissues and converts plasminogen to plasmin.
  • Urokinase is produced by certain types of bacteria (like hemolytic streptococci).
  • Thrombin and active factor XII activate plasminogen along with t-PA.
  • t-PA and urokinase are used in the treatment of early acute myocardial infarction to dissolve the clot.

• Plasmin inhibitor: Regulates the activity of plasmin.

Protein C Role in Fibrinolysis

• Protein C inactivates the inhibitor for tissue plasminogen activator (t-PA).
• This release in turn stimulates fibrinolysis.

Significance of Fibrinolysis

• Reopens blood vessels after flow blockage by clots.
• Prevents blood clotting in the urinary tract.
• Prevents blood clots in menstrual blood.
• Stimulates early stages of myocardial infarction fibrinolysis by intravenous injection of t-PA or local injection of streptokinase or urokinase via cardiac catheter.

Anti-coagulants

• In vitro: prevent clotting in collected blood samples using citrate, EDTA, silicone-coated tubes, or heparin addition.
  • Citrate: used to precipitate calcium.

Anti-coagulants (In vivo)

• Heparin: Acts by activating antithrombin III
• Coumarin derivatives (e.g., dicumarol, warfarin): Inhibit vitamin K dependent clotting factors.

Thromboembolic Conditions

• Thrombus: Abnormal blood clot inside a blood vessel.
• Embolus: Detached thrombus that travels through blood vessels.
• Deep Vein Thrombosis (DVT): Blood clot in a deep vein.
  • Causes include slow blood flow, rough endothelium, and long bed rest.

Thromboembolic Conditions: Prevention and Treatment

• Prevention: Anticoagulant drugs (heparin, warfarin), tissue plasminogen activators (t-PA).
• Treatment: t-PA, streptokinase, urokinase for clot dissolution.