Skip to main content

Hematology

Fibrinolytic Pathways

Overview of Fibrinolysis

  • Definition: The process by which fibrin clots are broken down and removed from blood vessels once tissue repair has occurred
  • Purpose: To restore normal blood flow, prevent excessive clot formation, and maintain vascular patency
  • Key Components:
    • Plasminogen
    • Plasmin
    • Plasminogen Activators
    • Plasmin Inhibitors
    • Fibrin Degradation Products (FDPs)

Components of the Fibrinolytic System

  • Plasminogen:

    • Definition: An inactive zymogen (precursor) synthesized in the liver and found in the plasma and other body fluids
    • Structure: A single-chain glycoprotein
    • Function: When activated, plasminogen is converted to plasmin, the primary enzyme responsible for breaking down fibrin
    • Binding to Fibrin: Plasminogen binds to fibrin, making it available for activation at the site of the clot

  • Plasmin:

    • Definition: An active serine protease enzyme that degrades fibrin, leading to clot breakdown
    • Formation: Formed by the activation of plasminogen through plasminogen activators
    • Function:
      • Degradation of Fibrin: Breaks down fibrin into fibrin degradation products (FDPs)
      • Degradation of Other Proteins: Plasmin can also degrade other proteins, including fibrinogen, factors V and VIII, and other components of the coagulation system

  • Plasminogen Activators:

    • Definition: Enzymes that convert plasminogen to plasmin
    • Key Plasminogen Activators:
      • Tissue Plasminogen Activator (tPA):
        • Synthesized and released by endothelial cells
        • Most active when bound to fibrin
        • Plays a key role in dissolving clots within blood vessels
      • Urokinase Plasminogen Activator (uPA):
        • Found in various tissues and body fluids
        • Activates plasminogen in the extravascular space
      • Streptokinase:
        • Exogenous plasminogen activator produced by streptococcal bacteria
        • Used therapeutically as a thrombolytic agent

  • Plasmin Inhibitors:

    • Definition: Proteins that regulate the activity of plasmin and plasminogen activators
    • Key Inhibitors:
      • Alpha-2-Antiplasmin (α2-AP):
        • The primary inhibitor of plasmin
        • Rapidly inactivates plasmin that is free in the circulation, preventing it from degrading other proteins
        • Forms a stable complex with plasmin, which is then cleared from the circulation
      • Plasminogen Activator Inhibitor-1 (PAI-1):
        • The primary inhibitor of tPA and uPA
        • Produced by endothelial cells, platelets, and other tissues
      • Thrombin Activatable Fibrinolysis Inhibitor (TAFI):
        • TAFI, when activated by thrombin, modifies fibrin to make it less susceptible to plasminogen binding and subsequent degradation by plasmin.

  • Fibrin Degradation Products (FDPs):

    • Definition: Fragments produced when plasmin degrades fibrin
    • Examples:
      • D-dimer: A specific marker for cross-linked fibrin degradation
      • Fibrin monomers
      • Fragment X, Fragment Y, Fragment D, and Fragment E
    • Cleared from the circulation by the liver and kidneys

Process of Fibrinolysis

  1. Clot Formation:
    • The coagulation cascade is activated, leading to the formation of a fibrin clot at the site of vascular injury
  2. Plasminogen Binding:
    • Plasminogen binds to the fibrin clot
  3. tPA Release:
    • Endothelial cells release tPA, which also binds to fibrin
  4. Plasmin Activation:
    • tPA activates plasminogen to plasmin on the surface of the fibrin clot
  5. Fibrin Degradation:
    • Plasmin degrades fibrin into fibrin degradation products (FDPs), including D-dimer
  6. Inhibition:
    • α2-AP rapidly inactivates any plasmin that escapes from the clot into the circulation, preventing it from degrading other proteins
    • PAI-1 inhibits tPA and uPA
    • TAFI inhibits plasminogen binding
  7. Clearance:
    • FDPs are cleared from the circulation by the liver and kidneys

Regulation of Fibrinolysis

  • Localized Activation: tPA is most active when bound to fibrin, which ensures that plasmin is primarily generated at the site of the clot
  • Inhibition: PAI-1 and α2-AP inhibit the activity of plasminogen activators and plasmin, respectively
  • TAFI Thrombin-activatable fibrinolysis inhibitor inhibits the activity of plasminogen activator.

Clinical Significance

  • Thrombosis: Impaired fibrinolysis can lead to excessive clot formation and thrombosis (e.g., deep vein thrombosis, pulmonary embolism)
  • Bleeding: Excessive fibrinolysis can lead to bleeding disorders (e.g., disseminated intravascular coagulation, DIC)
  • Therapeutic Use: Fibrinolytic agents (like tPA and streptokinase) are used to treat thromboembolic disorders (e.g., myocardial infarction, stroke)

Laboratory Testing

  • D-dimer Assay:

    • Measures the level of D-dimer in the blood
    • Elevated in conditions with increased fibrinolysis (e.g., DVT, PE, DIC)
    • Used as a screening test for venous thromboembolism (VTE)

  • Fibrinogen Level:

    • Measures the amount of fibrinogen in the blood
    • Decreased in conditions with excessive fibrinolysis (e.g., DIC)

  • tPA and PAI-1 Assays:

    • Measure the levels of tPA and PAI-1 in the blood

  • Euglobulin Lysis Time:

    • Assesses global fibrinolytic activity.

Key Terms

  • Fibrinolysis: The breakdown of fibrin clots
  • Plasminogen: Inactive precursor to plasmin
  • Plasmin: Active enzyme that degrades fibrin
  • tPA (Tissue Plasminogen Activator): Plasminogen activator released by endothelial cells
  • uPA (Urokinase Plasminogen Activator): Plasminogen activator found in various tissues and body fluids
  • α2-Antiplasmin (α2-AP): Primary inhibitor of plasmin
  • PAI-1 (Plasminogen Activator Inhibitor-1): Inhibitor of tPA and uPA
  • TAFI Thrombin-activatable fibrinolysis inhibitor: inhibits the activity of plasminogen activator.
  • Fibrin Degradation Products (FDPs): Fragments produced when plasmin degrades fibrin
  • D-dimer: A specific marker for cross-linked fibrin degradation