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Hematology

Fibrinolytic

Overview of the Fibrinolytic System

  • Definition: The fibrinolytic system is responsible for the breakdown and removal of fibrin clots 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)
  • Disorders: Can be caused by:
    • Deficiency or dysfunction of components of the fibrinolytic system
    • Excessive activation or inhibition of fibrinolysis

Disorders of the Fibrinolytic System

  • Excessive Fibrinolysis (Hyperfibrinolysis)

    • General Features: Leads to increased breakdown of fibrin clots and a bleeding tendency
    • Common Causes:
      • Disseminated Intravascular Coagulation (DIC):
        • A complex disorder characterized by widespread activation of coagulation and fibrinolysis
        • DIC can lead to excessive fibrinolysis due to the consumption of coagulation factors and the release of plasminogen activators
      • Liver Disease:
        • Impaired synthesis of α2-antiplasmin (the main inhibitor of plasmin) can lead to unopposed plasmin activity
      • Malignancy:
        • Certain cancers (e.g., acute promyelocytic leukemia) can release tissue plasminogen activator (tPA), leading to excessive fibrinolysis
      • Streptokinase or tPA Therapy:
        • Overuse or inappropriate use of thrombolytic agents can lead to excessive fibrinolysis
    • Clinical Features:
      • Bleeding: Oozing from IV sites, surgical wounds, and mucosal surfaces
      • Thrombosis: Can also occur due to the underlying cause (e.g., malignancy)
    • Laboratory Findings:
      • Prolonged PT and aPTT: Due to consumption of coagulation factors
      • Decreased Fibrinogen Level: Due to plasmin degradation
      • Elevated D-dimer: A specific marker for cross-linked fibrin degradation
      • Elevated FDPs: Other fibrin degradation products are also increased
      • Decreased α2-Antiplasmin Level: In some cases of severe fibrinolysis
    • Treatment:
      • Treat the Underlying Cause: Essential for resolving the hyperfibrinolytic state
      • Supportive Care: Transfusions (platelets, fresh frozen plasma, cryoprecipitate) to replace consumed coagulation factors and platelets
      • Antifibrinolytic Agents:
        • Aminocaproic acid or tranexamic acid: Inhibit plasminogen activation and reduce fibrinolysis
        • Used with caution, as they can promote thrombosis if the underlying cause is not addressed

  • Impaired Fibrinolysis (Hypofibrinolysis)

    • General Features: Leads to decreased breakdown of fibrin clots and an increased risk of thrombosis
    • Causes:
      • Deficiency of Plasminogen: Rare inherited disorder
      • Deficiency of tPA or uPA: Rare inherited disorder
      • Elevated Levels of PAI-1: More common; can be acquired or inherited
        • Acquired: Associated with obesity, metabolic syndrome, and certain inflammatory conditions
        • Inherited: Rare mutations in the PAI-1 gene
      • Thrombophilia: Inherited or acquired conditions that increase the risk of thrombosis (e.g., factor V Leiden, prothrombin mutation)
    • Clinical Features:
      • Increased Risk of Thrombosis:
        • Deep vein thrombosis (DVT)
        • Pulmonary embolism (PE)
        • Arterial thrombosis (stroke, myocardial infarction)
      • May be asymptomatic until a thrombotic event occurs
    • Laboratory Findings:
      • Routine coagulation tests (PT and aPTT): Usually normal
      • D-dimer: May be normal or slightly elevated
      • Plasminogen Activity Assay: Decreased in plasminogen deficiency
      • tPA and PAI-1 Assays: May show decreased tPA or increased PAI-1 levels
      • Thrombophilia Testing: To evaluate for other inherited or acquired thrombotic risk factors
    • Treatment:
      • Anticoagulation:
        • Warfarin (Coumadin)
        • Direct oral anticoagulants (DOACs): Dabigatran, rivaroxaban, apixaban, edoxaban
      • Thrombolytic Therapy:
        • Tissue plasminogen activator (tPA) to dissolve acute thrombi
      • Management of Underlying Risk Factors:
        • Lifestyle modifications (e.g., weight loss, exercise)
        • Control of underlying medical conditions (e.g., diabetes, hyperlipidemia)

Laboratory Testing for Disorders of Fibrinolysis

  • D-dimer Assay:

    • Measures the level of D-dimer in the blood
    • A negative D-dimer result can be used to rule out VTE in low-risk patients

  • Fibrinogen Level:

    • Measures the amount of fibrinogen in the blood
    • Decreased in DIC and severe liver disease

  • tPA and PAI-1 Assays:

    • Measure the levels of tPA and PAI-1 in the blood
    • Used to evaluate fibrinolytic capacity

  • Plasminogen Activity Assay:

    • Measures the activity of plasminogen in the blood
    • Decreased in plasminogen deficiency

  • Euglobulin Lysis Time:

    • Global assessment of fibrinolytic activity
    • Prolonged lysis time indicates impaired fibrinolysis

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
  • Fibrin Degradation Products (FDPs): Fragments produced when plasmin degrades fibrin
  • D-dimer: A specific marker for cross-linked fibrin degradation
  • Thrombosis: Formation of a blood clot inside a blood vessel
  • Embolism: A blood clot that travels from one location to another
  • Disseminated Intravascular Coagulation (DIC): A consumptive coagulopathy with widespread clotting and bleeding
  • Thrombophilia: A tendency to develop blood clots due to inherited or acquired factors