Fibrinolysis and Thrombolysis Disorders

Fibrinolysis and Thrombolysis Disorders

 

Congenital deficiencies in the fibrinolytic/thrombolytic systems are uncommon, while acquired deficiencies are not unusual.

Pathophysiology

  • Components of the fibrinolytic system include plasminogen, plasminogen activator and plasminogen activator inhibitors.
  • Fibrin is the final response to vascular injury and is deposited in tissue and blood vessels
  • Fibrin is the end product of the action of thrombin on fibrinogen
  • Once fibrin is no longer needed, the fibrinolytic system is activated, converting fibrin to its soluble degradation products
  • Fibrinolysis is precisely regulated by activators, inhibitors and cofactors in physiologic states

Plasminogen Disorders – Types I and II

  • Incidence – disorder is uncommon
  • Pathophysiology
    • Plasminogen is synthesized in liver
    • Function – role in fibrinolysis after being converted to active form which is plasmin
    • Decreased levels – disseminated intravascular coagulation (DIC), liver disease, fibrinolytic therapy and plasminogen deficiency
  • Clinical Presentations
    • Presence of plasminogen deficiency increases the risk of thrombosis
    • Half of patients with plasminogen disorder have other factor deficiencies (eg, protein C, S)
  • Diagnosis
    • Laboratory testing – plasminogen activity

Plasminogen Activators Disorders

  • Pathophysiology
    • Tissue plasminogen activator (t-PA)
      • Synthesized mainly in the endothelial cells
      • Function – activate plasminogen facilitating conversion to plasmin
        • Both single-chain and double-chain forms of t-PA can activate plasminogen
        • Plasmin degrades fibrin to soluble degradation products in the fibrinolytic pathway
  • Clinical Presentation
    • Decreased t-PA may reduce fibrinolysis and may cause thrombosis
    • Increased t-PA levels may cause excessive fibrinolysis and bleeding episodes
  • Diagnosis
    • Laboratory testing
      • The assessment of t-PA is complicated
        • Typically, t-PA is found in very small amounts
        • Plasminogen activator inhibitor (PAI-1) rapidly binds to t-PA and inhibits its activity
        • As a result, it is necessary to acidify the patient's plasma to determine active t-PA

Plasminogen Activator Inhibitor-1 (PAI-1) Disorder

  • Incidence
    • Rare autosomal recessive disorder
  • Pathophysiology
    • PAI-1 is synthesized by endothelial cells, platelets and hepatocytes
    • Function -- inhibits tissue plasminogen activator (t-PA), a key enzyme in fibrinolysis
    • Identified forms of PAI-1 include 1 active and 2 latent inactive forms
    • As PAI-1 levels increase, active levels of t-PA decrease, causing impaired fibrinolytic function
  • Clinical Presentation
    • Decreased levels – associated with hemorrhage
    • Elevated levels of PAI-1 in deep-vein thrombosis and myocardial infarction, as well as in normal pregnancy and sepsis
      • In young survivors of myocardial infarction, increased PAI-1 is an independent risk factor for reocclusion
  • Diagnosis
    • Laboratory testing – PAI-1 levels

See Also