Fibrinolytic Disorders

Abnormalities in the fibrinolytic system may be associated with thrombosis or bleeding. Acquired clotting or bleeding abnormalities should be considered before the less common congenital fibrinolytic abnormalities.

Diagnosis

Indications for Testing

Laboratory Testing

  • Plasminogen activator inhibitor-1 (PAI-1)
    • Diurnal variation – higher values in the morning, lower values in the afternoon
    • Identification of PAI-1 deficiency is complex – values should be interpreted in conjunction with tissue plasminogen activator (tPA) values
      • Many laboratory assays are designed to identify elevated PAI-1 levels and cannot accurately quantify low values
      • Levels below the limit of quantification may be seen in both PAI-1-deficient patients and in individuals with normal levels
      • Specialized testing may be necessary to definitively diagnose severe PAI-1 deficiency
  • Plasminogen – activity testing
  • Alpha-2-antiplasmin – activity testing
  • tPA – antigen testing
  • Genotyping (SERPINE1)

Differential Diagnosis

Background

Pathophysiology

  • Formation of a fibrin clot occurs in response to vascular injury
  • Fibrinolytic system breaks down fibrin clot, converting fibrin to soluble degradation products
    • Components of the fibrinolytic system include plasminogen, plasminogen activators, plasminogen activator inhibitors, and alpha-2-antiplasmin
    • Fibrinolysis is precisely regulated by these activators, inhibitors, and cofactors

Components of Fibrinolytic System

Plasminogen

  • Pathophysiology
    • Synthesized in the liver and converted to its active form (plasmin) by plasminogen activators
    • Plasmin degrades fibrin (and fibrinogen), forming soluble fibrin degradation products
    • Excessive plasmin formation may result in increased fibrinolysis and bleeding
  • Deficiency
    • Inherited
      • Incidence – <1/million (rare)
      • Inheritance – autosomal recessive
      • Clinical presentation – ligneous conjunctivitis; similar ligneous lesions in gingiva, ear, respiratory tract, and female genitourinary tract; altered wound healing; pseudomembrane function
    • Acquired
  • Thrombotic risk
    • Heterozygotes – no apparent increase in risk of thrombosis
    • Homozygotes – risk of thrombosis remains unclear

tPA

  • Pathophysiology
    • Plasminogen activator is synthesized by endothelial cells and released in response to endothelial cell stimulation
    • tPA converts plasminogen to plasmin, which subsequently degrades fibrin (and fibrinogen), forming soluble fibrin degradation products
      • Low concentrations of circulating tPA are found in the blood
  • Clinical presentation
    • Increased tPA results in increased fibrinolysis and bleeding
    • Acquired abnormalities
      • tPA is an acute phase reactant and may be elevated in patients with sepsis, cancer, surgery, pregnancy, or metabolic syndrome
  • Thrombotic risk
    • Deficiency may raise risk for thrombosis, but association is uncertain

PAI-1

  • Pathophysiology
    • Released primarily by the liver and adipose tissue
    • Levels are regulated by metabolic factors such as triglycerides, cholesterol, and insulin
    • Binds to and inhibits plasminogen activators such as tPA, forming inactive complexes that are cleared by the liver
      • PAI-1 is found in its active form in blood, as well as in an inactive form (primarily in platelets), and in complexes with plasminogen activators
      • Acquired abnormalities
        • PAI-1 is an acute phase reactant and may be elevated in patients with metabolic syndrome, cancer, surgery, pregnancy, or inflammation such as sepsis
      • Most PAI-1 assays are designed to detect increased PAI-1 concentration rather than PAI-1 deficiency; low concentrations may not be accurately quantified
  • Bleeding potential
    • Inherited deficiency (congenital PAI-1 deficiency)
      • Incidence – rare (in U.S., most common in the Old Order Amish community)
      • Inheritance – autosomal recessive
    • Clinical presentation
      • Heterozygotes usually do not present with bleeding disorders
      • Homozygotes may present with moderate to severe bleeding
        • Bleeding is usually posttraumatic rather than spontaneous
  • Thrombotic risk
    • Elevated levels of PAI-1 may be associated with venous or arterial thrombosis, although routine testing of patients with thrombophilia for this disorder is not recommended
    • Inherited polymorphism – single guanosine nucleotide deletion/insertion polymorphism (4G/5G) at -675 bp of the SERPINE1 gene is the major genetic determinant of PAI-1 expression
      • Clinical presentation
        • Individuals with 4G/5G and 4G/4G genotypes, especially those with other thrombophilic risk factors, have increased risk for venous thromboembolism (VTE)
        • 4G/5G and 4G/4G genotypes are associated with increased risk of myocardial infarction (MI)
        • Some studies have associated the 5G/5G genotype with elevated risk of ischemic stroke

Alpha-2-antiplasmin

  • Pathophysiology
    • Secreted by the liver
    • Binds to and inhibits plasmin
  • Deficiency
    • Inherited (autosomal recessive)
    • Rare incidence
  • Clinical presentation
    • Heterozygotes – usually asymptomatic or with mild mucosal bleeding
    • Homozygotes – may have severe bleeding episodes resembling those of congenital hemophilia
      • Umbilical cord bleeding
      • Hemarthrosis
      • Excessive postoperative and posttrauma bleeding
  • Thrombotic risk
    • Elevated alpha-2-antiplasmin not reported to be associated with increased thrombosis risk

ARUP Laboratory Tests

Screen for genetic susceptibility for VTE or MI in individuals with a personal or family history of thrombotic events­

Aid risk/benefit assessment for preventive or therapeutic interventions for VTE or MI

Variants other than the 4G/5G polymorphism are not evaluated

Diagnostic errors can occur due to rare sequence variations

Detect elevated concentrations of PAI-1

Low concentrations of PAI-1 may not be accurately quantified

Not a first-line test for diagnosing inherited thrombotic or bleeding disorders

Screen for plasminogen deficiency

Not a first-line test for diagnosing inherited thrombotic or bleeding disorders

Screen for alpha-2-antiplasmin deficiency

Not a first-line test for diagnosing inherited thrombotic or bleeding disorders

Determine quantity of tissue plasminogen in plasma

May be helpful in detecting disorders of the fibrinolytic system

Not a first-line test for diagnosing inherited thrombotic or bleeding disorders

Medical Experts

Contributor
Contributor

Smock

Kristi J. Smock, MD
Professor of Clinical Pathology, University of Utah
Medical Director, Hemostasis/Thrombosis, ARUP Laboratories

References

Additional Resources