Fibrinolytic Disorders

Diagnosis

Indications for Testing

• High clinical suspicion for a fibrinolytic disorder after exclusion of common disorders of coagulation
  • Uncommon factor deficiencies should also be considered

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)
  • Consider in patient with recurrent deep vein thrombosis and negative workup for common defects

Differential Diagnosis

• Factor deficiency
  • Factor VIII or IX deficiency most common
  • von Willebrand disease
• Functional platelet disorder

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
    • May be due to liver disease or disseminated intravascular coagulation
• 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