Fibrinolytic Disorders

Diagnosis

Indications for Testing

• Clinical suspicion for a fibrinolytic disorder is high and common disorders of coagulation have been ruled out (also consider uncommon factor deficiencies)

Laboratory Testing

• Laboratory identification of tPA deficiency is complex due to fluctuation of tPA levels in blood (acute phase reactant), as well as fluctuating levels of PAI-1 (acute phase reactant, diurnal variation), which binds and inactivates tPA
• Laboratory measurement of PAI-1 must address several issues
  • PAI-1 is an acute phase reactant
  • PAI-1 has diurnal variation, with higher values in the morning and decreased values in the afternoon
  • Identification of PAI-1 deficiency is complex, and values should be interpreted in conjunction with values for tPA
    • 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
• Suspected plasminogen deficiency – order plasminogen activity test
• Suspected alpha-2-antiplasmin deficiency – order alpha-2-antiplasmin activity test
• Recurrent deep vein thrombosis in patient with negative workup for common defects – consider genotyping

Differential Diagnosis

• Factor deficiency
• Hemophilia
• Functional platelet disorder

Clinical Background

Abnormalities in the fibrinolytic system may be associated with thrombosis or bleeding. Congenital fibrinolytic abnormalities are uncommon; acquired abnormalities are not unusual.

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

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 may be inherited or acquired due to disseminated intravascular coagulation, liver disease, or fibrinolytic therapy Inherited plasminogen deficiency is rare, usually autosomal dominant; may be quantitative (type 1) or qualitative (type 2) Incidence – <1/1,000,000 Clinical presentation – ligneous conjunctivitis, altered wound healing, or pseudomembrane formation Presence of isolated heterozygous plasminogen deficiency does not appear to increase the risk of thrombosis Thrombotic risks caused by homozygous deficiency remain unclear

Tissue plasminogen activator (tPA)

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 Increased tPA may result in increased fibrinolysis and bleeding tPA is an acute phase reactants and may be elevated in patients with metabolic syndrome, cancer, surgery, pregnancy, or sepsis Deficiency has an uncertain association with thrombosis

Plasminogen activator inhibitor-1 (PAI-1)

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 Increased PAI-1 levels may be associated with venous or arterial thrombosis, although routine testing of thrombophilic patients is not recommended PAI-1 is an acute phase reactant and may be elevated in patients with metabolic syndrome, cancer, surgery, pregnancy, or sepsis or other inflammation PAI-1 has diurnal variation with higher concentration in the morning and decreased concentration in the afternoon Inherited deficiency Rare autosomal recessive disorder Clinical manifestations – associated with moderate to severe bleeding in homozygous individuals (complete deficiency) Bleeding is usually post-traumatic rather than spontaneous Most PAI-1 assays are designed to identify elevated PAI-1 concentrations rather than PAI-1 deficiency Low concentrations may not be accurately quantified 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 4G/5G and 4G/4G genotypes are associated with increased risk of myocardial infarction Some studies have associated the 5G/5G genotype with elevated risk of ischemic stroke (IS)

Alpha-2-antiplasmin

Secreted by the liver Binds to and inhibits plasmin Contribution of elevated alpha-2-antiplasmin to thrombotic risk has not been reported Inherited deficiency Rare autosomal recessive disorder Clinical presentation Heterozygotes – usually mild mucosal bleeding Homozygotes – may manifest with severe bleeding episodes (may resemble congenital hemophilia)

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory