Fibrinolytic Disorders

Abnormalities in the fibrinolytic system may be associated with thrombosis or bleeding. Congenital fibrinolytic abnormalities are uncommon, while 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

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, and 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 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 reactant 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 which 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 presentations
  - 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 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

Tests generally appear in the order most useful for common clinical situations

Test name: Plasminogen Activity

ARUP #: 0030190

Methodology: Chromogenic Assay

Use:

Determine plasminogen activity in plasma

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

Limitations: Not recommended for patients receiving fibrinolytic inhibitors

Test name: Tissue Plasminogen Activator, Antigen

ARUP #: 0099187

Methodology: Enzyme-Linked Immunosorbent Assay

Use: Determine quantity of tPA in plasma

May be helpful in detecting disorders of the fibrinolytic system

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

Limitations:

Acute phase reactant

Test name: Plasminogen Activator Inhibitor 1, Activity

ARUP #: 0098781

Methodology: Bioimmunoassay

Use:

Quantify active PAI-1 in human plasma

Assay designed to detect elevated PAI concentrations; low concentrations not accurately quantified

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

Limitations:

Acute phase reactant

Diurnal variation