Fibrinolytic Disorders

Diagnosis
Background
Lab Tests
References
Related Topics

Indications for Testing

Clinical suspicion for a fibrinolytic disorder is high
Common disorders of coagulation have been ruled out – also consider uncommon factor deficiencies

Laboratory Testing

Suspected deficiency – clinical history consistent with this disorder and other more common disorders have been ruled out
- Plasminogen activator inhibitor-1 (PAI-1)
  - Diurnal variation – higher values in the morning, lower values in the afternoon
  - PAI-1 deficiency identification is complex – values should be interpreted in conjunction with 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
Recurrent deep vein thrombosis in patient with negative workup for common defects – consider genotyping (SERPINE1)

Differential Diagnosis

Factor deficiency
- Factor VIII or IX deficiency most common
- VonWillebrand disease
Functional platelet disorder

Abnormalities in the fibrinolytic system may be associated with thrombosis or bleeding. Congenital fibrinolytic abnormalities are uncommon, but acquired abnormalities in this system 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 – 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, disseminated intravascular coagulation
Thrombotic Risk
- Heterozygotes – do not appear to have increased risk of thrombosis
- Homozygotes – risk of thromboses remains unclear

Tissue plasminogen activator (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
  - tPA is an acute phase reactant and may be elevated in patients with metabolic syndrome, cancer, surgery, pregnancy, sepsis, or other inflammation
Thrombotic Risk
- Deficiency has potential for but uncertain association with thrombosis

Plasminogen activator inhibitor-1 (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
  - PAI-1 is an acute phase reactant and may be elevated in patients with metabolic syndrome, cancer, surgery, pregnancy, or sepsis or other inflammation
  - Most PAI-1 assays are designed to identify elevated PAI-1 concentrations rather than PAI-1 deficiency
    - Low concentrations may not be accurately quantified
Deficiency
- Inherited
- Incidence – rare (in U.S., most common in the Old Order Amish community)
- Inheritance – autosomal recessive
- Clinical manifestations
  - Heterozygotes – usually do not present with bleeding disorders
  - Homozygotes – moderate to severe bleeding
    - Bleeding is usually post-traumatic rather than spontaneous
Thrombotic Risk
- Elevated levels may be associated with venous or arterial thrombosis, although routine testing of thrombophilic patients 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
    - 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

Pathophysiology
- Secreted by the liver
- Binds to and inhibits plasmin
Deficiency
- Inherited
  - Incidence – rare
  - Inheritance – autosomal recessive
Clinical Presentation
- Heterozygotes – usually mild mucosal bleeding or asymptomatic
- Homozygotes – may manifest with severe bleeding episodes resembling congenital hemophilia
  - Umbilical cord bleeding
  - Hemarthroses
  - Postoperative and post-trauma excessive bleeding
Thrombotic Risk
- Elevated alpha-2-antiplasmin has not been reported to be associated with increased risk for thromboses

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.

Plasminogen Activator Inhibitor-1, PAI-1 (SERPINE1) Genotyping 2004980
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Recommended Use

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

Clinical sensitivity – unknown

Limitations

Variants other than 4G/5G are not evaluated

Diagnostic errors can occur due to rare sequence variations

Alpha-2-Antiplasmin, Activity 0098727
Method: Chromogenic Assay

Recommended Use

Screen for alpha-2-antiplasmin deficiency

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

Plasminogen Activator Inhibitor 1, Activity 0098781
Method: Bioimmunoassay

Recommended Use

Screen for PAI-1 deficiency

Assay detects elevated PAI concentrations; low concentrations may not be accurately quantified

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

Limitations

Acute phase reactant

Diurnal variation

Tissue Plasminogen Activator, Antigen 0099187
Method: Enzyme-Linked Immunosorbent Assay

Recommended 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

Plasminogen Activity 0030190
Method: Chromogenic Assay

Recommended Use

Screen for plasminogen deficiency

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

Limitations

Not recommended for patients receiving fibrinolytic inhibitors

General References

Carpenter SL, Mathew P. Alpha2-antiplasmin and its deficiency: fibrinolysis out of balance. Haemophilia. 2008; 14(6): 1250-4. PubMed

Mehta R, Shapiro AD. Plasminogen activator inhibitor type 1 deficiency. Haemophilia. 2008; 14(6): 1255-60. PubMed

Mehta R, Shapiro AD. Plasminogen deficiency. Haemophilia. 2008; 14(6): 1261-8. PubMed

Rare Coagulation Disorders Resource Room. Rare Bleeding Disorders. Indiana Hemophilia & Thrombosis Center, and Rare Coagulation Disorders Subcommittee of the National Hemophilia Foundation. [Accessed: Sep 2015]

Schuster V, Hügle B, Tefs K. Plasminogen deficiency. J Thromb Haemost. 2007; 5(12): 2315-22. PubMed

Westrick RJ, Eitzman DT. Plasminogen activator inhibitor-1 in vascular thrombosis. Curr Drug Targets. 2007; 8(9): 966-1002. PubMed