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.

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Clinical Overview

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

ARUP Lab Tests

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

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

Limitations

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

Diagnostic errors can occur due to rare sequence variations

Plasminogen Activator Inhibitor 1, Activity 0098781
Method: Bioimmunoassay

Recommended Use

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

Plasminogen Activity 0030190
Method: Chromogenic Assay

Recommended Use

Screen for plasminogen deficiency

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

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

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

Recommended Use

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

Lyon, Elaine, PhD, FACMG, Medical Director, Molecular Genetics and Genomics, Medical Director, Pharmacogenomics at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

Rodgers III, George M., MD, PhD, Medical Director, Hemostasis/Thrombosis at ARUP Laboratories; Professor of Internal Medicine and Adjunct Professor of Clinical Pathology, University of Utah

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

References

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 Coagulation Disorders. Rare Coagulation Disorders Subcommittee of the National Hemophilia Foundation, and Indiana Hemophilia & Thrombosis Center. [Accessed: Apr 2018]

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

Last Update: July 2018

Fibrinolytic Disorders

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Background

Pathophysiology

Components of Fibrinolytic System

Plasminogen

tPA

PAI-1

Alpha-2-antiplasmin

ARUP Lab Tests

Medical Experts

References

General References

ARUP Laboratories

ARUP Websites

ARUP Consult


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Fibrinolytic Disorders

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Background

Pathophysiology

Components of Fibrinolytic System

Plasminogen

tPA

PAI-1

Alpha-2-antiplasmin

ARUP Lab Tests

Medical Experts

References

General References

ARUP Laboratories

ARUP Websites

ARUP Consult