COAGULATION TEST HANDBOOK      
 
 

From: Elizabeth M. Van Cott, M.D., and Michael Laposata, M.D., Ph.D., "Coagulation." In: Jacobs DS et al, ed. The Laboratory Test Handbook, 5th Edition. Lexi-Comp, Cleveland, 2001; 327-358.

Index of Tests

Plasminogen Activator Inhibitor 1 [CO003600]

Related Information

Synonyms PAI-1

Applies to Acute Phase Reactant; Tissue Plasminogen Activator; tPA

Abstract PAI-1 inhibits tissue plasminogen activator (tPA). High levels of PAI-1 may be associated with an increased risk of arterial thrombosis due to inhibition of fibrinolysis, and low levels of PAI-1 characterize a rare familial bleeding disorder due to excessive fibrinolysis.1,2 A causal effect of high levels of PAI-1 on arterial thrombosis has not yet been established.

Specimen Plasma

Container Blue top (sodium citrate) tube. Specialized tubes containing platelet inhibitors (to prevent platelet release of PAI-1) or acid (to prevent PAI-1 from forming a complex with tPA) have been recommended, but are not necessary if specimens are handled appropriately.3

Sampling Time PAI-1 has a circadian rhythm: its plasma concentration is highest in the morning, and lowest in the afternoon and evening. In one study, the mean level was 23 ng/mL at 9 AM and 10 ng/mL at 4 PM.3

Collection Collect blood from a steadily flowing venipuncture. Discard the first 3-5 mL if PAI-1 is the only test being drawn. If multiple tests are being drawn, draw blue top tubes after any red top tubes but before any lavender top (EDTA), green top (heparin), or gray top (oxalate/fluoride) tubes. Immediately invert tube gently at least 4 times to mix. Tubes must be appropriately filled. Deliver tubes immediately to the laboratory.

Storage Instructions Separate plasma from cells as soon as possible. Laboratories should avoid platelet contamination of plasma because platelets contain PAI-1. Centrifugation at 2000-3000 g for 15 minutes helps ensure platelet-free plasma.3 Store plasma on ice for up to 2 hours, or store frozen.

Causes for Rejection Specimen received more than 2 hours after collection; tubes not filled; clotted specimens; antifibrinolytic agent present in specimen, such as aprotinin or epsilon-aminocaproic acid, which interfere with functional PAI-1 assays

Turnaround Time Usually at least several days, as testing is often batched

Reference Interval Approximately 4-40 ng/mL in antigen assay4 and 0-12 units/mL in functional assay (see Sampling Time for note regarding circadian rhythm)

Use Not a commonly performed clinical assay. May be considered in patients with strong evidence for a familial bleeding disorder and normal test results for more common bleeding disorders (eg, von Willebrand disease). May be considered in patients with unexplained premature myocardial infarction.

Limitations PAI-1 is an acute phase reactant.5 Therefore, it becomes elevated following a thrombotic event and it should not be measured in the acute setting following thrombosis. A related inhibitor, PAI-2, is normally not present in plasma. However, it becomes elevated in pregnant women and can cause overestimations of PAI-1 during pregnancy. PAI-1 also becomes elevated during pregnancy. Antigen assays will not detect qualitative deficiencies.

Methodology

Functional (activity) assays:6 Patient plasma is added to a known amount of urokinase; PAI-1 in the patient plasma binds and inhibits the urokinase. The amount of residual urokinase is detected by adding plasminogen, which is converted to plasmin by urokinase. Plasmin cleaves a chromogenic synthetic substrate, releasing a colored compound which can be detected spectrophotometrically. The amount of released color is inversely proportional to the amount of PAI-1 in the sample. This assay contains an inhibitor of antiplasmin and other plasmin inhibitors to prevent these other inhibitors from interfering with the assay. Another version of this assay uses tPA instead of urokinase, and an acidification step to destroy antiplasmin and other plasmin inhibitors.

Antigen (enzyme-linked immunosorbent) assays are also available.4

Additional Information PAI-1 is produced by the endothelium and liver and is also present in platelets. PAI-1 inhibits both tPA and urokinase-type plasminogen activator (uPA). PAI-1 may be active, inactive, or complexed with tPA.

The relationship between elevated PAI-1 and coronary artery disease may be at least partly due to its association with established cardiovascular risk factors, namely, the syndrome of insulin resistance. Elevated PAI-1 is associated with an increased incidence of myocardial infarction in prospective studies, but the association has not always remained significant after adjusting for other factors such as insulin resistance.7 The synthesis of PAI-1 is increased by high glucose or insulin levels. PAI-1 levels are elevated in insulin resistance, which is associated with a constellation of lipid and other abnormalities and an increased risk of coronary artery disease. Weight loss, which may reduce insulin resistance, also reduces PAI-1.8 Studies are conflicting regarding an association between a PAI-1 polymorphism, higher PAI-1 levels, and myocardial infarction.9

Footnotes

1. Fay WP, Shapiro AD, Shih JL, et al, "Brief Report: Complete Deficiency of Plasminogen-Activator Inhibitor Type 1 Due to a Frame-Shift Mutation,"N Engl J Med, 1992, 327(24):1729-33.

2. Takahashi Y, Tanaka T, Minowa H, et al, "Hereditary Partial Deficiency of Plasminogen Activator Inhibitor-1 Associated With a Life-Long Bleeding Tendency,"Int J Hematol, 1996, 64(1):61-8.

3. Macy EM, Meilahn EN, Declerck PJ, et al, "Sample Preparation for Plasma Measurement of Plasminogen Activator Inhibitor-1 Antigen in Large Population Studies,"Arch Pathol Lab Med, 1993, 117(1):67-70.

4. Declerck PJ, Alessi MC, Verstreken M, et al, "Measurement of Plasminogen Activator Inhibitor 1 in Biologic Fluids With a Murine Monoclonal Antibody-Based Enzyme-Linked Immunosorbent Assay,"Blood, 1988, 71(1):220-5.

5. Jansson JH, Norberg B, and Nilsson TK, "Impact of Acute Phase on Concentrations of Tissue Plasminogen Activator and Plasminogen Activator Inhibitor in Plasma After Deep Vein Thrombosis or Open Heart Surgery,"Clin Chem, 1989, 35(7):1544-5.

6. Contant G, Nicham F, and Martinoli JL, "Determination of Plasminogen Activator Inhibitor (PAI) by a New Venom-Based Assay,"Fibrinolysis, 1992, 6(Suppl 3):85-6.

7. Juhan-Vague I, Pyke SD, Alessi MC, et al, "Fibrinolytic Factors and the Risk of Myocardial Infarction or Sudden Death in Patients With Angina Pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities,"Circulation, 1996, 94(9):2057-63.

8. Svendsen OL, Hassager C, Christiansen C, et al, "Plasminogen Activator Inhibitor-1, Tissue-Type Plasminogen Activator, and Fibrinogen. Effect of Dieting With or Without Exercise in Overweight Postmenopausal Women,"Arterioscler Thromb Vasc Biol, 1996, 16(3):381-5.

9. Mikkelsson J, Perola M, Wartiovaara U, et al, "Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G Polymorphism, Coronary Thrombosis, and Myocardial Infarction in Middle-Aged Finnish Men Who Died Suddenly,"Thromb Haemost, 2000, 84(1):78-82.

References

Kohler HP and Grant PJ, "Plasminogen-Activator Inhibitor Type I and Coronary Artery Disease,"N Engl J Med, 2000, 342(24):1792-801.

Lane DA and Grant PJ, "Role of Hemostatic Gene Polymorphisms in Venous and Arterial Thrombotic Disease,"Blood, 2000, 95(5):1517-32.

 

     
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