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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