Plasminogen activator inhibitor-1(PAI-1), or serpin E1, is a serine protease inhibitor (serpin) encoded by the human SERPINE1 gene. PAI-1 is a major inhibitor of fibrinolysis, a process that prevents blood clots from growing and becoming problematic. Increased PAI-1 activity results in depressed fibrinolytic activity resulting in elevated risk for thrombosis (formation of blood clots).
Tissue plasminogen activator (tPA) and urokinase, also called urokinase-type plasminogen activator (uPA), are serine proteases that activate plasminogen and, therefore, fibrinolysis (the physiological breakdown of blood clots). PAI-1 inhibits tPA and uPA and, therefore, inhibits fibrinolysis.
The normal (wild-type) promoter for the PAI-1 gene contains a tract of five consecutive G residues. However, there a mutant form of the PAI-1 promoter that have been identified that only contains four consecutive G residues. This mutant promoter causes higher amounts of PAI-1 to be made, compared to the wild-type. Increased amounts of PAI-1 inhibit more tPA and uPA and, therefore, inhibits fibrinolysis more than the wild-type gene, resulting in elevated risk of thrombosis.
The human PAI-1gene is SERPINE1and is located on chromosome 7 (7q21.3-q22). The following three genotypes of the PAI-1 promoter are possible:
(5G/5G) – Normal
(4G/5G) – Heterozygous: increased PAI-1 activity
(4G/4G) – Homozygous: significantly increased PAI-1 activity
The test was developed using CLSI guidelines. Control DNA samples of known genotype are tested together with each patient sample to monitor the performance of the test. Genomic DNA is extracted from the submitted blood specimen and analyzed by Polymerase chain reaction (PCR) followed by restriction digest.
Whole blood in a purple top (EDTA) tube
- Blood specimen:
- It is collected in a heparin-containing tube because heparin can inhibit the PCR reaction.
- It leaked in the shipping container.
- The name on the tube does not match the name on the paperwork.
- It is older than 10 days.
Homozygous wild-type (5G/5G) – Normal PAI-1 activity and normal risk of thrombosis
Heterozygous (4G/5G) – Increased PAI-1 activity resulting in depressed fibrinolysis and increased risk of thrombosis.
Homozygous mutant (4G/4G) – Significantly increased PAI-1 activity resulting in depressed fibrinolysis and increased risk of thrombosis.
This genotype result is but one factor affecting thrombosis risk, and other genetic and clinical factors should also be considered. Multiple thrombosis risk factors are usually additive. Additional risk factors for development of thrombosis include: older age, surgery, obesity, prolonged travel, immobility, hospitalization, oral contraceptive use, hormonal replacement therapy, pregnancy, and malignancy.
Other genetic variants of the PAI-1 gene that are not detected in this assay may influence PAI-1 activity. Other genetic and non-genetic factors may also influence the balance of proper thrombosis. The detection of genetic variants does not replace the need for appropriate clinical monitoring by the health care provider. These tests were developed and the performance characteristics were determined by MDL. This test has not been cleared or approved by the US Food and Drug Administration.
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