Clinical Background
Congenital deficiencies in the fibrinolytic/thrombolytic systems are uncommon, while acquired deficiencies are not unusual.
Pathophysiology
- Components of the fibrinolytic system include plasminogen, plasminogen activator and plasminogen activator inhibitors.
- Fibrin is the final response to vascular injury and is deposited in tissue and blood vessels
- Fibrin is the end product of the action of thrombin on fibrinogen
- Once fibrin is no longer needed, the fibrinolytic system is activated, converting fibrin to its soluble degradation products
- Fibrinolysis is precisely regulated by activators, inhibitors and cofactors in physiologic states
Plasminogen Disorders - Types I and II
- Incidence - disorder is uncommon
- Pathophysiology
- Plasminogen is synthesized in liver
- Function - role in fibrinolysis after being converted to active form which is plasmin
- Decreased levels - disseminated intravascular coagulation (DIC), liver disease, fibrinolytic therapy and plasminogen deficiency
- Clinical Presentations
- Presence of plasminogen deficiency increases the risk of thrombosis
- Half of patients with plasminogen disorder have other factor deficiencies (eg, protein C, S)
Plasminogen Activators Disorders
- Pathophysiology
- Tissue plasminogen activator (t-PA)
- Synthesized mainly in the endothelial cells
- Function - activate plasminogen facilitating conversion to plasmin
- Both single-chain and double-chain forms of t-PA can activate plasminogen
- Plasmin degrades fibrin to soluble degradation products in the fibrinolytic pathway
- Clinical Presentation
- Decreased t-PA may reduce fibrinolysis and may cause thrombosis
- Increased t-PA levels may cause excessive fibrinolysis and bleeding episodes
Plasminogen Activator Inhibitor-1 (PAI-1) Disorder
- Incidence
- Rare autosomal recessive disorder
- Pathophysiology
- PAI-1 is synthesized by endothelial cells, platelets and hepatocytes
- Function -- inhibits tissue plasminogen activator (t-PA), a key enzyme in fibrinolysis
- Identified forms of PAI-1 include 1 active and 2 latent inactive forms
- As PAI-1 levels increase, active levels of t-PA decrease, causing impaired fibrinolytic function
- Clinical Presentation
- Decreased levels - associated with hemorrhage
- Elevated levels of PAI-1 in deep-vein thrombosis and myocardial infarction, as well as in normal pregnancy and sepsis
- In young survivors of myocardial infarction, increased PAI-1 is an independent risk factor for reocclusion
See Also
Diagnosis
Plasminogen Disorders - Types I and II
- Diagnosis
- Laboratory testing - plasminogen activity
Plasminogen Activators Disorders
- Diagnosis
- Laboratory testing
- The assessment of t-PA is complicated
- Typically, t-PA is found in very small amounts
- Plasminogen activator inhibitor (PAI-1) rapidly binds to t-PA and inhibits its activity
- As a result, it is necessary to acidify the patient's plasma to determine active t-PA
Plasminogen Activator Inhibitor-1 (PAI-1) Disorder
- Diagnosis
- Laboratory testing - PAI-1 levels
| Tests |  |
Tests generally appear in the order most useful for common clinical situations
| Test name: Plasminogen Activity
|
| ARUP #: 0030190 |
| Methodology: Chromogenic Assay
|
| Use:
Determine plasminogen activity or deficiency
Order only if APC resistance, homocystinemia, proteins C and S deficiencies, antithrombin deficiency and the prothrombin mutation have been excluded as possible causes of thrombotic activity
This is not a first-line test for diagnosing inherited thrombotic disorder |
| Limitations: Not recommended for patients receiving fibrinolytic inhibitors |
| Follow-up:
|
| Test name: Tissue Plasminogen Activator, Antigen
|
| ARUP #: 0099187 |
| Methodology: Enzyme-Linked Immunosorbent Assay
|
| Use:
Determine quantity of t-PA in plasma
May be helpful in detecting disorders of the fibrinolytic system
This is not a first-line test in diagnosing inherited thrombotic disorders |
| Limitations: Patient's plasma must be acidified |
| Follow-up:
|
| Test name: Plasminogen Activator Inhibitor 1, Activity
|
| ARUP #: 0098781 |
| Methodology: Bioimmunoassay
|
| Use:
Quantify active plasminogen activator inhibitor (PAI-1) in human plasma; this may be useful in the diagnosis of thrombotic disease
This is not a first-line test for diagnosing inherited thrombotic disorder |
| Limitations: |
| Follow-up:
|
Additional Information
Plasminogen activator inhibitor 1 has diurnal variation, with higher values in the morning and decreased values in the afternoon
References
General References
Benarroch EE. Tissue plasminogen activator: beyond thrombolysis. Neurology.
2007;
69(
8):
799-802.
Brandt JT. Plasminogen and tissue-type plasminogen activator deficiency as risk factors for thromboembolic disease. Arch Pathol Lab Med.
2002;
126(
11):
1376-1381.
Castellino FJ, Ploplis VA. Structure and function of the plasminogen/plasmin system. Thromb Haemost.
2005;
93(
4):
647-654.
de Maat MP, Verschuur M. Fibrinogen heterogeneity: inherited and noninherited. Curr Opin Hematol.
2005;
12(
5):
377-383.
Fay WP, Garg N, Sunkar M . Vascular functions of the plasminogen activation system. Arterioscler Thromb Vasc Biol.
2007;
27(
6):
1231-1237.
Hayes T. Dysfibrinogenemia and thrombosis. Arch Pathol Lab Med.
2002;
126(
11):
1387-1390.
Horrevoets AJ. Plasminogen activator inhibitor 1 (PAI-1): in vitro activities and clinical relevance. Br J Haematol.
2004;
125(
1):
12-23.
Liu M, Counsell C, Zhao XL, Wardlaw J. Fibrinogen depleting agents for acute ischaemic stroke. Cochrane Database Syst Rev.
2003;
(
3):
CD000091.
Lowe GD, Rumley A, Mackie IJ. Plasma fibrinogen. Ann Clin Biochem.
2004;
41(
Pt 6):
430-440.
Plow EF, Hoover-Plow J. The functions of plasminogen in cardiovascular disease. Trends Cardiovasc Med.
2004;
14(
5):
180-186.
Westrick RJ, Eitzman DT. Plasminogen activator inhibitor-1 in vascular thrombosis. Curr Drug Targets.
2007;
8(
9):
966-1002.
Medical Reviewers
Rodgers, George M. III, M.D., Ph.D. Medical Director, Hemostasis/Thrombosis at ARUP Laboratories; Professor, Medicine, Adjunct Professor, Pathology, University of Utah
Comprehensive Review: March 2008
Last Update: March 2008
