What causes elevated plasminogen activity in laboratory tests?

From the Guidelines

High plasminogen activity on every lab test is most likely caused by conditions that stimulate the body's fibrinolytic system, such as inflammation, infection, or liver disease, as these conditions can lead to increased production of plasminogen activators like tissue plasminogen activator (tPA) 1.

Causes of High Plasminogen Activity

The causes of high plasminogen activity can be diverse and include:

• Inflammation and infection, which can stimulate the production of plasminogen activators
• Liver disease, as the liver is the primary site of plasminogen synthesis
• Pregnancy and estrogen therapy, which can increase plasminogen levels
• Certain medications like streptokinase or tPA, which can directly activate plasminogen
• Genetic factors, as some individuals may naturally produce higher levels of plasminogen
• Certain malignancies, particularly those affecting the liver or blood
• Stress and exercise, which can temporarily elevate plasminogen levels

Clinical Implications

High plasminogen activity itself is not necessarily harmful but may indicate an underlying condition requiring attention, as it suggests increased fibrinolytic potential in the blood 1. If consistently high plasminogen activity is found without an obvious cause, further evaluation by a hematologist is recommended. Treatment depends on identifying and addressing the underlying cause rather than directly targeting the plasminogen levels.

Diagnostic Considerations

The diagnosis of hyperfibrinolysis, which can be associated with high plasminogen activity, is made indirectly with immunochemical methods that detect the elevation of biomarkers such as D-Dimer or by viscoelastic methods in whole blood 1. Plasminogen quantitation is routinely performed via functional assays, which quantify levels of functional plasminogen, as total antigen levels do not indicate whether plasminogen is activatable or how much was activated 1.

From the FDA Drug Label

Urokinase administered by intravenous infusion is rapidly cleared by the liver with an elimination half-life for biologic activity of 12.6 ± 6.2 minutes and a distribution volume of 11. 5 L. Although the pharmacokinetics of exogenously administered urokinase have not been characterized in patients with hepatic impairment, endogenous urokinase-type plasminogen activator plasma levels are elevated 2- to 4-fold in patients with moderate to severe cirrhosis. Intravenous infusion of Kinlytic™ in doses recommended for lysis of pulmonary embolism is followed by increased fibrinolytic activity in the circulation This effect disappears within a few hours after discontinuation, but a decrease in plasma levels of fibrinogen and plasminogen and an increase in the amount of circulating fibrin and fibrinogen degradation products may persist for 12-24 hours.

The cause of high Plasminogen Activity is not directly stated in the provided drug label. However, it can be inferred that elevated endogenous urokinase-type plasminogen activator plasma levels may be associated with hepatic impairment, such as moderate to severe cirrhosis 2. Additionally, intravenous infusion of urokinase may also lead to increased fibrinolytic activity in the circulation, which could potentially cause high plasminogen activity.

• Hepatic impairment may lead to reduced clearance of urokinase, resulting in elevated plasminogen activator levels.
• Exogenous administration of urokinase may increase fibrinolytic activity, potentially causing high plasminogen activity.

From the Research

Causes of High Plasminogen Activity

• High plasminogen activity can be caused by various factors, including liver disease, as the liver is the main site of synthesis and/or clearance of proteins involved in fibrinolysis 3.
• Chronic liver disease, including cirrhosis, can lead to altered plasma levels of fibrinolytic proteins, resulting in elevated levels of tissue-type plasminogen activator and altered levels of plasminogen activator inhibitor-1 3, 4.
• Liver damage due to paracetamol overdose and partial hepatectomy can also result in increased plasma concentrations of plasminogen activator inhibitor-1 4.
• Patients with liver disease may have appreciable increases in circulating tissue-type plasminogen activator antigen concentrations, which can be associated with increased concentrations of plasminogen activator inhibitor-1 antigen and tissue-type plasminogen activator-plasminogen activator inhibitor-1 complex 4.
• The balance between activator and inhibitor does not always result in systemic plasmin generation, and reduced plasminogen activator inhibitor-1 activity in cirrhosis or a critical difference in the ratio of tissue-type plasminogen activator to plasminogen activator inhibitor-1 concentrations may explain the enhanced plasminogen activator activity previously noted in cirrhosis but not metastatic disease 4.
• Impaired liver function may account for increased concentrations of free and complexed tissue-type plasminogen activator due to reduced hepatic clearance 4.
• Excessive amounts of thrombin and plasmin are actually generated in patients with liver disease, as evidenced by elevated plasma levels of thrombin-antithrombin III complex and plasmin-alpha 2-antiplasmin complex 5.

Fibrinolysis and Plasmin Generation

• Fibrinolysis is an important process in hemostasis responsible for dissolving the clot during wound healing, and plasmin is a central enzyme in this process via its capacity to cleave fibrin 6.
• The kinetics of plasmin generation and inhibition during fibrinolysis have been poorly understood until the recent development of assays to quantify these metrics 6.
• The assessment of plasmin kinetics allows for the identification of fibrinolytic dysfunction and better understanding of the relationships between abnormal fibrin dissolution and disease pathogenesis 6.
• The fibrinolytic system is also involved in physiological processes, and in pathological situations such as thrombosis, arteriosclerosis, endometriosis, and cancer 7.