Plasminogen activator inhibitors, also known as PAIs for short, are proteins in the blood that play a role in blood clotting. They inhibit the dissolution of blood clots.
What is plasminogen activator inhibitor?
A plasminogen activator inhibitor is a protein found in the blood that is involved in blood clotting. Blood clotting is an important process by which bleeding can be stopped. It is the only way to prevent the excessive leakage of blood from the bloodstream in the event of injury. Four different types of plasminogen activator inhibitors can be distinguished. The most important plasminogen activator inhibitor is type 1 (PAI-1). It inhibits tissue-specific plasminogen activator and urokinase. Type 2 plasminogen activator inhibitor (PAI-2) occurs in greater amounts exclusively during pregnancy.
Function, effects, and roles
Plasminogen activator inhibitor is produced by various cells of visceral fat. Visceral fat is also called intra-abdominal fat. It is located within the abdominal cavity and coats the internal organs. It serves to protect these organs and also as an energy reserve. Within this visceral fat, endothelial cells, adipocytes, and megakaryocytes produce plasminogen activator inhibitor type 1, but the majority of the inhibitor is produced in platelets. Platelets are blood cells and are the smallest cells in the blood. They also play an important role in blood clotting and release PAI-1 during primary closure of wounds in defects of the vessel wall. Only in obesity and type 2 diabetes mellitus does the production of plasminogen activator inhibitors increase. The reason is the increase in visceral fat. Plasminogen activator inhibitor type 1 is inhibited by aleplasinin, a drug used primarily to treat Alzheimer’s disease. Plasminogen activator inhibitor type 2 is produced by the placenta during pregnancy. Outside of pregnancy, this inhibitor is virtually absent. The other two types are also negligible.
Formation, occurrence, properties, and optimal levels
The main function of PAI-1 is to inhibit plasminogen activators. The two major plasminogen activators are tPA (tissue plasminogen activator) and uPA (urokinase plasminogen activator). Both tPA and uPA convert the inactive proenzyme plasminogen into the active enzyme plasmin. Plasmin is an enzyme that belongs to the group of peptidases. It can cleave and degrade proteins in the blood. In particular, plasmin breaks down the fibrin in blood clots. This process is also known as fibrinolysis. The difficulty in fibrinolysis is finding the optimal balance between bleeding and thrombosis. Fibrinolysis is activated simultaneously with blood clotting. Inhibition follows the general reaction mechanism of serpins by PAI-1, and most of this inhibitor is found in platelets. In case of vascular or tissue injury, platelets circulating in the blood get stuck to the defective cell walls. Due to various factors, they change their appearance to loosely cover the wound area. The platelets also stick together. This creates an initial provisional wound closure. In a second step, secondary hemostasis, this loose closure is reinforced by fibrin threads. The clotting factors are relevant for this. In order that this fibrin scaffold does not now dissolve again directly, the platelets release the plasminogen activator inhibitor type 1.
Diseases and disorders
When there is an increase in visceral fat, there is an increase in the production of plasminogen activator inhibitor type 1, as mentioned earlier. One cause of such an increase in visceral fat is diabetes mellitus type 1, which is a metabolic disease associated with elevated levels of sugar in the blood serum. Obesity, i.e. morbid overweight, also leads to an increase in abdominal fat. The same applies to metabolic syndrome. The metabolic syndrome is often referred to as the fatal quartet, as it is considered one of the decisive risk factors for vascular diseases. The metabolic syndrome includes abdominal-emphasized obesity, hypertension, elevated blood lipids, deficiency of HDL cholesterol, and elevated blood sugar concentration or insulin resistance.The metabolic syndrome is found particularly in industrialized countries and is forced by overeating and lack of exercise. An increase in the secretion of PAI-1 leads to reduced fibrinolysis. This promotes clot formation in peripheral vessels. With increased clot formation within the vessels, the risk of developing a secondary disease also increases. It becomes dangerous when a clot breaks loose and causes an embolism. An embolism is a vessel occlusion caused by a blood clot, a fat droplet or air bubbles. If a thrombus detaches from a vein, this can result in a pulmonary embolism. In this case, the thrombus blocks one or more pulmonary arteries. This results in a buildup of blood in front of the clot and thus also in an increase in pressure in the pulmonary circulation. This is also referred to as pulmonary hypertension. This increase in pressure puts a strain on the right heart. There is a risk of heart failure. However, clots can also form in the coronary vessels due to an increase in plasminogen activator inhibitor type 1. If a vessel becomes completely blocked in the process, a heart attack can result. In myocardial infarction, heart tissue dies due to a lack of oxygen supply. Characteristic symptoms of a heart attack are sudden onset of severe pain. These are also called crushing pains. They may radiate to the neck, back or arms. Common accompanying symptoms include cold sweats, shortness of breath, nausea and pallor. The consequence of plasminogen activator inhibitor excess can also be a stroke. Here, as a result of a clot, there is a lack of blood supply to the brain and thus a failure of important functions of the central nervous system.
