Blood clots can occur under many different circumstances and in many different locations. Blood clotting, or also know as coagulation, is a process that prevents bleeding when a blood vessel is injured. Blood clots that forms due to an injury or cut are beneficial, stopping potentially unsafe bleeding or excessive blood loss.
The ability of the body to control the flow of blood following vascular injury is paramount to continued survival. The process of blood clotting along with the subsequent dissolution of the clot, following repair of the injured tissue, is termed hemostasis.
Hemostasis comprises four major events that occur in a set of order following the loss of vascular integrity:
1. The initial phase of the process is vascular constriction. This limits the flow of blood to the area of injury.
2. Next, platelets become activated by thrombin and aggregate at the site of injury, forming a temporary, loose platelet plug. The protein fibrinogen is primarily responsible for stimulating platelet clumping. Platelets clump by binding to collagen that becomes exposed following the rupture of the endothelial lining of vessels.
Upon activation, platelets release the nucleotide, ADP and the eicosanoid, TXA2 (both of which activate additional platelets), serotonin, phospholipids, lipoproteins, and other proteins important for the coagulation cascade.
In addition to induced secretion, activated platelets change their shape to accommodate the formation of the plug.
3. To insure stability of the initially loose platelet plug, a fibrin mesh (also called the clot) forms and entraps the plug. If the plug contains only platelets it is termed a white thrombus; if red blood cells are present it is called a red thrombus.
4. Finally, the clot must be dissolved in order for normal blood flow to resume following tissue repair. The dissolution of the clot occurs through the action of plasmin.
Essentials About Plasmin
How is a clot broken down? A clot breakdown occurs when it is broken down into Fibrin Degradation Products and for this to happen, Plasmin is needed.
1. What is a Plasmin?
Plasmin is a proteolytic enzyme that causes fibrinolysis in blood clots. Fibrinolysis is a normal body process. It prevents blood clots that occur naturally from growing and causing problems.
Primary fibrinolysis refers to the normal breakdown of clots while secondary fibrinolysis is the breakdown of blood clots due to a medical disorder or other cause. This may result to dangerous bleeding.
2. Plasmin is an important enzyme.
Plasmin degrades many blood plasma proteins, including fibrin clots. Fibrin is an insoluble protein that is produced in response to bleeding and is the major component of a blood clot.
Fibrin is a protein substance that is arranged in long fibrous chains; it is formed from fibrinogen, a soluble protein that is produced by the liver and found in blood plasma.
3. Plasmin is the main enzyme in a process called Fibrinoloysis.
In fibrinolysis, a fibrin clot, the product of coagulation, is broken down. Its main enzyme plasmin cuts the fibrin mesh at various places, leading to the production of circulating fragments that are cleared by other proteases or by the kidney and liver.
Fibrin is a cofactor for plasminogen activation by tissue plasminogen activator. Urokinase plasminogen activator receptor (uPAR) is a cofactor for plasminogen activation by urokinase plasminogen activator. The conversion of plasminogen to plasmin involves the cleavage of the peptide bond between Arg-561 and Val-562.
4. The breakdown of fibrin (fibrinolysis) can be due to the following reasons:
– Bacterial infections
– Intensive exercise
– Low blood sugar
– Not enough oxygen to tissues
5. Plasmin activates Collagenases
Collagenase is a key enzyme in collagen turnover. It is considered to be a primary agent responsible for cartilage and bone destruction in joint diseases. They are active proteinases that degrade collagen and proteoglycan.
All four main classes of proteolytic enzymes are involved in either the normal turnover of connective tissue or its pathological destruction. The collagenases are the enzymes essential to initiate collagen turnover in diseases and in normal connective tissue turnover.
6. Plasmin is released as a zymogen called plasminogen.
A zymogen (also denoted as a proenzyme) is a group of proteins that can also be described as an inactive enzyme. Also, digestive enzymes are released in inactive forms called zymogens. This is necessary to prevent the digestive enzymes from digesting the cells that produce them.
In a zymogen, a peptide blocks the active site of the enzyme. Cleaving off this peptide activates the enzyme. In circulation, plasminogen adopts a closed, activation resistant conformation.
Upon binding to clots, or to the cell surface, plasminogen adopts an open form that can be converted into active plasmin by a variety of enzymes, including tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), kallikrein, and factor XII (Hageman factor).
7. Role of Plasminogen Activator
A plasminogen activator is a serine protease which converts plasminogen to plasmin, thus paving way into the start of a process called fibrinolysis.
The serine proteases are a family of enzymes that cut certain peptide bonds in other proteins. This activity depends on a set of amino acid residues in the active site of the enzyme — one of which is always a serine.
In mammals, serine proteases perform many important functions, especially in digestion, blood clotting, and the complement system.
The plasminogen activators are also useful for controlling coagulation. Because tPA is highly selective for the degradation of fibrin in clots, it is extremely helpful in restoring the patency of the coronary arteries following thrombosis, in particular during the short period following myocardial infarction.
Streptokinase (an enzyme from the Streptococci bacterium) is another plasminogen activator useful from a therapeutic standpoint. However, it is less selective than tPA, being able to activate circulating plasminogen as well as that bound to a fibrin clot.
8. Plasma contains Plasminogen
Plasma contains plasminogen, which binds to the fibrin molecules in a clot.
Nearby healthy cells release tissue plasminogen activator (TPA), which also binds to fibrin and, as its name suggests, activates plasminogen forming plasmin.
Plasmin proceeds to digest fibrin, thus dissolving the clot.
9. Plasminogen binds to both fibrinogen and fibrin.
It is incorporated into a clot as it is formed. Tissue plasminogen activator (tPA) and, to a lesser degree, urokinase are serine proteases which convert plasminogen to plasmin.
Inactive tPA is released from vascular endothelial cells following injury. It binds to fibrin and is consequently activated. Urokinase is produced as the precursor, prourokinase by epithelial cells lining excretory ducts.
The role of urokinase is to activate the dissolution of fibrin clots that may be deposited in these ducts.
10. Mechanism of tPA activation of fibrin clot breakdown
Release of tissue plasminogen activator (tPA) from vascular endothelial cells leads to the onset of the dissolution of fibrin clots.
Low levels of circulating tPA are kept inactive by interaction with various inhibitors, where plasminogen activator inhibitor-1 and -2 (PAI-1 and PAI-2) are the most significant. tPA is also removed from the circulation by heptaic cell uptake.
The clot dissolving enzyme, plasminogen, binds to the fibrin clot as the inactive zymogen. Once tPA interacts with plasminogen it hydrolyzes the protein releasing catalytically active plasmin.
Plasmin then can hydrolyze the cross-linked fibrin polymers of the clot resulting in its dissolution (breakdown). Excess plasmin is controlled from over activity via interaction, in the plasma, with plasmin inhibitors such as α2-antiplasmin.
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