The clotting factor thrombin is formed from the inactive protein prothrombin in a biosynthesis process. Thrombins convert fibrinogens into fibrin, thus realizing the final step of the coagulation cascade. In genetic prothrombin mutations, increased prothrombin concentration in plasma leads to thrombosis tendency.
What is thrombin?
Thrombin occurs as a protein in blood plasma and is involved in plasmatic coagulation of blood. Its precursor is known as factor II of blood clotting. Thrombin is produced in the liver, from where it is permanently released into the blood. To prevent the blood from clotting in healthy vessels, the body produces its own antithrombins, which have an inhibitory effect on clotting. In open wounds and tissue injuries, thrombin is produced directly at the site of the injury. Therefore, mainly its inactive precursor prothrombin is present in the plasma, whereas the actual thrombin is only present in small amounts in the plasma. The enzyme was first described by Schmidt, who mentioned it in his book on blood science at the end of the 19th century. With heparin and similar substances, the pharmaceutical industry has developed numerous agents to inhibit thrombin and reduce blood clotting during medical procedures such as dialysis. These antithrombins are modeled on the body’s own antithrombins.
Anatomy and structure
Endogenous thrombin is a protein. It is formed in the liver as part of a biosynthesis from the inactive form prothrombin. For humans, on a genetic basis, the F2 gene on chromosome 11 in particular plays a role in this process and the formation of prothrombin. This gene extends over more than 20,000 base pairs and accounts for a full 14 exons. After transcription, the 1,997 base mRNA is translated into protein consisting of 622 amino acids. Via modifications, the product of this translation results in prothrombin and thus the precursor of thrombin, which comprises 579 amino acids. This precursor of thrombin is inactive until it is converted to thrombin in biosynthesis. This conversion occurs through the enzymatic cleavage of prothrombins. The enzymatic prothrombinase complex plays the major role in this process. The conversion of inactive prothrombins to active thrombins is vitamin K-dependent and is a step in the so-called coagulation cascade.
Function and Tasks
Thrombin catalyzes the final step in the coagulation cascade. This cascade protects the body from major blood loss and closes the wound to protect against infection. The coagulation cascade is the systematic activation of the individual coagulation factors. As a so-called serine protease, thrombin initiates the conversion of fibrinogen into fibrin. For this purpose, thrombin hydrolyzes a so-called arginylglycine bond in the α- and β-chains of the fibrinogens and cleaves four polypeptides. This reduces the molecular weight from 340,000 for fibrinogens to about 270,000 daltons for fibrin. Polymerization takes place as a result of the fibrin. In the process, non-covalent bonds are formed. Through coagulation factor XIII, the covalent peptide bonds are finally formed from these bonds and coagulation is complete. In simplified terms, thrombin cleaves peptide residues from fibrinogen. Consequently, the conversion takes place proteolytically, i.e. by the degradation of proteins. In the course of this process, fibrin threads are formed from the fibrinogens. The blood changes its consistency in this way. Instead of being in liquid form, it is in the form of jelly due to the threads, which is finally processed by coagulation factor XIII into a network of fibrins. Fibrinogens are also known as coagulation factor I because of their relevance in the coagulation cascade. Thrombin serves as their catalyst in this system, thus performing clotting functions behind the scenes, so to speak, by assisting in the change of blood consistency in the event of injury.
Diseases
One of the most important diseases involving thrombin is the so-called prothrombin mutation or factor II mutation. Patients with this blood clotting disorder have an increased risk of developing a blood clot. Compared to the blood of healthy people, their blood clots more quickly. This is caused by a change in the genetic information of prothrombin. This genetic anomaly is a point mutation of the prothrombin gene. Due to the incorrect genetic information, significantly larger amounts of prothrombin are present in the patients’ blood.Therefore, their blood tends to form clots. As a consequence, thrombosis or even embolism may occur if the thrombus is carried away. Heart attacks and strokes or kidney infarctions can be the result. In combination with risk factors such as smoking or taking the contraceptive pill, vascular occlusions and infarctions occur even more frequently for those affected by the prothrombin mutation. The mutation affects about two in 100 people in Germany and can be detected by genetic analysis. Treatment with antithrombins can significantly reduce the risk of serious consequences. A deficiency of prothrombins in the blood can also be congenital. Those affected by such a deficiency suffer from a tendency to bleed. In addition to hereditary coagulation disorders, acquired bleeding tendencies may also be present, for example in the case of damage to the liver. Clotting is also sometimes disturbed in the case of deficiency symptoms. Thrombins are produced with the consumption of vitamin K, so a deficiency of this vitamin in particular can manifest itself in an insufficiency in the coagulation cascade.
