Background of Prothrombin
Prothrombin, a vital glycoprotein in the human body, is essential for the proper clotting of blood, making it a key player in maintaining hemostasis. It is synthesized in the liver and activated by clotting factors in the blood.
The story of Prothrombin dates back to the early 20th century, when it was discovered by a notable biochemist, Paul Morawitz, in 1905. He named it Prothrombin, derived from the word 'prothromb' alluding to its role as an initial factor in the clotting cascade. Prothrombin is encoded by the F2 gene located on chromosome 11 at the locus 11p11-q12. It has a complex structure which consists of a single chain of 579 amino acids and contains several functional domains.
Prothrombin Function
Fundamentally, the function of Prothrombin rests in blood-clotting activity. When blood vessels are injured or compromised, the clotting cascade is promptly initiated. Herein, Prothrombin, in its inactive form, is converted to an active enzyme thrombin, by the action of factor X and V. This thrombin further aids in the conversion of fibrinogen to fibrin, which forms the basis of the blood clot.
In order to initiate and regulate the clotting process, Prothrombin relies on the coagulation extrinsic pathway and intrinsic pathway. The extrinsic pathway, activated by tissue factor (TF), combines with factor VII to form a complex that triggers several reactions, readily converting Prothrombin into thrombin. Simultaneously, the intrinsic pathway is activated via contact with a damaged endothelial surface, consequently activating factors XII, XI, IX, VIII, and X, leading to the activation of Prothrombin. These pathways work synergistically to maintain hemostasis in the body.
Prothrombin related diseases
Abnormalities or mutations in the Prothrombin gene can result in several diseases, the most common of which is the Prothrombin G20210A mutation-causing hypercoagulability. This mutation increases the production of Prothrombin, resulting in a higher risk for deep vein thrombosis and pulmonary embolism. Prothrombin is also implicated in stroke, myocardial infarction, and other thrombotic disorders. Additionally, patients with deficient Prothrombin levels often suffer from bleeding disorders like hemophilia.
The application of Prothrombin in medicine
In the field of medicine, Prothrombin time (PT) tests are often utilized to measure the activation time of Prothrombin. It is a critical tool to monitor patients on anticoagulant therapy, those with liver diseases, and individuals with suspected vitamin K deficiency, which is necessary for Prothrombin synthesis. Furthermore, Prothrombin complex concentrates (PCCs) and recombinant Prothrombins have advanced the treatment options for patients with hemorrhagic disorders.
List of drug candidates related to Prothrombin
Moreover, several drug candidates related to Prothrombin are currently in use or under investigation. Notably, Warfarin, a commonly used anticoagulant, directly impacts the activity of Prothrombin by inhibiting the synthesis of vitamin K-dependent clotting factors, including Prothrombin. Similarly, direct thrombin inhibitors like dabigatran provide anticoagulation by binding to the active site of thrombin, preventing the conversion of fibrinogen to fibrin. Recombinant hirudin and argatroban are two other thrombin inhibitors used in clinical settings, showing promising therapeutic effects.
