Hirudin is one of the most active and studied components extracted from leech and its salivary gland. It is a small molecular polypeptide composed of 65-66 amino acids. Leech is rich in hirudin. Hirudin has a strong inhibitory effect on thrombin. It is the strongest natural specific inhibitor of thrombin found so far. Hirudin has a strong inhibitory effect on coagulation and antithrombotic effect. It has a broad application prospect in clinical treatment and prevention of various thrombosis.
Brief Introduction
In 1927, Shionoya first studied it as an effective antithrombotic drug. 1955 markward pointed out that it was a protein substance and named hirudin. Natural hirudin is an anticoagulant protein extracted from medical leech. It is a single chain polypeptide composed of 65 or 66 amino acid residues with a relative molecular weight of 70000dalton. Hirudin has three pairs of disulfide bonds at the N-terminal, which makes the N-terminal peptide chain wind and stack into a dense cyclic peptide structure, which plays a role in stabilizing the protein structure. Its N-terminal contains an active center, which can recognize and bind to the substrate, thrombin basic amino acid enrichment site. The C-terminal is rich in acidic amino acid residues, and 6 of the last 9 amino acids are acidic amino acids.
Principle of hirudin acting on thrombin
A series of enzymatic cascade amplification reactions activate prothrombin and produce thrombin in the process of endogenous and exogenous coagulation. Thrombin is a serine protease, which plays a key role in the process of thrombosis, including cascade reaction of hemagglutination, fibrin deposition and platelet activation. Anticoagulant inhibitors can be divided into indirect thrombin inhibitors and direct antithrombin inhibitors. The former produces anticoagulation through natural inhibitors of thrombin (ATIII or heparin cofactor II). Hirudin is a specific thrombin inhibitor, which can directly bind to thrombin. Its anticoagulant effect does not depend on ATIII or heparin cofactor II. It is a direct thrombin inhibitor. Hirudin combines with thrombin 1:1 to form an irreversible complex by acting on the recognition site of inactive substrate and the active center of thrombin, so as to make thrombin lose its function. The anticoagulant effect of hirudin is not only specific, but also its anticoagulant activity is significantly stronger than that of heparin. In addition, hirudin can not only inhibit free thrombin in plasma.
Function
Animal experiments and clinical studies show that hirudin can effectively anticoagulate and antithrombotic, and prevent further blood stasis such as thrombin catalyzed coagulation factor activation and platelet reaction. In addition, it can inhibit the proliferation of fibroblasts induced by thrombin and the stimulation of endothelial cells by thrombin. Compared with heparin, it not only has less dosage, does not cause bleeding, but also does not depend on endogenous cofactors; Heparin has the risk of bleeding. Antithrombin III is often reduced in the pathogenesis of disseminated intravascular coagulation, which will limit the efficacy of heparin. Leech will have a better effect.
Application
Animal tests and clinical studies show that there are no obvious toxic and side effects of intravenous or subcutaneous injection of hirudin. No matter the acute or subacute toxicity test, it will not affect the blood pressure, heart rate, blood phase, bleeding time and blood chemical composition, nor the respiratory system. There is no allergic reaction, and generally no specific antibody is found. The LD50 of the half lethal dose was more than 50 mg AG, which was much greater than the dose used for treatment (1 mg Ag). In particular, hirudin can be taken orally, which brings great convenience to medication. Hirudin is relatively stable, trypsin and chymotrypsin do not destroy its activity, and some hydrolytic fragments of hirudin still inhibit thrombin, which can explain why hirudin extract is still effective
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