Antithrombin III (AT3), often simply called Antithrombin, is a naturally occurring protein in the blood plasma. It functions as a powerful natural anticoagulant, maintaining the balance between bleeding and clotting. AT3 acts as a crucial regulator within the complex cascade of reactions that lead to blood clot formation. Its presence ensures the body can stop bleeding when injured while preventing excessive or inappropriate clot formation that could obstruct blood flow.
Molecular Structure and Origin
Antithrombin III is a small, single-chain glycoprotein that circulates freely throughout the bloodstream. It is classified as a member of the serine protease inhibitor family, commonly abbreviated as serpins. Serpins regulate physiological processes by neutralizing specific enzymes. The gene encoding AT3 is found on chromosome 1, and its synthesis occurs predominantly within the liver.
The protein circulates in the plasma primarily in its alpha form, containing four carbohydrate chains. The serpin structure features a mobile section called the reactive center loop, which is central to its function as a molecular trap. Target clotting enzymes attempt to cleave this loop, leading to their irreversible inactivation. This mechanism allows AT3 to maintain its inhibitory function.
Function as a Coagulation Inhibitor
The principal function of Antithrombin III involves neutralizing several key enzymes in the coagulation cascade. These enzymes are serine proteases that drive clot formation, and AT3 acts by forming a permanent, inactive complex with them. When acting alone, AT3 slowly inhibits these enzymes by binding to their active site, trapping them in a stable 1:1 ratio. This inhibitory action serves to terminate the clotting process once blood vessel damage has been controlled.
The two most important targets for AT3 are Thrombin (Factor IIa) and Factor Xa, which are central to the final steps of clot formation. Thrombin converts fibrinogen into the fibrin mesh that stabilizes a clot. Factor Xa facilitates the conversion of prothrombin into Thrombin, sitting higher up in the cascade. AT3 also neutralizes other activated clotting factors, including Factor IXa, Factor XIa, and Factor XIIa, regulating both the initiation and progression of coagulation.
The Essential Role of Heparin
The inhibitory activity of Antithrombin III is accelerated by its interaction with Heparin or its natural equivalent, heparan sulfate, found on blood vessel walls. This binding causes a conformational change in the AT3 molecule, converting it from a slow inhibitor into a rapid, highly efficient one. Heparin can accelerate the rate of the AT3-protease reaction by a factor of 1,000 or more, underscoring its importance as a cofactor.
Heparin acts as a template, linking Antithrombin III and the target protease, such as Thrombin, together. This physical approximation increases the speed and likelihood of the inhibitory reaction. Once AT3 inactivates the target enzyme, the Heparin molecule is released unchanged, ready to bind to another Antithrombin molecule and repeat the process. This catalytic mechanism explains why Heparin is an effective therapeutic anticoagulant, as its action depends entirely on sufficient circulating Antithrombin III.
When Antithrombin Levels Are Low
Insufficient levels or reduced activity of Antithrombin III lead to hypercoagulability, increasing the risk of forming abnormal blood clots. This condition, known as Antithrombin Deficiency, can be inherited or acquired due to other medical conditions. Inherited deficiency is a genetic disorder where the first thrombotic event often occurs relatively early in life. Individuals with this condition face a higher risk of developing venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE).
Acquired Antithrombin deficiency is more common and arises from decreased production or increased consumption of the protein. Severe liver disease reduces the liver’s ability to synthesize AT3, lowering circulating levels. Deficiency can also result from protein loss through the kidneys, as seen in nephrotic syndrome. Conditions involving widespread clotting, such as sepsis or disseminated intravascular coagulation (DIC), lead to the rapid consumption of AT3, depleting the body’s natural anticoagulant supply.