SERPINC1 - serpin family C member 1 |Elisa - Clia - Antibody - Protein

Background

SERPINC1, commonly known as the gene encoding antithrombin (AT), is a critical member of the serine protease inhibitor (serpin) family. Antithrombin is primarily synthesized in the liver and secreted into the bloodstream, where it plays a vital role in regulating blood coagulation. As a serpin, its primary function is to inhibit proteases involved in coagulation, such as thrombin and factor Xa, thereby preventing excessive clot formation.

Deficiencies or abnormalities in the SERPINC1 gene are closely associated with thrombotic disorders, as they lead to an increased risk of blood clots due to insufficient antithrombin activity. This deficiency can be inherited or acquired, and it plays a significant role in conditions such as deep vein thrombosis (DVT) and pulmonary embolism (PE).

Protein Structure

Antithrombin is a glycoprotein composed of 432 amino acids with a molecular weight of approximately 58 kDa. Structurally, it belongs to the serpin family, which shares a similar configuration characterized by three β-sheets and several α-helices. These structures are crucial for the protein's ability to undergo conformational changes during protease inhibition.

The active site of antithrombin contains a reactive center loop (RCL), which is essential for its interaction with target proteases. This loop presents a bait to thrombin and other proteases, triggering a conformational change when cleaved, which traps the protease in an inactive state.

Antithrombin's activity is significantly enhanced by heparin, a sulfated polysaccharide that induces a conformational change in the protein, increasing its affinity for thrombin and factor Xa. The heparin-binding site of antithrombin is located near the N-terminal region of the protein, and this interaction is the basis for the clinical use of heparin as an anticoagulant.

Classification and Subtypes

Antithrombin belongs to the serpin superfamily, which includes a wide range of proteins involved in various regulatory processes, such as blood coagulation, inflammation, and immune response. SERPINC1 is part of the C1 subgroup within the serpin family, where members share a common mechanism of action involving protease inhibition.

There are two main isoforms of antithrombin: AT-α and AT-β. The AT-α isoform is the predominant form in circulation and is fully glycosylated, whereas AT-β has a lower level of glycosylation and a reduced affinity for heparin. Despite these differences, both isoforms are functionally active in inhibiting thrombin and other proteases.

Function and Biological Significance

The primary function of antithrombin is to regulate blood coagulation by inhibiting serine proteases, particularly thrombin and factor Xa. Thrombin plays a central role in the coagulation cascade by converting fibrinogen to fibrin, which forms the structural framework of blood clots. Factor Xa, on the other hand, activates prothrombin into thrombin. By inhibiting these proteases, antithrombin prevents uncontrolled clot formation, ensuring that coagulation occurs only in response to injury.

Antithrombin also has anti-inflammatory properties and contributes to the regulation of immune responses. Beyond its anticoagulant activity, it inhibits several other proteases, including factor IXa, factor XIa, and kallikrein. These activities underline the broader physiological roles of antithrombin in maintaining homeostasis beyond clot prevention.

Clinical Issues

Antithrombin Deficiency:

Antithrombin deficiency is a significant risk factor for venous thromboembolism (VTE). It can be inherited in an autosomal dominant manner (hereditary antithrombin deficiency) or acquired due to conditions like liver disease, nephrotic syndrome, or during certain therapies (e.g., heparin-induced antithrombin deficiency).

1. Type I Deficiency: This form is characterized by reduced levels of antithrombin due to mutations in the SERPINC1 gene that affect protein synthesis or stability.
2. Type II Deficiency: In this type, the level of antithrombin is normal, but its function is impaired due to mutations that affect its ability to inhibit proteases. Type II deficiency can further be subdivided based on whether the defect affects the heparin-binding site, the reactive center loop, or other regions of the molecule.

Individuals with antithrombin deficiency have an increased risk of developing spontaneous blood clots, particularly in deep veins (DVT), which can lead to life-threatening pulmonary embolism (PE) if the clot migrates to the lungs.

Heparin Resistance:

Since heparin works by enhancing the activity of antithrombin, patients with antithrombin deficiency may exhibit resistance to heparin therapy, meaning that higher doses of heparin are required to achieve therapeutic anticoagulation. In severe cases of deficiency, alternative anticoagulant strategies, such as direct thrombin inhibitors (e.g., argatroban) or factor Xa inhibitors (e.g., fondaparinux), may be needed.

Therapeutic Use of Antithrombin Concentrates:

In certain clinical situations, particularly in individuals with severe antithrombin deficiency or during major surgeries, antithrombin concentrates are administered to prevent thrombotic events. These concentrates are derived from human plasma or produced via recombinant technologies. They are used in cases of hereditary deficiency and in high-risk situations, such as pregnancy, surgery, or during anticoagulation therapy.

Summary

SERPINC1, encoding antithrombin, is a key regulator of coagulation, preventing excessive clot formation by inhibiting thrombin and factor Xa. Its structure, characterized by a reactive center loop and a heparin-binding site, allows it to interact with and inactivate proteases involved in coagulation. Deficiency in antithrombin, whether hereditary or acquired, significantly increases the risk of venous thromboembolism and poses challenges in anticoagulant therapy, particularly with heparin. Understanding the function and clinical implications of SERPINC1 is critical for the management of thrombotic disorders and the development of therapeutic interventions.