Antithrombin, also known as antithrombin III (ATIII), is a hepatic protein found in the blood. Its main function is to inactivate free FIIa by binding to it and transporting it to the liver. This process prevents FIIa from participating in blood clotting. ATIII is classified as a serine protease inhibitor, or "serpin," which means it contains a reactive loop where a specific protease binds. Once the protease binds, it cleaves a peptide bond in the serpin, causing a conformational change that traps the enzyme in a covalent complex. Another example of a serpin is α1-antitrypsin. The affinity of ATIII for FIIa is significantly enhanced when ATIII is bound to heparin, a glycosaminoglycan released in response to injury by mast cells associated with blood vessels. Heparin is an anticoagulant used therapeutically to limit the formation of blood clots. ATIII also inactivates other serine proteases involved in clotting, such as FXa, FIXa, FXIa, FXIIa, and the FVIIa-TF complex. The inhibition of FIIa requires the oligosaccharide form of heparin, while the inhibition of FXa only requires the pentasaccharide form. Fondaparinux, a synthetic version of the pentasaccharide, is used in clinical practice to inhibit FXa.

The protein C-protein S complex is another important component of the anticoagulation system. Protein C, a Gla-containing protein produced in the liver, is activated by FIIa complexed with thrombomodulin. Thrombomodulin, an integral membrane glycoprotein found in endothelial cells, binds to FIIa, reducing its affinity for fibrinogen and increasing its affinity for protein C. When protein C is complexed with protein S, which is also a Gla-containing protein, it forms the activated protein C (APC) complex. The APC complex cleaves the accessory proteins FVa and FVIIIa, which are necessary for optimal FXa activity. Protein S helps anchor APC to the clot. Thrombomodulin plays a crucial role in modulating the activity of thrombin, transforming it from a protein of coagulation to a protein of anticoagulation. This conversion limits the extent of clotting. Factor V Leiden is a mutated form of FV, where glutamine is substituted for arginine at position 506. This mutation confers resistance to APC and is the most common inherited cause of thrombophilia in the United States, particularly among the Caucasian population. Heterozygotes carrying one copy of the mutation have a seven-fold increased risk of venous thrombosis, while homozygotes with two copies have up to a 50-fold increased risk. Women with FV Leiden are at an even higher risk of thrombosis during pregnancy or when taking estrogen.

Thrombophilia, also known as hypercoagulability, can occur due to deficiencies of proteins C, S, and ATIII. It can also result from the presence of FV Leiden and antiphospholipid antibodies, as well as excess production of FII caused by the G20210A mutation. Deep venous thrombosis (DVT) refers to the formation of a blood clot in the deep veins of the leg. If the clot or a part of it breaks off and travels to the lungs, it can cause a pulmonary embolism (PE) by blocking circulation.
1. Antithrombin: Antithrombin III (ATIII), also referred to simply as antithrombin (AT), is a hepatic protein that circulates in the blood. It inactivates free FIIa by binding to it and carrying it to the liver (Fig. 35.17). Thus, ATIII removes FIIa from the blood, preventing it from participating in coagulation. [Note: ATIII is a serine protease inhibitor, or “serpin.” A serpin contains a reactive loop to which a specific protease binds. Once bound, the protease cleaves a peptide bond in the serpin causing a conformational change that traps the enzyme in a covalent complex. α1-Antitrypsin (see p. 50) is also a serpin.] The affinity of ATIII for FIIA is greatly increased when ATIII is bound to heparin, an intracellular glycosaminogly-can (see p. 159) released in response to injury by mast cells associated with blood vessels. Heparin, an anticoagulant, is used therapeutically to limit clot formation. [Note: In contrast to the anticoagulant warfarin, which has a slow onset and a long half-life and is administered orally, heparin has a rapid onset and a short half-life and requires intravenous administration. The two drugs are commonly used in an overlapping manner in the treatment (and prevention) of thrombosis.] ATIII also inactivates FXa and the other serine proteases of clotting, FIXa, FXIa, FXIIa, and the FVIIa–TF complex. [Note: ATIII binds to a specific pentasaccharide within the oligosaccharide form of heparin. Inhibition of FIIa requires the oligosaccharide form, whereas inhibition of FXa requires only the pentasaccharide form. Fondaparinux, a synthetic version of the pentasaccharide, is used clinically to inhibit FXa.] 2. Protein C–protein S complex: Protein C, a circulating Gla-containing protein made in the liver, is activated by FIIa complexed with thrombomodulin. Thrombomodulin, an integral membrane glycoprotein of endothelial cells, binds FIIa, thereby decreasing FIIa’s affinity for fibrinogen and increasing its affinity for protein C. Protein C in complex with protein S, also a Gla-containing protein, forms the activated protein C (APC) complex that cleaves the accessory proteins FVa and FVIIIa, which are required for maximal activity of FXa (Fig. 35.18). Protein S helps anchor APC to the clot. Thrombomodulin, then, modulates the activity of thrombin, converting it from a protein of coagulation to a protein of anticoagulation, thereby limiting the extent of clotting. Factor V Leiden is a mutant form of FV (glutamine is substituted for arginine at position 506) that is resistant to APC. It is the most common inherited cause of thrombophilia in the United States, with highest frequency in the Caucasian population. Heterozygotes have a 7-fold increase in the risk for venous thrombosis, and homozygotes have up to a 50-fold increase. [Note: Women with FV Leiden are at even greater risk of thrombosis during pregnancy or when taking estrogen.]
Thrombophilia (hypercoagulability) can result from deficiencies of proteins C, S, and ATIII; from the presence of FV Leiden and antiphospholipid antibodies; and from excess production of FII (G20210A mutation). [Note: A thrombus that forms in the deep veins of the leg (deep venous thrombosis, or DVT) can cause a pulmonary embolism (PE) if the clot (or a piece of it) breaks off, travels to the lungs, and blocks circulation.]
B. Fibrinolysis