Four naturally occurring thrombin inhibitors exist in normal plasma. The most important is antithrombin, which contributes approximately 75% of the antithrombin activity. Antithrombin can also inhibit the activities of factors IXa, Xa, XIa, XIIa, and VIIa complexed with tissue factor. α2-macroglobulin contributes most of the remainder of the antithrombin activity, with heparin cofactor II and α1-antitrypsin acting as minor inhibitors under physiologic conditions.

The endogenous activity of antithrombin is greatly potentiated by the presence of sulfated glycosaminoglycans (heparans). Heparans bind to a specific cationic site of antithrombin, which induces a conformational change that promotes binding of antithrombin to thrombin and factor Xa, as well as to its other substrates. This mechanism is the basis for the use of heparin, a derivatized heparan, in clinical medicine to inhibit coagulation. The anticoagulant effects of heparin can be antagonized by strongly cationic polypeptides such as protamine, which bind strongly to heparin, thus inhibiting the binding of heparin to antithrombin.

Low-molecular-weight heparins (LMWHs), derived from enzymatic or chemical cleavage of unfractionated heparin, have more clinical use. They can be administered subcutaneously at home, have greater bioavailability than unfractionated heparin, and do not need frequent laboratory monitoring.

Individuals with inherited deficiencies of antithrombin are prone to develop venous thrombosis, providing evidence that antithrombin has a physiologic function and that the coagulation system in humans is normally in a dynamic state.

Thrombin is involved in an additional regulatory mechanism that operates in coagulation. It combines with thrombomodulin, a glycoprotein present on the surfaces of endothelial cells. The complex activates protein C on the endothelial protein C receptor. In combination with protein S, activated protein C (APC) degrades factors Va and VIIIa, thereby limiting their actions in coagulation (see Table 1). A genetic deficiency of either protein C or protein S can cause venous thrombosis. Furthermore, patients with factor V Leiden(which has a glutamine residue in place of an arginine at position 506) have an increased risk of venous thrombotic disease because activated factor V Leiden is resistant to inactivation by APC; this condition is also termed APC resistance.

Table1. The Functions of the Proteins Involved in Blood Coagulation

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مواضيع ذات صلة

Conversion of Fibrinogen to Fibrin Is Catalyzed by Thrombin

Factor Xa Leads to Activation of Prothrombin to Thrombin

Most Transmembrane Proteins Have Membrane Spanning α Helices

Lipid Composition Is Different in the Exoplasmic and Cytosolic Leaflets

Lipid Composition Influences the Physical Properties of Membranes

The Intrinsic Pathway Also Leads to Activation of Factor X

The Extrinsic Pathway Leads to Activation of Factor X

Both Extrinsic & Intrinsic Coagulation Pathways Result in the Formation of Fibrin

Most Lipids and Many Proteins Are Laterally Mobile in Biomembranes

Biomembranes Contain Three Principal Classes of Lipids

Platelet Aggregation Requires Outside-In and Inside-Out Transmembrane Signaling

Phagocyte-Derived Proteases can Damage Healthy Cells