Antithrombin, heparin degradation

There are various inhibitors within the coagulation system that counterregulate activation of the coagulation cascade. Among them, antithrombin III (AT-III) and protein C (PC) are the most important (SI). AT-III binds in the presence of heparin the activated factors F-IXa, F-Xa, and F-IIa (thrombin). PC is activated by a complex formed between thrombin and thrombomodulin, a surface protein of endothelial cells. Once activated, PC in the presence of protein S (PS) specifically degrades activated factors F-Va and F-VIIIa. PC decreases in the course of sepsis in relation to the severity of the condition (L15). Experimental studies have... 

Degradation of heparin followed by affinity chromatography on immobilized AT III led to the identification of a pentasaccharide unit with high antithrombin affinity. This pentasaccharide 3 is characterized by a imique highly sulfated central glucosamine unit with a 3-0-sulfate group (Structures 2). 

WeitzJI, Leslie B, Hudoba M, Thrombin binds to soluble fibrin degradation products where it is protected from inhibition by heparin-antithrombin but susceptible to inactivation by antithrombin-independent inhibitors, Circulation 1998 97 544-552. 

Antithrombin. A serine protease inhibitor (serpin) that degrades the serine proteases of thrombin, factors IXa, Xa, XIa and Xlla. It is constantly active, but its adhesion to these factors is increased by the presence of heparin sulphate (a glycosaminoglycan) or the administration of heparins (different heparinoids increase affinity to factor Xa, thrombin, or both). Deficiency of antithrombin (inborn or acquired, e.g. in proteinuria) leads to thrombophilia. 

Antithrombin inhibits the activity of factors Ka, Xa, Xlla, and thrombin (Ila). It also inhibits thrombin-induced activation offactors V and VIII. UFH prevents the growth and propagation of a formed thrombus and allows the patient s own thrombolytic system to degrade the clot. Contrainchcations to heparin therapy include hypersensitivity to the drug, active bleeding, hemophilia, severe hver chsease with elevated prothrombin time (PT), severe thrombocytopenia, malignant hypertension, and inability to meticulously supervise and monitor treatment. 

The excess vessel wall fibrin accumulation and atherosclerosis seen as a long-term complication of diabetes may well result from the glycosylation-induced inhibition in fibrinogen (fibrin)-plasmin degradative function and heparin-catalyzed antithrombin III activity. 

The degradation of heparin by the reactor is a multistep process. Heparin and the heparin-antithrombin complex must first diffuse from the bulk phase to the surface of the immobilized enzyme particle. The two species diffuse into the agarose particles where they encounter immobilized heparinase. The heparin-anti thrombin complex is assumed to be sterically inhibited from binding to immobilized heparinase, and under these conditions only unbound heparin is enzymatically degraded. As unbound heparin is consumed, heparin dissociates from the heparin-antithrombin complex to generate more free heparin. The breakdown of heparin is given by the following chemical reaction ... 

As octasaccharide products are generated, they compete for the binding site on the antithrombin molecule as well as diffuse out of the catalyst particles. Heparin is displaced from antithrombin by the octasaccharide product, and the concentration of unbound heparin available for degradation is increased. 

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