Plasma antithrombin III

Heparin is an important anticoagulant. It binds with factors IX and XI, but its most important interaction is with plasma antithrombin III (discussed in Chapter 51). Heparin can also bind specifically to lipoprotein lipase present in capillary walls, causing a release of this enzyme into the circulation. 

Plasma amine oxidase 886 Plasma antithrombin III 177 Plasma membrane 12, 379 Plasmalemma. See Plasma membrane Plasmalogens 383s, 384 Plasmids 5, 248249 ColEl 248 drug resistance 248 Plasmin 634 Plasminogen 634 Plasmodesmata 10... 

Sowers, J. R., Tuck, M. L., and Sowers, D. K., Plasma antithrombin III and thrombin generation time correlation with hemoglobin Ai and fasting serum glucose in young diabetic women. Diabetes Care 3, 655-658 (1980). 

Walker, I. D., Davidson, J. F., Yound, P., and Conkie, J. A., 1975, Effect of anabolic steroids on plasma antithrombin III, a2-iriacroglobulin and -antitrypsin levels, Thromb. Diath. Haemorrh. 34 106. 

Affinity chromatography is used in the preparation of more highly purified Factor IX concentrates (53—55) as well as in the preparation of products such as antithrombin III [9000-94-6] (56,57). Heparin [9005-49-6], a sulfated polysaccharide (58), is the ligand used most commonly in these appHcations because it possesses specific binding sites for a number of plasma proteins (59,60). 

Factor VIII, immunoglobulin, and albumin are all held as protein precipitates, the first as cryoprecipitate and the others as the Cohn fractions FI + II + III (or FII + III) and FIV + V (or FV), respectively (Table 7, Fig. 2). Similarly, Fractions FIVj + FIV can provide an intermediate product for the preparation of antithrombin III and a-1-proteinase inhibitor. This abiUty to reduce plasma to a number of compact, stable, intermediate products, together with the bacteriacidal properties of cold-ethanol, are the principal reasons these methods are stiU used industrially. 

Alpha-1-proteinase inhibitor and antithrombin III are used to treat people with hereditary deficiencies of these proteins. Both can be recovered from Cohn Fraction IV (Table 7) using ion-exchange chromatography (52) and affinity chromatography (197), respectively. Some manufacturers recover antithrombin III directiy from the plasma stream by affinity adsorption (56,198,199). 

Four naturally occurring thrombin inhibitors exist in normal plasma. The most important is antithrombin III (often called simply antithrombin), which contributes approximately 75% of the antithrombin activity. Antithrombin III can also inhibit the activities of factors IXa, Xa, XIa, Xlla, and Vila complexed with tissue factor. a2-Macroglobulin contributes most of the remainder of the antithrombin activity, with heparin cofactor II and aj-antitrypsin acting as minor inhibitors under physiologic conditions. 

With respect to both the coagulation and fibrinolytic cascade systems, in 28 patients who developed septic shock a relation was found between lowered plasma levels of F-XII and antithrombin III and elevated levels of PAI-1 and thrombin-antithrombin III complexes at the diagnosis of sepsis and the severity of disease, expressed according to the APACHE II scoring system (L7). Nevertheless, administration of inhibitors of coagulation or enhancement of fibrinolysis did not improve the outcome in patients with sepsis (B35). 

PDI is a noncovalent homodimer with a molecular weight of 57 kDa for each subunit. The protein is generally involved in the formation, reduction and rearrangement of disulfide bridges and plays an important role in platelet function. PDI is localized at the extracellular side of the plasma membrane and is secreted after platelet activation (Chen etal, 1992). In platelets, PDI catalyzes the formation of disulfide-bridged complexes of thrombospondin 1 and thrombin-antithrombin III and is thus involved in hemostasis and wound healing (Milev and Essex, 1999). 

Several inhibitors of plasma origin have been identified as important inhibitors of the coagulation process including antithrombin III (ATIII), protein C, TFPI and heparin cofiictor n. Of these inhibitors, ATIII is fee only agent which has been developed for commercial purposes. Patients wife hereditary thrombophilia due to a classic deficiency of ATin can be treated wife ATTII concentrate. In addition patients wife disseminated intravascular coagulation (DIG), renal insufficiency, post-surgical thrombosis, thermal injury and trauma which are associated with a decrease of ATTII in proportion to the degree of illness/injury, can also be treated (51). 

Mode of action. Heparin depends for its anticoagulant action on the presence in plasma of a single chain glycoprotein, antithrombin (formerly antithrombin III), a naturally-occurring inhibitor of... 

As a prophylaxis against bleeding in the upper gastrointestinal area, H2 antagonists and omeprazole are recommended. The timely and repeated administration of fresh plasma (FFB) as well as of antithrombin III has proved to be the most effective measure for balancing plasmatic coagulation disorders. 

Antithrombin III is a plasma alpha2-glycoprotem that accounts for most of the antithrombin activity in plasma and also inhibits other proteolytic enzymes. Hereditary or acquired antithrombin III deficiency results in thromboembolism. The effectiveness of treatment with antithrombin III, prepared as a concentrate from human plasma, is stiU a matter of dispute (1,2). Apart from vasodilatation, leading to a reduction in blood pressure, remarkably few adverse effects have been noted (2,3). The fall in blood pressure seems to be related to the rate of the infusion. 

Although there is much anecdotal evidence that TPN (as opposed to no nutrition) may be beneficial in hospitalized horses, this has not been proven (Lopes White 2002). The administration of TPN increases the risk of sepsis and thrombophlebitis in hospitalized human patients (loannides-Demos et al 1995). This may result, at least in part, from decreased intracellular killing by neutrophils (Okada et al 2000) and increased plasma thrombin-antithrombin III concentrations, which result in increased plasma coagulability (van der Poll et al 1998). 

Heparin acts as a catalyst for antithrombin III (AT III), increasing its activity by approximately a thousand times. Antithrombin III is a plasma enzyme that inactivates certain activated serine proteases of the coagulation cascade, most importantly activated factors II (thrombin) and X. The larger heparin species (found in unfractionated heparin) catalyzes the inactivation of activated factors II and X. In contrast, LMWH chiefly inactivates activated factor X. The final effect of both is systemic anticoagulation. Heparin also possesses inherent platelet-aggregating properties and may also induce the production of platelet-aggregating antibodies. Heparin can inhibit aldosterone synthesis. 

Pancreatitis. In severe attacks of acute pancreatitis, plasma levels of antithrombin III and AMG may be markedly depressed other inhibitors are normal or increased, and protease-antiprotease complexes are increased. In the peritoneal fluid, all major protease inhibitors are decreased or absent. 

In the last several years, it has become known and more appreciated that the in vivo role of heparin as an anticoagulant may be less important as an inhibitor of thrombin and more important as an inhibitor of Factor Xa.8B Actually heparin is not an anticoagulant, but a cofactor for a protein (a8 globulin - antithrombin III) in the plasma that neutralizes Factor Xa or thrombin by molecular combination. Without heparin this neutralization, which is concentration dependent, is slow. In the presence of heparin, it is greatly accelerated. Heparin has no effect on thrombin... 

During blood coagulation either an intrinsic (all blood) system or an extrinsic (tissue juice-lipoprotein) system is activated.. In either case the pathways meet at the activation of Factor X, forming a proteolytic enzyme Factor X. This enzyme in the presence of cofactors (calcium ion, phospholipid and Factor V) will form thrombin from prothrombin. Heparin is a cofactor for a protein called antithrombin III which circulates in the plasma and is an inhibitor of both Factor Xg and thrombin. Antithrombin III neutralizes these 2 enzymes by molecular combination heparin increases the rate of this neutralization. In the past 2 years work has continued on the mechanism of blood coagulation More... 

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