Coagulation system inhibitors

Fig. 2. The intrinsic and extinsic cascade coagulation systems. activation -I, inhibition HMK, high molecular kininogen Cl-inh., complement-1 esterase inhibitor AT-III, antithrombin HI a 1 -PI, alpha-1 protein inhibitor pf-3, platelet factor 3.

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... 

Grzesiak A, Krokoszynska I, Krowarsch D, Buczek O, Dadlez M, Otlewski J. Inhibition of six serine proteinases of the human coagulation system by mutants of bovine pancreatic trypsin inhibitor. J Biol Chem 2000 275 33346-33352. 

Antithrombin III is formed in the hepatocytes as an U2-globulin. It serves as a physiological inhibitor of serin proteases in the coagulation system and thus inhibits activating factors Ila, IXa, Xa, XIa and Xna. As the name implies, AT III is most effective as an inhibitor of thrombin. Half-life is 2-3 days. 

The coagulation proteins that are synthesized in the liver are listed in Table 47-1. These proteins interact to produce a fibrin clot. Inhibitors of the coagulation system, including antithrombin, protein C, and protein S, are also synthesized in the fiver. Some of the coagulation factors (II, VII, IX, and X) require vitamin K for posttranslational carboxylation within the hepatocyte. Protein C and S are also carboxylated by a vitamin K-dependent enzyme. Activated protein C in plasma inhibits coagulation by inactivating factors V and... 

Cardiovascular effects of prostaglandins are more complex. The coagulation system is clearly modulated by platelet-derived thromboxanes, which have procoagulation effects and the anticoagulative effects of endothelial cell-derived prostacyclin. Thromboxanes are clearly COX-1 derived because platelets do not express COX-2. The source of endothelial cell prostacyclin production is less clear with both enzymes expressed and mixed opinions on the relative contribution of the two enzymes. Recent results with Vioxx, a selective COX-2 inhibitor, imply a modest effect on myocardial infarction rate in patients taking the compound but do not define whether this is caused by a change in ratio simply by a lack of platelet effect or that inhibition of endothelial cell prostacyclin also skews the pro- and anticoagulant ratio. 

Those which do not inhibit coagulation directly but on being added to plasma produce an inhibitor. Heparin in concentrations sufficient to exert an anticoagulant effect in blood and plasma is the best example. This is a very poor inhibitor when added to purified coagulation systems, but with a special plasma protein, the so-called heparin cofactor , it gives rise to an active anticoagulant. 

Plasma Inhibitors, In Vivo Anticoagulants. Fourteen naturally occurring compounds that normally exert an inhibiting effect on the activity of coagulation, platelet function, and fibrinolytic activity and complement systems have been identified within the circulating blood. 

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). 

The table also lists important globulins in blood plasma, with their mass and function. The a- and p-globulins are involved in the transport of lipids (lipoproteins see p. 278), hormones, vitamins, and metal ions. In addition, they provide coagulation factors, protease inhibitors, and the proteins of the complement system (see p. 298). Soluble antibodies (immunoglobulins see p. 300) make up the y-globulin fraction. 

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