Clotting, blood

Blood coagulation and fibrinolysis are controlled by various plasma glycoproteins and cellular elements. The carbohydrate moiety of the soluble coagulation factors, fibrinolytic enzymes and glycoproteins of the thrombocyte plasma membrane protects the protein from degradation, serves to stabilize its structure and plays a part in signal mediation. The terminal sialic acid of the carbohydrate often makes an important contribution to these various functions. 

The carbohydrate sequence of some coagulation factors has been determined (prothrombin or F II, thromboplastin or F X, fibrinogen or F I, and the fibrinolytic serine protease, plasmin), but only a few investigations have been reported on the functional significance of the carbohydrate residues (Mizuochi et al 1979, Mizuochi et al 1980, Gati and Straub 1978, Hayes and Castellino 1979, Lijinen et al 1981). 

Desialylation destroys the protease activity of plasminogen. Functional prothrombin arises from its precursor by two post-translational modifications a vitamin K-dependent carboxylation of glutamic acid residues, followed by glycosylation in the carboxylated region (prothrombin fragment 1 AS 1-156). Deglycosylation of prothrombin in the presence of Ca leads to greatly increased self-association this occurs at certain contact points on the molecule, which are probably concealed by carbohydrate chains in the intact molecule (Fletcher et al 

Following injury to blood vessels, hemostasis ensures that blood loss is minimized. Initially, thrombocyte activation leads to contraction of the injured vessel and the formation of a loose clot consisting of thrombocytes (hemostasis). Slightly later, the action of the enzyme thrombin leads to the formation and deposition in the thrombus of polymeric fibrin (coagulation, blood clotting). The coagulation process is discussed here in detail. 

The most important reaction in blood clotting is the conversion, catalyzed by thrombin, of the soluble plasma protein fibrinogen (factor 1) into polymeric fibrin, which is deposited as a fibrous network in the primary thrombus. Thrombin (factor 11a) is a serine proteinase (see p. 176) that cleaves small peptides from fibrinogen. This exposes binding sites that spontaneously allow the fibrin molecules to aggregate into polymers. Subsequent covalent cross-linking of fibrin by a transglutaminase (factor Xlll) further stabilizes the thrombus. 

Normally, thrombin is present in the blood as an inactive proenzyme (see p. 270). Prothrombin is activated in two different ways, both of which represent cascades of enzymatic reactions in which inactive proenzymes (zymogens, symbol circle) are proteolytically converted into active proteinases (symbol sector of a circle). The proteinases activate the next proenzyme in turn, and so on. Several steps in the cascade require additional protein factors (factors 111, Va and Villa) as well as anionic phospholipids (PL see below) and Ca ions. Both pathways are activated by injuries to the vessel wall. 

In the extravascular pathway (right), tissue thromboplastin (factor 111), a membrane protein in the deeper layers of the vascular wall, activates coagulation factor Vll. The activated form of this (Vila) autocatalytically promotes its own synthesis and also generates the active factors IXa and Xa from their precursors. With the aid of factor Villa, PL, and Ca factor IXa produces additional Xa, which finally— with the support of Va, PL, and Ca —releases active thrombin. 

The intravascular pathway (left) is probably also triggered by vascular injuries. It 

---

Surfaces can be active in inducing blood clotting, and there is much current searching for thromboresistant synthetic materials for use in surgical repair of blood vessels (see Ref. 111). It may be important that a protective protein film be strongly adsorbed [112]. The role of water structure in cell-wall interactions may be quite important as well [113]. 

Physiological responses to prostaglandins encompass a variety of effects Some prostaglandins relax bronchial muscle others contract it Some stimulate uterine con tractions and have been used to induce therapeutic abortions PGEj dilates blood vessels and lowers blood pressure it inhibits the aggregation of platelets and offers promise as a drug to reduce the formation of blood clots... 

Liver and Gallbladder. High dosages of oral estrogens have been reported to increase the risk for jaundice, cholestatic hepatitis, gallstones, and hepatic vein blood clots. Estrogens promote the development of hepatic neoplasms associated with increased hepatic cell regenerative activity (186,187). 

The calcium ion, necessary for blood-clot formation, stimulates release of bloodclotting factors from platelets (see Blood, coagulants and anticoagulants) (25). Neuromuscular excitabihty also depends on the relative concentrations of Na", Ca ", Mg ", and (26). Upon a decrease in... 

Patients immediate post-operative pain is lower compared to a standard operation and healing and rehabiUtation more rapid. Patients can resume near-normal activities in just days. In some cases athletes, who are in prime physical condition, can return to challenging athletic activities within a few weeks. CompHcations are rare, but do occur on occasion. Most complications associated with this surgery are infection, phlebitis, excessive swelling or bleeding, blood clots, or damage to blood vessels or nerves. 

Biochemical Reactions. The quinones in biological systems play varied and important roles (21,22). In insects they are used for defense purposes, and the vitamin K family members, eg, vitamin [11104-38-4] (32) and vitamin [11032-49-8] (33), which are based on 2-meth5l-l,4-naphthoquiaone, are blood-clotting agents (see Vitamins, vitamin k). 

The importance of quinones with unsaturated side chains in respiratory, photosynthetic, blood-clotting, and oxidative phosphorylation processes has stimulated much research in synthetic methods. The important alkyl- or polyisoprenyltin reagents, eg, (71) or (72), illustrate significant conversions of 2,3-dimethoxy-5-methyl-l,4-ben2oquinone [605-94-7] (73) to 75% (74) [727-81-1] and 94% (75) [4370-61-0] (71—73). 

Calcium is essential to several steps in the enzyme cascade of the blood clotting process, such as the conversion of prothrombin to thrombin (23). Clotting can be inhibited in stored blood suppHes by addition of complexing agents such as EDTA or citrate which reduce the levels of the free ion, Ca(Il). 

Coumarin/warfarin, given at a typical dosage of 4 to 5 mg/day, prevents the deleterious formation in the bloodstream of small blood clots and thus reduces the risk of heart attacks and strokes for individuals whose arteries contain sclerotic plaques. Taken in much larger doses, as for example in rodent poisons, Coumarin/warfarin can cause massive hemorrhages and death. 

BLOOD CLOTTING. The formation of blood clots is the result of a series of zymogen activations (Figure 15.5). The amplification achieved by this cascade of enzymatic activations allows blood clotting to occur rapidly in response to injury. Seven of the clotting factors in their active form are serine proteases ... 

FIGURE 15.5 The cascade of activation steps leading to blood clotting. The intrinsic and extrinsic pathways converge at Factor X, and the final common pathway involves the activation of thrombin and its conversion of fibrinogen into fibrin, which aggregates into ordered filamentous arrays that become cross-linked to form the clot. 

FIGURE 18.40 The glutamyl carboxylase reaction is vitamin K-dependent. This enzyme activity is essential for the formation of 7-car-boxyglutamyl residues in several proteins of the blood-clotting cascade (Figure 15.5), accounting for the vitamin K dependence of coagulation. 

---