Hemostatic reactions

Protein C is activated by thrombin in the complex with thrombomodulin to produce activated protein C, the proteolytic inactivator of factors Va and Villa. The binding of thrombin to thrombomodulin changes thrombin from a procoagulant proteinase to an anticoagulant proteinase. Whereas the hemostatic reactions that prevent blood loss at the injury site are associated with the ruptured blood vessels, thrombomodulin is on the endothelium (Figure 36-15). 

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One of the most characteristic reactions of the aminochromes is the ready formation of mono-derivatives with typical ketone reagents, e.g. semicarbazide, phenylhydrazine, etc. A relatively large number of derivatives of this nature have been prepared because of then-reported hemostatic activity (cf. refs. 2 and 3). Compounds of this type that had been described in the literature prior to December 1959 are listed in a previous review (Heacock3). Some further examples of this class of compounds have been described recently. They are N-ethylnoradrenochrome semicarbazone (84) (orange-red needles, m.p.180 215°)65 7-iodoadrenochrome methyl ether semicarbazone... 

Platelets provide the initial hemostatic plug at sites of vascular injury. They also participate in reactions that lead to atherosclerosis and pathological thrombosis. Antagonists of platelet function have thus been used in attempts to prevent thrombosis and to alter the natural history of atherosclerotic vascular disease. 

High and fast hemostatic action Quick absorption of blood Minimal tissue reaction Nonantigenicity Pliability... 

Dr. David Calverley is a hematologist with a research interest in the molecular mechanisms of platelet adhesion and activation. His clinical interest lies in the area ofplatelet and hemostatic disorders. In addition to research, clinical, and teaching activities, he is Associate Director of the University of Southern Califomia/Nonis Cancer Hospital Qinical Coagulation Laboratoiy. Dr. Gerald Roth is a hematologist with interests in both research and clinical aspects of platelets. He has studied molecular aspects of aspirin s effect on platelets and observed the acetylation reaction between aspirin and platelet cyclo-oxygenase. 

Primary and even tertiary structures are now known for many of the hemostatic system proteins. Gene structures have been identified for all of the known components of the hemostatic system. Databases listing mutations and their related hemorrhagic or thrombotic risks are growing rapidly. For many reactions, the molecular mechanisms responsible for the properties of the hemostatic... 

Although the many components of the hemostatic system inevitably create a high level of complexity, the functional and structural similarities between and among the different molecules permit the simplification described above. Simplification can be obtained by representing many of the molecules as ellipses, the two-dimensional representations of the generally ellipsoid shapes of the molecules in solution (see Figure 36-9 below). However, the common motifs and similar proteinase domain structures can be presented even more simply in the form of bar diagrams, which are usually used in the descriptions of reactions that follow. 

The proteolytic reactions of the hemostatic system are neither catalytically efficient nor localized when proteinase and proteinase precursor only are present. The rapid, localized proenzyme activation required for normal hemostatic response occurs only in a complex of proteinase, proteinase precursor, and cofactor protein assembled on the surface of a damaged cell membrane, or in vitro, on the surface of phospholipid bilayers. The catalytic efficiency of an enzyme-catalyzed reaction is expressed by the ratio of the kinetic constants /ic and kJKm). In the activation complexes, kJKm values can be greater than lO M s . With proteinase and proenzyme alone, the kJKm values are only approximately 100 M s and thus the reactions are 10 times less efficient. Expressed in terms of the same amount of product formed in the two situations, a 10 increase represents the difference between requiring 1 minute and about 6 months to form the product ... 

The fibrinolytic system removes the fibrin of the hemostatic plug and thus is responsible for the temporary existence of the fibrin clot. The proteolytic action of plasmin on fibrin and fibrinogen is extensive and more like the digestive proteolysis catalyzed by trypsin and chy-motrypsin than the proteolysis involved in proteinase precursor activation. The fibrinolytic subsystem includes the reactions of plasminogen activation, plasmin inactivation, and fibrin digestion. As is common throughout the hemostatic system, irreversible activation reactions of the fibrinolytic system are opposed by irreversible proteinase inactivation. 

Accepting the above limitations of our knowledge of the true in vivo reaction sequence, a series of clot-endpoint tests has been used for many years to determine the hemostatic balance in any patient. The first, known as the thrombin time test, can be used to measure the concentration of fibrinogen (B15). The second assay, the activated partial thromboplastin time test (APTT), measures the components of the intrinsic pathway (M4). These include the serine proteases (Factors XII, XI, X, and II), the cofactors (Factors VIII and V) and again, fibrinogen. Most of the hereditary deficiencies... 

Several hematologists are of the view that the primary step in hemostasis is the adhesion of platelets to exposed collagen fibers. " It has been proposed that the adhesion is due to the formation of an enzyme-acceptor complex between the incomplete carbohydrate chains (galactosyl residues) of collagen and an enzyme of the platelet membrane (glycosyl transferase). Platelets in contact with collagen fibers contract and release adenosine diphosphate (ADP) as well as other platelet constituents. ADP causes more platelets to adhere and the autocatalytic reaction proceeds towards the formation of a hemostatic plug. 

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