Blood coagulation mechanisms

Therapy for the control or prevention of the acute events in death due to vascular disease can be approached in several ways. One general approach would be to control the interaction of blood components with the diseased blood vessel or with each other. In both these cases antithrombotic agents of diverse mechanism should be helpful. Whether control of fibrin formation, fibrinolysis or platelet function is desirable, each patient s problem would dictate the therapy best suited. Several reviews are available in which the different blood coagulation mechanisms that may be helpful in such therapy are discussed s " Reviews have also been published in which methodology is discussed for the testing of compounds and for the determination of abnormalities in platelet function. ... 

Vitamins and K2 exist in nature and are essential to the animal for their effect on the blood-clotting mechanism. While 2-methylnaphthoquinone itself and its related derivatives having isoprenoid side chains in position 3 also promote blood coagulation in varying degrees, coenzyme Q10 shows no activity in the blood-coagulating mechanism. Coenzyme Q10, also called ubiquinone because of its ubiquitous occurrence in animal tissues, is important in its own right, since it plays an essential role in oxidative phosphorylation. As in the case of the vitamin K series, the size of the isoprenoid side chain does not appear to be critical with respect to the oxidative phosphorylation activity of the coenzyme Q series. 

Messinger WJ, Samet CM. The effect of a bowel sterilizii antibiotic cn blood coagulation mechanisms. The anti-cholesterol effect of paromomycin. Angiology (1965) 16, -36. 

Hematological and Electrochemical Aspects of Blood Coagulation Mechanisms... 

D. Thrombin-Like Enzymes. Ancrod (arvin), a very specific snake venom component, has been investigated extensively for its anticoagulant action. Ancrod is a very specific protease whose action has some similarity to that of thrombin and occurs in the terminal sequence of a complex blood coagulation mechanism. Ancrod hydrolyzes only the Aa chain of fibrinogen and produces a polymer of the type (a Bp y)n rather than the (aPy)n type normal fibrin clot. The microclot produced by ancrod from fibrinogen is readily hydrolyzed by plasmin that was activated from tissue plasminogen. This results in a defibrination effect. This property is extensively used in the treatment of a patient who has suffered from myocardial infarction. 

Dismption of the endothehal surface of blood vessels expose coUagen fibers and connective tissue. These provide surfaces that promote platelet adherence, platelet release reaction, and subsequent platelet aggregation. Substances Hberated from the platelets stimulate further platelet aggregation, eg, adenosine diphosphate maintain vasoconstriction, eg, serotonin and participate in blood coagulation, eg, platelet Factors III and IV. In addition, the release reaction modifies platelet membranes in a manner that renders phosphoHpid available for coagulation. The thrombin [9002-04-4] elaborated by the coagulation mechanism is a potent agent in the induction of the platelet release reaction. 

A proteolytic cascade occurs when one peptidase activates the next in a proteolytic pathway, and this in turn activates the next and so on. This is a mechanism to amplify the initial signal, because one peptidase molecule can activate many zymogen molecules. Examples of proteolytic cascades include blood coagulation, activation of digestive peptidases in the intestine, and apoptosis. 

Distinguish between the extrinsic and intrinsic mechanisms of blood coagulation... 

Platelets play a role in each of the mechanisms of normal hemostasis vasoconstriction, formation of the platelet plug, and blood coagulation. However, they are also involved in pathological processes that lead to atherosclerosis and thrombosis (formation of a blood clot within the vascular system). Antiplatelet drugs interfere with platelet function and are used to prevent the development of atherosclerosis and formation of arterial thrombi. 

The extrinsic mechanism of blood coagulation begins when a blood vessel is ruptured and the surrounding tissues are damaged. The traumatized tissue releases a complex of substances referred to as tissue thromboplastin. The tissue thromboplastin further complexes with factor VII and Ca++ ions to activate factor X directly. 

Figure 9.4. Schematic representation of the mechanism of action of the coaguligand approach. Cross linking of truncated Tissue Factor to tumour endothelial cells leads to local blood coagulation via the tTF/fVIIa complex. tTF, truncated Tissue Factor fVIIa, factor Vila fX (A), factor X (A).

Blood coagulation resulting in the formation of a stable fibrin clot involves a cascade of proteolytic reactions involving the interaction of clotting factors, platelets, and tissue materials. Clotting factors (see table) exist in the blood in inactive form and must be converted to an enzymatic or activated form before the next step in the clotting mechanism can be stimulated. Each factor is stimulated in turn until an insoluble fibrin clot is formed. 

Mechanism of Action An electrolyte that is essential for the function and integrity of the nervous, muscular, and skeletal systems. Calcium plays an important role in normal cardiac and renal function, respiration, blood coagulation, and cell membrane and capillary permeability. It helps regulate the release and storage of neurotransmitters and hormones, and it neutralizes or reduces gastric acid (increase pH). Calcium acetate combines with dietary phosphate to form insoluble calcium phosphate. Therapeutic Effect Replaces calcium in deficiency states controls hyperphosphatemia in end-stage renal disease. 

Mechanism of Action A blood modifier that interferes with blood coagulation by blocking conversion of prothrombin to thrombin and fibrinogen to fibrin Therapeutic Effect Prevents further extension of existing thrombi or new clot formation. Has no effect on existing clots. 

Unprogrammed activation of the caspases has serious consequences for the cell. Therefore, activation of caspases is strictly controlled. In the normal state of the cell, the caspases are maintained in an inactive state but can be rapidly and extensively activated by a small inducing signal. At present, not all proteins involved in the activation are known. Possibly, the activation occurs by a complex mechanism, as in blood coagulation. 

It is also important to note that the coagulation mechanism in vivo does not occur in solution, but is localized to activated cell surfaces expressing anionic phospholipids such as phosphatidylserine, and is mediated by Ca2+ bridging between the anionic phospholipids and 7-carboxyglutamic acid residues of the clotting factors. This is the basis for using calcium chelators such as ethylenediamine tetraacetic acid (EDTA) or citrate to prevent blood from clotting in a test tube. 

In ihe mammalian body, calcium is required to insure the integrity and permeability of cell membranes. 10 regulate nerve and muscle excitubiliiy. to help maintain normal muscular contraction, and to assure cardiac rhvthmicity. Calcium plays an essential role in several of ihe enzymatic steps involved in blood coagulation and also activates certain other enzyme-catalyzed reactions not involved in any of ihe foregoing processes. Calcium is ihe niosi important element of bone sail. Together with phosphate and carbonate, calcium confers on bone most of its mechanical and structural properties. 

FIGURE 25-1 Mechanism of blood coagulation. Factors involved in clot formation are shown above the dashed line factors involved in clot breakdown are shown below the dashed line. See text... 

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