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Clotting and Fibrinolysis J Clin Pathol: first published as 10.1136/jcp.s3-9.1.50 on 1 January 1975. Downloaded from J. clin. Path., 28, Suppl. (Roy. Coll. Path.), 9, 50-53 Clotting and fibrinolysis C. R. M. PRENTICE From the University Department ofMedicine, Royal Infirmary, Glasgow increased ATP reduced Vascular disease accounts for more than 50 % of adhesiveness adhesiveness deaths and in most cases the cause lies in obstruction adenyl cyclase adrenaline _ to blood flow by the twin perils of atheroma forma- j prostaglandin tion and thrombosis. collagen El The major constituents of thrombi are platelets Idecreasev and fibrin, together with trapped red cells and other C-AMP elements. Our main antithrombotic drugs are the I antiplatelet agents to prevent platelets sticking phosphodiesterase together; anticoagulants to prevent fibrin formation; t dipyridamole and fibrinolytic agents which, hopefully, will lyse IMP RA 233 and remove formed fibrin deposits. Antithrombotic Fig Possible mechanism by which platelet metabolism therapy may also conveniently be classified as (1) may be affected by aggregating agents and inhibitory prophylactic, to cover an event, such as a surgical drugs operation, known to be associated with an increased thrombotic risk, and (2) therapeutic, to treat a thrombus which has already formed. It must also be AMP by inhibition of phosphodiesterase. The remembered that the problems of arterial and venous different groups of platelet-inhibitory drugs are the copyright. thrombosis are different. Arterial thrombi are anti-inflammatory drugs-acetylsalicylic acid, indo- composed largely of aggregated platelets, together methacin, sulphinpyrazone-dipyramidole (RA 233), with fibrin; it is thought that platelet adhesion to the prostaglandins, and the dextrans. The aspirin the vessel wall is an important event which may and anti-inflammatory group of drugs have probably initiate arterial thrombosis. Conversely, thrombi a different inhibitory mechanism. They appear to formed in veins consist mainly of fibrin and it is in stabilize the platelet membrane and also the lyzo- this situation where the conventional anticoagulants somal membranes, inhibiting release of lyzosomal http://jcp.bmj.com/ are likely to be useful. enzymes. This subject has beenreviewedbyVermylen, de Gaetano, and Verstraete (1973). Antiplatelet Agents INDICATIONS FOR ANTIPLATELET AGENTS First, I will give a brief account of the platelet The therapeutic trials for antiplatelet agents are aggregation process, and then continue with an still in their infancy but the probable and possible account of the proposed mechanism by which some indications are shown in table I. If the antiplatelet on September 29, 2021 by guest. Protected of the antiplatelet agents operate. Activation of the agents were found to have a prophylactic effect platelet membrane can be carried out by stimuli, against myocardial infarction this would represent such as ADP, collagen, basement membrane, a major advance. We are still dealing with the first thrombin, adrenaline, serotonin, and antigen- generation of antiplatelet agents and it is probable antibody complexes. The common pathway of activation may be related to the level of cyclic-AMP within the platelet. Most of the aggregating agents tend to diminish cyclic-AMP production by in- hibitingadenylcyclase, asseen inthefigure. Conversely Indication Condition antiplatelet agents increase the level of platelet Definite Nil cyclic-AMP. This is achieved in two ways. First, Probable Embolism from prosthetic heart valves increased production of cyclic-AMP by stimulation Possible Myocardial infarction-secondary prevention Transient cerebral ischaemia of adenylcyclase activity is caused by agents such as Extracorporeal bypass circulations the prostaglandins. Second, the dipyridamole group of drugs causes decreased degradation of cyclic- Table I Indicationsfor antiplatelet agents 50 J Clin Pathol: first published as 10.1136/jcp.s3-9.1.50 on 1 January 1975. Downloaded from Clotting andfibrinolysis 51 that the development of new derivatives and com- to over 60 minutes (Lindsay, Prentice, Ferguson, bination therapy regimes will improve their effec- Burton, and McNicol, 1972). tiveness in the future. One advantage of the antiplatelet agents is that ORAL ANTICOAGULANTS they appear to be free from haemorrhagic com- These drugs act as vitamin K antagonists, blocking plications. This is in contrast to the anticoagulants the action of vitamin K in completion of the and fibrinolytic agents, both of which are associated synthesis of factors II (prothrombin), VII, IX, and with significant haemorrhagic side effects. X. The drugs most widely used in Britain are war- farin sodium and phenindione. In the absence of The Anticoagulants vitamin K, either due to deficiency or the presence of the oral anticoagulants, precursor molecules of The anticoagulants inhibit the coagulation enzyme factors II, VIII, IX, and X are apparentlysynthesized sequence which causes fibrin formation. Anti- by the liver and released into the circulation. The coagulants form three main groups: heparin, the prothrombin precursor, known as preprothrombin, coumadin compounds, and ancrod. is antigenically similar to prothrombin but differs in electrophoretic mobility from prothrombin when HEPARIN subjected to electrophoresis in the presence of Heparin is an immediately acting, negatively charged calcium. Preprothrombin does not bind calcium, mucopolysaccharide prepared from animal lung or unlike prothrombin, and for this reason is converted intestinal mucosa. Heparin BP is a heterogeneous into thrombin only at very low rates in the presence compound having molecules of widely differing of activated factor X, factor V, and phospholipid. molecular weights, although the main component is However, other enzymes, such as staphylocoagulase, about 22 000 mw. When administered intravenously are able to convert preprothrombin to thrombin as it acts as a potent, immediately acting inhibitor of easily as prothrombin. The precursor molecules of thrombin and activated factor X as well as possibly the vitamin K-dependent factors act as competitive other coagulation factors. Heparin first combines inhibitors to their active analogues, and thus the with antithrombin III, an alpha globulin ofmolecular action of the oral anticoagulants is both to produce copyright. weight 64 000. A low level of antithrombin III may a deficiency of vitamin K-dependent clotting factors reflect a predisposition to thrombosis. For this and to induce inhibitors to them. These inhibitors reason, antithrombin III concentration is frequently are known as PIVKA (protein induced by vitamin measured by the immunological technique. But we K absence or antagonists) and the inhibitor to factor have not been able to find a correlation between the X has been studied most intensively (Hemker, biological and immunological assays ofantithrombin Veltkamp, and Loeliger, 1968). in that there are The chief complication of all anticoagulants is, of III, reflecting, all probability, http://jcp.bmj.com/ numerous antiproteases in the circulation which can course, haemorrhage. The cause of the haemorrhage inhibit thrombin (Whigham, Howie, Forbes, and is usually due either to excessive dosage of the anti- Prentice, unpublished). coagulants or to an unidentified source of haemor- The two main methods of giving heparin are rhage, such as a peptic ulcer. either by six hourly intermittent injections or by One major problem of the oral anticoagulants is continuous intravenous infusion. We prefer the that they interact with numerous other drugs with latter method as a more uniform plasma concen- the result that their effect may either b_ diminished tration is obtained, although neither method has or increased (Eipe, 1972). In the first instance, loss on September 29, 2021 by guest. Protected been the subject of sufficient clinical evaluation. of control may lead to further thrombosis and in the One problem about heparin in the treatment of second instance to haemorrhag.. The coumadin arterial thrombosis is that it may enhance platelet compounds are transported bound to albumin and aggregation. We have studied the effects of thera- drugs which displace the coumadins from their peutic concentrations of heparin in modifying ADP- binding sites increase their anticoagulant action; induced platelet aggregation. Heparin enhanced the such drugs are phenylbutazone, indomethacin, and aggregating effect of ADP and lowered the threshold clofibrate. Other drugs which can enhance the effect at which the release reaction and secondary platelet of anticoagulants include those (1) causing impaired aggregation took place (Thomson, Forbes, and vitamin K absorption, eg, neomycin; (2) causing Prentice, 1973). We have also found that platelet delayed degradation of coumadins, eg, diphenyl- deposition and fibrin formation may take place on hydantoin, tolbutamide; (3) causing increased extracorporeal membranes during haemodialysis, affinity of coumadins to the hepatic receptor site, despite the fact that the patient is heparinized eg, clofibrate, D-thyroxine. sufficiently to prolong the whole blood clotting time Many drugs causing enzyme induction increase J Clin Pathol: first published as 10.1136/jcp.s3-9.1.50 on 1 January 1975. Downloaded from 52 C. R. M. Prentice the rate at which the coumadins are degraded leading There are, at present, no definite indications for to a diminution in the anticoagulant effect. Drugs in ancrod. It appears to be as effective as heparin for this category include the
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