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Home , Alpha globulin, Ancrod, 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

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 . collagen El The major constituents of thrombi are Idecreasev and , together with trapped red cells and other C-AMP elements. Our main drugs are the I antiplatelet agents to prevent platelets sticking phosphodiesterase together; to prevent fibrin formation; t and fibrinolytic agents which, hopefully, will lyse IMP RA 233 and remove formed fibrin deposits. Antithrombotic Fig Possible mechanism by which 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 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 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. . 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 this would represent such as ADP, collagen, basement membrane, a major advance. We are still dealing with the first , adrenaline, , and antigen- generation of antiplatelet agents and it is probable 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 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 . 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 factors II, VIII, IX, and X are apparentlysynthesized sequence which causes fibrin formation. Anti- by the and released into the circulation. The coagulants form three main groups: , the prothrombin precursor, known as preprothrombin, coumadin compounds, and . 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 , , 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 III, an alpha 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 ( 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 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 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 barbiturates and mepro- the treatment of , and control bamate. of ancrod may be easier than of heparin. Possibly A few families have a remarkable hereditary the most dramatic effects with ancrod have been resistance to the effect of the oral anticoagulants obtained in the treatment of priapism (Bell and (O'Reilly, 1970). Individuals may take up to twenty Pitney, 1969). times the normal dose yet show merely the normal or even less than normal anticoagulant effect. The Thrombolytic Therapy absorption rate, albumin binding, and turnover rate in these families are normal. The defect appears to In many ways the idea of a drug that dissolves an lie in an altered affinity of the hepatic receptor site existing thrombus instead of merely preventing for the anticoagulant and for vitamin K, caused by further fibrin deposition is attractive. Unfortunately, a single dominant effect on an autosomal chromo- there appears to be great variability in the suscep- some. tibility of different thrombi to lysis, and it is not easy to predict which thrombi will respond to lytic ANCROD therapy. The main fibrinolytic enzyme is strepto- Ancrod is the purified coagulant fraction of the kinase (molecular weight 43 000) obtained from the of Agkistrodon rhodostoma, the Malayan pit streptococcus. acts in a complex viper. This enzyme removes fibrinopeptide A from manner which is not fully understood. It appears to leading to the formation of an unstable react with a plasminogen pro-activator to activate form of fibrin which is rapidly removed from the plasminogen to . Streptokinase then com- circulation by fibrinolysis (Ewart, Hatton, Basford, plexes with plasmin to activate further plasminogen and Dodgson, 1970). We have evidence to suggest by first-order kinetics. Plasmin is a of wide that the fibrin is cleared from the circulation as soon specificity, digesting not only fibrin and fibrinogen as it is in the form of high molecular weight soluble but also factors V and VIII. When it is remembered fibrin complexes, and that the formation of in- that the digestion products of fibrinogen are anti- copyright. soluble 'micro-thrombi' does not occur under coagulant it is not surprising that streptokinase can normal circumstances (McKillop, Edgar, Forbes, produce a severe bleeding tendency. and Prentice, 1975). One interesting consequence of The major problem arising from streptokinase is defibrination by ancrod is that the whole blood and that it can give rise to pyrogenic and allergic plasma viscosity are diminished. This may be an reactions. Additionally, due to the different levels important effect in promoting blood flow in small ofstreptococcal present in the population,

vessels and there are encouraging reports from the ideally a streptokinase sensitivity test should be http://jcp.bmj.com/ Continent that ancrod may be helpful in the treat- carried out before treatment. Treatment with ment of peripheral arterial diseases. streptokinase cannot be repeated within six months of a previous course. INDICATIONS FOR ANTICOAGULANTS , prepared from human urine, is not The indications for anticoagulants are shown in generally available and the cost for a course ofwhole table II. It should be noted that the main indications body lysis is prohibitive. Unlike streptokinase, occur in the realm of venous disease, such as deep urokinase is a direct activator of plasminogen by vein thrombosis and . The splitting of lysine and arginine bonds and appears on September 29, 2021 by guest. Protected indications for arterial disease, such as transient to cause less systemic digestion of fibrinogen in cerebrovascular ischaemia or .myocardial infarction, comparison with streptokinase. It is not associated are much less certain. with pyrogenic reactions and predicting dosage is easier than with streptokinase as it is unaffected by Indication Condition the streptococcal inhibitors. Some of the earlier Definite Deep-vein thrombosis preparations of urokinase were contaminated with a Pulmonary embolism coagulant moiety, but this problem has now been Mitral valve disease Prosthetic cardiac valves overcome. Extracorporeal circulations Prophylaxis-deep-vein thrombosis Pharmacological Enhancement of Fibrinolysis Probable Transient ischaemic attacks Possible Myocardial infarction A number of agents have the ability to augment the Ingravescent angina level ofcirculatingplasminogen activatorwhichcanbe Table II Indications for anticoagulants demonstrated in low amounts within the normal J Clin Pathol: first published as 10.1136/jcp.s3-9.1.50 on 1 January 1975. Downloaded from Clotting andfibrinolysis 53 circulation. One source of this activator is vascular pulmonary embolism has yet been found. Strepto- endothelium, in particular venous endothelium. As kinase is widely used for the treatment of peripheral patients with arterial disease, such as survivors of arterial disease on the Continent, but this approach myocardial infarction, tend to have reduced plas- has not been tested widely in Britain. minogen activator levels, these compounds are clearly of great interest. The main agents under trial are phenformin, ethyloestrenol, and stanozolol, an anabolic steroid. The mode of their action is not References known. Bell, W. R., and Ptiney, W. R. (1969). Management of priapism by therapeutic defibrination. New Engl. J. Med., 280, 649-650. Eipe, J. (1972). Drugs affecting therapy with anticoagulants. Med. Indications for Fibrinolytic Therapy Clin. N. Amer., 56, 255-262. Ewart, M. R., Hatton, M. W. C., Basford, J. M., and Dodgson, K. S. (1970). The proteolytic action of Arvin on human fibrinogen. As seen in table III, there are to date no definite Biochem, J., 118, 603-609. indications for fibrinolytic therapy, although many Hemker, W. C., Veltkamp, J. J., and Loeliger, E. A. (1968). Kinetic would now use as the aspects of the interaction of blood clotting enzymes. III. clinicians streptokinase Demonstration of an inhibitor of prothrombin conversion in treatment of first choice in massive pulmonary Vitamin K deficiency. Thrombos. Diathes. haemorrh. (Stuttg.), 19, 346-363. Lindsay, R. M., Prentice, C. R. M., Ferguson, D., Burton, J. A., and Indication Condition McNicol, G. P. (1972). Reduction of thrombus formation on dialyser membranes by aspirin and R.A.233. Lancet, 2, Probable Massive pulmonary embolism 1287-1290. Ilio-femoral deep vein thrombosis McKillop, C., Edgar, W., Forbes, C. D., and Prentice, C. R. M. (1975). Hyphaema ofeye Soluble fibrin complex production and proteolysis during Possible Myocardial infarction Ancrod therapy. Communication to Scottish Society for Peripheral arterial disease Experimental Medicine, Edinburgh. O'Reilly, R. A. (1970). The second reported kindred with hereditary resistance to oral anticoagulant drugs. New Engl. J. Med., 282, Table III Indications for fibrinolytic agents 1448-1451. Prentice, C. R. M., and McNicol, G. P. (1973). Fibrinolytic therapy. In Recent Advances in Thrombosis, edited by L. Poller. pp. 151- embolism or ilio-femoral deep vein thrombosis. The 179 Churchill Livingstone, Edinburgh and London. subject has been reviewed recently (Prentice and Thomson, C., Forbes, C. D., and Prentice, C. R. M. (1973). The copyright. potentiation of platelet aggregation and adhesion by heparin McNicol, 1973). Although streptokinase and uro- in vitro and in vivo. Clin. Sci., 45, 485-494. kinase can, in massive pulmonary embolism, lower Vermylen, J., de Gaetano, G., and Verstraete, M. (1973). Platelets and thrombosis. In Recent Advances in Thrombosis, edited by L. the pulmonary artery pressure more rapidly than Poller, pp. 113-150. Churchill Livingstone, Edinburgh and heparin. no beneficial effect on the mortality from London. http://jcp.bmj.com/ on September 29, 2021 by guest. Protected