Fibrinolysis and Occlusive Vascular Disease

Based on a Dissertation read before the Royal Medical Society on Friday. 20th January, 1961. The magnitude of the problem of occlusive vascular disease needs no introduction ; we should therefore be acquaint with any new therapeutic developments, particularly if these h a v e reached the stage of clinical trials. I apologise for any bias and simplification in this article. The purpose of the original Dissertation was to arouse curiosity ; this article attempts to do no more. Copyright Royal Medical Society. All rights reserved. The copyright is retained by the author and the Royal Medical Society, except where explicitly otherwise stated. Scans have been produced by the Digital Imaging Unit at Edinburgh University Library. Res Medica is supported by the University of Edinburgh’s Journal Hosting Service: http://journals.ed.ac.uk ISSN: 2051-7580 (Online) ISSN: 0482-3206 (Print) Res Medica is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL Res Medica, Autumn 1961, 3(1): 26-29 doi: 10.2218/resmedica.v3i1.373

The magnitude of the problem of occlusive vascular disease needs no introduction ; we should therefore be acquaint with any new therapeutic developments, particularly if these h a v e reached the stage of clinical trials.I apologise for any bias and simplification in this article.The purpose of the original Dissertation was to arouse curiosity ; this article attempts to do no more.

The System
The end-product of the complicated clotting mechanism is a fibrin clot.Fibrinolysis appears to he an equally complicated mechanism, the end-product of which is an enzvme, Plasmin.which can lyse the fibrin clot.Less detail is known of the various stages in Fibrinolysis t h a n is known of the clotting mechanism.Astrup ( 19:;6), however, has produced a rough scheme which represents current thought fairly well.I lis scheme (Fig. 1) is based on the work of Christicnsen & McLeod ( 194:;).
Space does not permit discussion of known details in the fibrinolytic process.Suffice to say that circulating in the blood of all mammals so far studied is the precursor of the enzyme, Plasminogen.In the presence of an activator, which in turn is the end-product of a complicated process.Plasminogen is converted to Plasmin. the active fibrinolytic cnzvmc.
Inhibition of this mechanism appears to occur: So far the inhibitors appear to attack specifically at two sites.There arc specific inhibitors of Plasmin and of Plasmin activators.One circulating Plasmin inhibitor is known to be an a-globulin.Synthetic inhibitors have been produced.the most recent being D-amino caproic acid.

Physiology
Fearnley (1953, 19:;:;), pioneered the concept of a basal level of spontaneous fibrinolysis in normal people.I Hewas able to show a diurnal \'ariation.and a measurably higher level of activity in venous blood, particularly in that from the muscles.Buckcll and Elliot ( 1959) using different assay methods have confirmed this, and agree with Mullerzt ( 1956) that the cause of the raised activity in venous blood was a raised level of a c t i v a t o r Sherry ( 1 9 6 0 has also confirmed a raised level of acti\'ator follo\\'ing periods of fear.parenteral adrenaline, anoxia and after i n t r a v e n o u s acetyl choline. The mechanisms behind the release o f Plasminogen activator arc still for the most part obscure.Two significant observations, however, deserve mention.Albrechtscn (1957) has shown that ecrtaiu organs store a high concentration of activator; the uterus.prostate, adrenal gland, thyroid.lungs and ovaries a r e s u c h organs.The kidneys, all muscle.testes a n d spleen have very littlc.while the liver has none.It is possible that those sources of activatorlisted above may be used to raise the level of circulating activator.M a n y \\'orkcrs have found a high level of fibrinolytic activity in venous blood draining mnsclcs, despite Albrechtscn's finding of a low yield of activator from muscle tissue.Kwaan & McFadyean ( 1957. 1958) in some brilliant experiments on this problem concluded that there existsin the walls of arteries.veins and of some capillaries, cholinergie effector mechanisms which can react locally and reflexly to release Plasminogen activator.They have very tentatively suggested that constriction of the vasa vasorum producing relative ischaemia may trigger off this mechanism.Confirmation of these observations is urgcn tly required.

Pathology
Thus we sec so far that Fibrinolysis is a complicated yet delicately controlled mechanism.It is now ncccssarv to look for a n y disturbance in the mechanism in association with occlusive vascular disease.• O v e r 100 years ago Rokitansky postulated that arteriosclerosis \\'as the result of organisation of mural fibrin thrombi.Duguid ( 1946Duguid ( , 1948) ) has recently revived this hypothesis as giving a part explanation for the origin of arteriosclerosis.Duguid's work has been confirmed by many other \\'orkers.but he has shown great restraint in explaining why focal deposits of fibrin occur.Mole ( 1948) and Astrup ( 1956) have concluded that the cause is an upset in the fibrinolytic mechanism.Gill man ( 1958) believes that a decreased level of fibrinolysis plays at least some part in thrombosis.
W o r k has only just begun in measuring the fibrinolytic activity of circula t i n g blood in patients with occlusive vascular disease.There is as yet no convincing evidence of reduced fibrinolvsis after mvocardial infarction.but Ncstcl ( 1959) has shown convincingly a 2/3 reduction in fibrinolytic activity in patients suffering from intermittent claudication. The

Therapeutics
The possibility of unblocking blood using fibrinolytic techniques is an exciting one.It is pcrhaps necessary to set apart atherosclerosis in epithelization has taken place a.s compared with thc more sudden proccss of thrombosis or embolism.The suggesting that fibrinolytic thcrapy is us ful in atherosclerosis is slight and the more intcrcstillg rcsults from treatment of thrombosis and embolism.
At the momcnt the only method thc usc of human Plasmin intr enously.An American company now produces a preparation k own as "' l'hrombolysin."Local infusions are necessary to bc really as the circulating Plasmin inhibitors soon nullify a raised systemic fibrinolysis.Ruegesegger & al. ( 1960)  obtained some important rcsults from radiographic studies, in the dog, of occluded coronary infuscd with "Thrombolysin.''Their work merits close study.both reported promising results.The latter successfully pcrfused the coronary with "Thrombolysin."The treatment of peripheral thromboembolic disease has more straightforward techniques and thc results therefore of more significance.Anylan & al. ( 1960) and in particular Clifton ( 1960) produced some most encouraging results, from patients \\'ith femoral embolism and femoral thrombosis.
The possibility of occlus scular disease becomes real, particularly when a patient has been enabled to a first acute attack.Since the limitations of long-term anticoagulant therapy arc daily more apparent, it must be considered whether a raised of spontaneous fibrinolysis would not be a safer and more prophylaxis.Certainly, at least, Fricman & al. ( 1960) unable to produce artificial thrombi in thcir dogs, once these had been thoroughly "thrombolysed." nous "Thrombolysin" for the rest of onc's life is inconbut attempts been made to find compounds which \\'hen taken orally will produce a raised of spontaneous fibrinolysis.Finding a powerful hypolipaemic agent is an start in the of this problem.Constantintidcs & al. ( 1960) reported that a snlphatcd polymannuronidc, " Paritol C" is a powerful hypolipaemic agent with no side effects.One oral dose is eff cti e for 24 hours.Fearnl y ( 1960) and Singh & al. ( 1960) have produced some remarkable improvements in patients \\'ith intermittent claudication by giving them oral sulphonylurcas, Tolbutamide and Chlorpropamide.Fearnley has demonstrated a raised level of spontaneous fibrinolysis in patients taking these drugs.
These advances in the study of Fibrinolysis promise an important breakthrough in the management of occlusi\'c vascular disease.The foregoing has been a brief, biased account; lest we become wildly enthusiastic it should be pointed out that no" double blind•• trials have yetbeen reported.There is a great need for more effective fibrinolytic agents and for careful.criticallyreported trials.Despite the many problems, the clinical and anatomical restitution of occluclcd vessels and prophylactic measures against such catastrophes by medical means, is an exciting goal.
. CASH, B.Sc., M.B .. Ch.B.Based on a Dissertation read before the Royal Medical Society on Friday.20th January, 1961.
Frieman & al. (196 ) also successful local infusions in dogs' pcriphcral The amount of work performed on patients is still limitcd.The problem of assessing the results is particularly difficult in such fields as coronary thrombosis and cerebral thrombosis.Nc rtheless, Richter & al. ( 1960) and Boucck & al. (1960) 1959)has shown that fats, specifically saturatcd fatty acids, inhibit fibrinolysis.It is perhaps all to easy and fashionable to relate the association of fats with occlusive vascular disease through fibrinolysis.M e a s u r e m e n t s of t h e fibrinolytic work of Kwaan & McFadyean ( 19:;7) and Buckell & Elliott (