FIBRINOLYSIS Paper read during the Annual Meeting of the Royal College of Surgeons of England on 17th December 1966 by G. R. Fearnley, M.D., F.R.C.P. Consultant Physician, North Gloucestershire Area To MOST PEOPLE the term fibrinolytic therapy means the use of exogenous thrombolytic agents like streptokinase for the treatment of established thrombosis, either arterial or venous. This aspect, and it is only one aspect of fibrinolysis, has evoked little interest in this country, and one reason for this in respect of arterial thrombosis is the question: Once the blood supply has diminished sufficiently to produce infarction what good can be expected from dissolving the putative cause, and in any case how often can we be certain that a fibrinous thrombus is present? These objec- tions certainly apply to the thrombolytic treatment of cerebral and coronary infarctions; but have less cogency in the case of venous thrombosis. First, because the problem of infarction does not arise and, secondly, because, while the platelet may be of greater importance in arterial ob- struction, fibrin contributes significantly to the bulk of venous thrombi. Theoretically, then, thrombolytic therapy might be more relevant to venous than to arterial obstruction, but experience of the use of thrombolytic agents in venous thrombosis is both limited and in general uncontrolled. Nevertheless there is good evidence confirmed by phlebography that streptokinase can dissolve occlusive venous thrombi. Be this as it may, 1 propose to consider the possibility that endogenous fibrinolytic activity may play a part in the prevention of and perhaps recovery from venous thrombosis, and further to suggest that it may prove possible to enhance the body's own fibrinolytic activity by means of drugs as a prophylactic measure against venous thrombo-embolism. Activator + Plasminogen Plasmin Plasmin + Fibrin - Fibrinolysis First, however, since fibrinolysis is not too familiar to everybody, may I briefly outline its mechanism? The end-product of the fibrinolytic system is plasmin, a proteolytic enzyme. Plasmin derives from an in- active precursor, plasminogen, present in plasma and other body fluids; and for the conversion of plasminogen to plasmin and hence for fibrino- lysis to take place an activator or activating system is required. Activators of plasminogen are present in the tissues, the blood and other body fluids, such as the urine. Blood activator appears to arise mainly from the endothelium of veins and venules, and the evidence for this is as follows: As first shown by Clarke and his colleagues (1960), venous occlusion of a limb by means of a cuff is followed by a rise of fibrinolytic activity in the trapped venous blood. My colleagues and I (Chakrabarti et al., 1963) have shown that when a vein exposed at operation is traumatized by 51 G. R. FEARNLEY pinching with forceps the fibrinolytic activity of blood down stream from the point of trauma increases, and that if a venous segment is isolated by clamps and the blood is aspirated from it and replaced by non-fibrinolytic plasma, such plasma acquires considerable fibrinolytic activity within two minutes of being placed in the vein. By the technique of fibrinolysis autography, in which a thin layer of tissue is incubated in contact with a layer of fibrin, the preparation being subsequently stained and examined under the microscope, Todd (1959) has shown that veins and venules, especially their endothelium, are a rich source of fibrinolytic activity. By contrast arterial endothelium appears to be deficient in such activity. There is therefore good evidence that venous endothelium releases a plasminogen activator into contiguous blood, and that the blood level of activator is increased by venous stasis and by trauma to the vein. This mechanism may be concerned in the maintenance and restoration of venous patency. A majority of investigators have shown that fibrinous thrombi have plasminogen incorporated within them and plasminogen activators appear capable of penetrating such thrombi by diffusion, and J \44 a b Fig. 1. (a) Mural venous thrombus: exposed to activator from passing blood, and also from contiguous venous endothelium. (b) Occlusive venous thrombus: exposed to activator secreted by contiguous venous endothelium. there converting the contained plasminogen to plasmin with consequent lysis of the thrombus. If we picture a deposit of fibrin on a venous wall, it will be exposed to activator on all sides, on the one hand from passing blood and on the other from contiguous venous endothelium (Fig. la). Such a mechanism could be concerned in maintaining the patency ofveins. If occlusive thrombosis occurs, activator penetration is still available from the venous wall (Fig. lb) and may in time dissolve the thrombus. Direct proof that this happens is difficult to obtain in Man, but circumstantial evidence favours the possibility. It is a matter of common observation that venous thrombosis in the human being may resolve quite rapidly, and artificial thrombi induced in the ear-veins of rabbits and the pulmonary arteries of dogs tend to disappear within 24 hours. It is hard to see what else but fibrinolysis could be responsible. It is possible, therefore, that the natural fibrinolytic mechanism is concerned in maintaining and re- storing venous patency, and that failure of this mechanism might contri- bute to venous thrombo-embolic disease. This would be supported if defective fibrinolysis were associated with a tendency to venous thrombosis. The spontaneous fibrinolytic activity of blood is known to be low in patients with extensive arteriosclerosis and in patients and healthy people 52 FIBRINOLYSIS who are obese. Low fibrinolytic activity has been reported in patients who in the past have had a deep vein thrombosis (Ellison and Brown, 1965). There is therefore some evidence of an association between defective fibrinolysis and phlebothrombosis and with conditions believed to pre- dispose to it. Hence there would seem to be an a priori case for enhancing blood fibrinolytic activity of such people when they are exposed to con- ditions which favour the occurrence of phlebothrombosis; namely hospitalization. Can this be done? During the past seven years we have been investigating the possibility of enhancing blood fibrinolytic activity with drugs given by mouth and we now have a combination of drugs which seems capable of producing a sustained increase of fibrinolytic activity in nearly all patients except those whose fibrinolytic activity is naturally high. The level of plasminogen activator in blood is measured either by the time required for lysis of a clot made with thrombin from diluted blood or from the euglobulin fraction of plasma, the former being known as the blood clot lysis time or B.L.T. for short, and the latter as the euglobulin lysis time or E.L.T. for short. Lysis time and fibrinolytic activity are, ofcourse, inversely related. Hence a long lysis time means low fibrinolytic activity and a short lysis time means high fibrinolytic activity. Drugs which increase fibrinolytic activity therefore shorten both the dilute blood clot and euglobulin lysis times. For a given blood sample the blood clot lysis time is about 3-4 times that of the euglobulin lysis time. A slide was shown giving the results of a two-year study of the effect of various drugs on the blood fibrinolytic activity of 18 patients with occlusive vascular disease of the heart or lower limb. The upper of the two bottom curves showed the blood clot lysis time and the lower showed the euglobulin lysis time. The mean values for the 18 patients were given throughout the trial. It could be seen that metformin on the one hand and phenformin on the other gave a temporary fibrinolytic effect, but that when phenformin was combined with ethyloestrenol a sustained reduction of both the blood clot and euglobulin lysis times was obtained over a year which is when the slide was made. Serum cholesterol and plasma fibrinogen levels were also reduced. Since resistance develops to the fibrinolytic effect of ethyloe- strenol alone even more rapidly than it does to that of phenformin, the two drugs given together seem to exercise a synergistic effect on fibrinolysis. The fibrinolytic effect of phenformin plus ethyloestrenol has been confirmed in about 80 survivors of myocardial infarction who are at present receiving this treatment. The slide gives only the mean values, but individual anal- ysis of these and the coronary patients indicates that this combination of drugs increases fibrinolytic activity in about 80 per cent of people so treated, and that the most marked effect is in those whose blood fibrinolytic activity islow. The euglobulinlysis time is believed to measure directlyplasminogen activator, so that this combination of drugs seems to raise the level of blood activator. We are at present trying to discover whether this is 53 G. R. FEARNLEY achieved by increasing the rate of formation of activator, that is its release from veins, or by decreasing its removal or excretion. It is thus possible to produce a sustained increase of blood fibrinolytic activity with drugs given by mouth, and in respect of the venous system this might provide an alternative to anticoagulant prophylaxis. Its value or otherwise could be determined only by clinical trial; but at present there is one considerable difficulty. These drugs do not achieve their maximal fibrinolytic effect until they have been given for 2-3 weeks, and we know of no way of accelerating this. In fact experience with other drugs which affect fibrinolysis suggests that this kind of slow response is a feature of the fibrinolytic system. Further research may uncover a pharmacological means of increasing fibrinolytic activity quickly, but unless this becomes possible pharmacological fibrinolysis is obviously not viable as a treatment for phlebothrombosis. It might be possible to evaluate it as a prophylactic measure, although the latent interval before a fibrinolytic response is obtained would make this difficult.