Eye (1991) 5,159-169

The Role of Fibrinolytic Factors in Ischaemia

M. PANDOLFI and A. AL-RUSHOOD Saudi Arabia

Summary The fibrinolytic system is an enzymatic cascade system whose activation leads to for­ mation of a trypsin-like serine protease, plasmin, which splits insoluble fibrin into soluble degradation products. It is believed that the main function of fibrinolysis is defence against thrombotic occlusion of vessels and dissolution of thrombi once they are formed (thrombolysis). The authors review the recent literature providing evidence that fibrinolysis plays a role in the pathogenesis of vascular occlusions. From earlier studies based on global assay methods it is known that fibrinolysis is depressed in patients with vascular occlusions. Selective assay methods show that almost invariably the fibrinolytic activity of these patients is depressed either following increased levels of fibrinolytic inhibitors (mainly plasminogen activator inhibitor I or PAl-I) and/or decreased· levels of a plasminogen activator (tissue plasminogen activator or t-PA). In a few cases the molecule of plasminogen shows a conformational abnormality making it less susceptible to conversion to plasmin. In the last decade numerous studies have been published showing a connection between a depressed fibrinolysis and venous thrombosis. In patients with coronary artery occlusion fibrinolysis is depressed mainly because of increased levels of PAl-I. Hypertriglyceridaemia seems to aggravate the defective fibrinolysis. There is also evidence of a decreased fibrinolysis in patients with peripheral ischaemic diseases. A depressed fibrinolysis has also been documented in states predisposing to vas­ cular occlusions. Thus Iwo levels of t-PA/increased levels of PAI-I have been found in obesity, diabetes mellitus, postoperative states, SLE, malignancies, and miscellan­ eous diseases oftencomplicated with thrombosis such as Beh�et's syndrome. In preg­ nancy fibrinolysis is depressed because of the presence in blood of PIA-2, an inhibitor of plasminogen activators secreted by the placenta.

The Fibrinolytic System vessels, dissolution of thrombi once they are The fibrinolytic system is an enzymatic cas­ formed (thrombolysis) and resolution of clots cade system whose activation leads to forma­ and fibrinous exudates occurring in various tion of a trypsin-like serine protease, plasmin, parts of the body. which is capable of degrading fibrin as well as fibrinogen, factor V and VIII. It is believed Activators of fibrinolysis that the main function of fibrinolysis is A simplifiedscheme of the fibrinolyticsystem defence against thrombotic occlusion of in man is shown in Figure 1.

From: Department of Ophthalmology, King Fahd Hospital of the University, Al-Khobar, Saudi Arabia.

Correspondence to: Prof Maurizio Pandolfi, Department of Ophthalmology, King Fahd Hospital of the University, P. O. Box 2208, Al-Khobar, Saudi Arabia. 160 M. PANDOLFI AND A. AL-RUSHOOD

ACTIVATORS OF PlASMINOGEN nant cells9 and corneal epithelium 10 have been (t-PA,U-PA) -'-- INHIBITORS OF PLASMINOGEN shown to produce u-PA. +I ,-- AC1lVATORS!E'AU PAI-2) The fibrinolytic system can be activated by

PLASMINOGEN - PLASMIN kallikrein as well as by F.XII of coagulation INHIBITORS OF PLASMIN (intrinsic activation system).11.12 The patho­ I --+e- + !aa� (X2-M, (Xl-AT) physiological role-if any--of thy intrinsic

RBRIN -FOP activation system is not clarified.

Fig. 1. A simplifiedscheme of the fibrinolyticsystem . Regulation of fibrinolysis. Fibrinolytic Plasmin splits fibrin into soluble fragments inhibitors (fibrindegradation products-FDP) of differ­ Since plasmin is capable of degrading proteins ent size. Plasmin results from activation of the other than plasmin it is necessary to confineits proenzyme plasminogen, a f3 -glycoprotein action to its primary substrate i.e. fibrin. 2 with molecular weight of about 90 kDI which Furthermore the effectiveness of the fibrino­ is synthetised in the liver. 2 It tends to be lytic system needs constant regulation since a adsorbed to fibrin,the site at which the bulk of too pronounced activity leads to a haemorr­ plasminogen activation occurs. hagic diathesis, while a depressed activity Circulating blood contains two types of leads to thrombosis. The mechanisms regu­ plasminogen activators: tissue type activator lating fibrinolysis have been the object of (t-PA) and urinary activator or urokinase (u­ comprehensive reviews.13-17 PA). Both activators may be present in native While circulating in blood as free enzymes single chain forms: weakly active sc t_PA3 with the activity of t-PA is weak. When fibrin is a molecular weight of 60 kD, and sc u-PA formed, plasminogen and t-PA are bound to (pro urokinase) with a molecular weight of fibrin. Fibrin bound t-PA increases 200 times -54 kD which is devoided of enzymatic activ­ its cathalytic activity and rapidly converts into ity.4 An important functional difference plasmin the fibrin bound plasminogen. The between the two activators is that t-PA binds result is a local fibrinolysis. Plasmin also con­ to fibrin which it needs to activate plasmino­ verts the inactive sc u-PA into active tc u-PA gen while u-PA does not bind to fibrin and is which takes part in the dissolution of fibrin. capable of activating plasminogen in absence However, the role played by u-PA in fibrin of fibrin.During activation of fibrinolysisboth dissolution inside the vascular tree is probably native forms are converted into the active two ancillary. chain t-PA and u-PA (tc t-PA and tc u-PA). The fibrinolyticprocess is restrained at two T-PA is produced and stored in the endo­ different levels by two classes of inhibitory thelium of certain blood vessels where it can agents present in plasma: the inhibitors of be demonstrated histochemically.5 From the plasminogen activators, 18 and the inhibitors of vascular endothelium t-PA is continously plasmin. The main plasminogen activator released into the circulation such release inhibitor (PAl-I) is contained in the vascular being enhanced by a variety of stimuli notably endothelium and in the platelet alpha gran­ venous stasis6 and physical exercise.7 The con­ ules; it immediately binds t-PA and u-PA. In centration of t-PA antigen in plasma is low, normal conditions it binds 95% of the circu­ about 5 [tg/L. It is believed that t -P A plays the lating t-PA forming a complex with molecular central role in maintaining the patency of the weight of 110 kD.7 Changes in PAl -1 plasma vascular tree by dissolving obstructing fibrin levels rather than changes in t-PA have been deposits or promoting the lysis of occluding recently related to diurnal variations of the thrombi. fibrinolytic activity.19 PAI-2 has probably a U-PA is produced mainly by the kidney and secondary importance being secreted by pla­ excreted with the urine. Its main role is prob­ centa and being present only in plasma of ably that of maintaining the urinary excretion pregnant women. However, PAI-2 has pathways free from obstructing fibrin.Plasma recently been found in the plasma of some contains minute amounts of u-PA mainly sc men and non-pregnant women.20 u-PA.8 A variety of other cells such as malig- In addition to its anticoagulimt activity, FIBRINOLYSIS AND ISCHAEMIA 161 activated protein C (APe) stimulates fibrino­ of purified fibrinolytic enzymes brings about lysis both in vitro and in ViV021,22 by binding dissolution of occluding thrombi (therapeutic PAI-l thus acting as an 'inhibitor of inhibi­ thrombolysis), tor' .23 A similar action as protein S which acts In inflammationand trauma fibrinis usually as a cofactor of APe. 24 formed. During the healing process fibrin, The primary inhibitor of plasmin, (X -anti­ which may act as matrix for neoformed 2 plasmin ((X -AP)25 rapidly forms a complex vessels; is gradually broken down by the 2 with circulating plasmin. In case of massive systemic and local fibrinolysis. A timely dis­ formation of plasmin-as during thrombo­ solution of fibrin is important to avoid bleed­ lytic treatment with streptokinase or in dis­ ing or scarring.31 seminated intravascular coagulation-an The role of fibrinolysis in tumour growth is exhaustion of available (X -AP occurs. The unclear. Tumoural cells secrete u-PA9 and it is 2 excess of plasmin is then complexed by generally known that certain tumours are sur­ (X -macroglobulin which functions as a reserve rounded by a wall of fibrin which may have a 2 ('second defence line') inhibitor of plasmin.26 containment action but which may also act as Az-AP inhibits fibrinolysis also by preventing a matrix for vascular proliferation. adsorption of plasminogen to fibrin, an essen­ Activators of fibrinolysis, mainly u-PA, tial step of physiological fibrinolysis. have been found in disparate areas of the Cl inhibitor is known to activate compon­ body such as kidney, prostate, cornea, pleura, ents of the complement CIs and C1r; it also aqueous humour. 33 Their function is probably inhibits clotting factor XIla, Xla and kallik­ that of maintaining the patency of small ducts rein, Furthermore it reacts with plasmin and and preventing the development of adherence with t-PA although at such low rates that its between surfaces. significance as inhibitor of fibrinolysis is The most manifest clinical significance of uncertainY fibrinolysis however, is its action of preven­ The balance between the pro fibrinolytic ting vascular occlusion by thrombi. A corol­ and antifibrinoliticactivity is regulated by the lary of such action is that a depressed synthesis of these agents and by their release fibrinolysis promotes thrombosis. To verify into circulation. Synthesis and release have this hypothesis numerous studies have been been found to be mediated by a number of done with the aim of detecting a decreased substances such as thrombin, histamin, epi­ fibrinolysisin patients suffering from vascular nephrine.28 Another mechanism of regulation occlusions of various type or presenting con­ is the presence of binding sites for plasmino­ ditions predisposing to vascular occlusion. gen, t-PA U_PA29,30 on cellular membranes. Fibrinolysis and Vascular Occlusions Clinical significance of fibrinolysis. Possible The studies directed towards establishing a role in the pathogenesis of vascular link between vascular occlusion and occlusions depressed fibrinolysis can be divided in two In the mid-50s there was enough knowledge groups, i.e. those investigating the fibrinolytic on the fibrinolytic system to allow Astrup to system in patients actually suffering from vas­ present a scheme of fibrinolysis which was cular occlusions and those dealing with the similar to the present one,31 the only signifi­ fibrinolytic system in conditions predisposing cant difference being that inhibitors of plas­ to vascular occlusions. minogen activators were not reported, A number of functions have been attributed to A. The fibrinolytic system of patients in the fibrinolytic system, whom vascular occlusion is the primary Fibrin deposits which may form within the disease vascular lumen are believed to be dissolved by 1. Venous thrombosis an intact fibrinolytic system before they grow The first unequivocal report linking throm­ enough to threaten the patency of the vesseL 32 bosis with depressed fibrinolysis was pub­ A corollary to the antithrombotic action of lished in 1961 by Nilsson and associates.34 the fibrinolytic system is that administration These authors described a young patient with 162 M. PANDOLFI AND A. AL-RUSHOOD severe and widespread venous thrombosis decreased plasminogen actiVIty (down to who showed a strongly increased plasma level 5-10% of the normal) and did not show of an inhibitor of plasminogen activation. The thrombosis. A normal plasminogen molecule inhibitor was most likely PAl-I, at that time but in low amounts was also found to be asso­ not yet identified. Later the same author ciated with thrombosis. 55 described four more patients including two Hereditary low levels of protein C56 and uniovular twins affected by recurrent severe protein S57 are accompanied by an increased thrombosis since childhood with a high blood incidence of venous thrombosis. However, content of inhibitor of plasminogen activa­ because these two proteins conrrected mainly tion.35 Histochemistry of vein specimens with inhibition of coagulation it is uncertain obtained by biopsy from patients with venous whether the supposed prote9ting action thrombosis showed a decreased plasminogen against thrombosis is mainly due to their anti­ activator activity of the vein wall.36 Increased coagulant action rather than to their profibri­ levels of fibrinolyticinhibitor was found in the nolytic activity. plasma of a patient affected by retinal vein occlusion in both eyes.37 2. Coronary artery occlusion In a large series of patients with idiopathic In the last decade endoscopic studies have venous thrombosis it was found that a large shown that thrombosis is not a sequel to myo­ number of these patients had a defective fibri­ cardial infarction (MI) as previously sup­ nolysis in the blood and/or vein walls.38 The posed, but the precipitating factor in MI and methods used were functional i.e. determina­ unstable angina.58,59 This evidence, together tion of the spontaneous fibrinolyticactivity of with the favourable results obtained with plasma and the activity following venous sta­ modern thrombolytic therapy,60 attracted new sis, as well as a histochemical method to assess interest on the fibrinolytic system in patients the activity in the wall of vein specimens with coronary artery disease. The results of obtained by biopsy. These finding were con­ earlier studies using only functional methods firmed by subsequent reports.43 of assessment suggested decreased fibrino­ Progress in the 80s led to the discovery and lytic activity in these patients. 61-63 Recent characterisation of PAl -1, review in18 the fast results64-66 provide evidence that the reduced acting inhibitor of t-PA. It was found that fibrinolysis is mainly due to increased plasma PAI-l masked the fibrinolytic response to levels of PAl-I, and in younger patients also venous stasis.44 Two mechanisms of defective to defective t-PA release from the vessels.65 fibrinolysis in thrombosis patients were iden­ Depressed fibrinolysis seems also to predis­ tified i.e. low levels of t-PA or increased con­ pose to reinfarction.66 Interestingly, numer­ centration of PAI_1.45-47 ous known risk factors for MI such as cigarette Of special interest is the occurrence of smoking,67 hyperlipoproteinaemia,68.69 obes­ either type of defective fibrinolysisassociated ity (see below) are associated with decreased with recurrent thrombosis in members of the fibrinolytic activity. In particular, a positive same family.42,43,48-51 The defect seems to be correlation between PAI-l levels and plasma inherited according to an autosomal domi­ triglycerides has been found.64 However, a nant mode with high penetrance. Nilsson and recent study,70 while confirming the finding Tengborn49 consider it odd that an inherited that PAI-l activity is positively correlated disorder should be due to an increased syn­ with levels of triglycerides, failed to observe thesis of inhibitor and hypothetised the pres­ either increased PAl-l or decreased t-PA in a ence of an abnormal inhibitor with increased group of 65 men with angiographically docu­ affinity for t-PA. mented coronary artery disease. Kirschstein In some cases recurrent venous thrombosis et al. 71 found that restenosis after percutane­ may be associated with the presence of an ous transluminal coronary angioplasty was abnormal plasminogen molecule.5 2-54 How­ significantly more frequent in patients who ever, the associated defective plasminogen­ devloped lower fibrinolytic activity and thrombosis seems weak considering that released lesser amount of t-PA following family members of the patients reported had a venous stasis. FIBRINOLYSIS AND ISCHAEMIA 163

Depressed fibrinolysis has been reported of inhibitors of plasminogen activator has also in ischaemic cerebrovascular diseases.7 2,73 been suggested to be behind the depression of fibrinolysis.87,88Interesting ly, a positive corre­ 3. Peripheral schaemic diseases lation has been found between the levels of According to a recent report there is an serum triglycerides and PAl -1 activity. 88 association between deficient releaseof t-PA Weight reduction has been found to revert the following venous stasis and occlusive arterial fibrinolytic defect in obese subjects90 while disease of the upper limbs.74 An abnormal physical exercise augments the fibrinolytic plasminogen molecule in patients with upper response to venous occlusion in healthy extremity ischaemia has also been reported.75 adults.91 There are numerous reports suggest­ In a large series of patients with peripheral ing that lipaemia inhibits fibrinolysis.92 vascular diseases both the resting fibrinolytic Recently it has been found that lipoprotein, activity of plasma and the activity increase fol­ an independent risk factor for ischaemic heart lowing venous stasis were significantly lower disease, binds to the plasminogen receptors in the patient group than in controls.76 No on endothelial cells thereby hindering the information is available on changes, if any, in mechanism of thrombolysis.93 No reports are the levels of PAl-I. Histochemical evaluation available connecting the depressed fibrinoly­ of the plasminogen activator activity in leg sis in obese subjects and the occurrence of arteries of patients undergoing below-knee thrombosis. amputation revealed an abnormally low activ­ ity.77 However, in collateral arteries plasmino­ 3. Post-operative states gen activator activity was as high as that of Like trauma,94,95 surgery has been reported to arteries in other parts of the body, a result sug­ produce a pronounced depression of fibrino­ gesting that atherosclerosis is not accom­ lysis.96-98 If fibrinolysis is already depressed, panied by a general suppression of the consequence may be a postoperative plasminogen activator activity in the arterial venous thrombosis. There are several studies vascular tree. Experimental ischaemia has on the fibrinolytic system in patients before been found to decrease the fibrinolytic activ­ surgery in order to evaluate the risk of post­ ity of the femoral artery of rat.78 operative thrombotic complications.99 -104 These studies, which are based on functional B. The Fibrinolytic System in Conditions assay methods, report a direct relationship Predisposing to Vascular Occlusions between low pre-operative fibrinolysisand an 1. Pregnancy increased risk of developing thrombosis after It is known that pregnancy is a predisposing surgery. More recent studies show that the factor to thrombosis. The fibrinolytic system depressed fibrinolysis observed before and in in pregnant women becomes increasingly connection with surgery is largey due to depressed during pregnancy,19 reponds poorly increase in the plasma levels of PAl-I.1 05-109 to venous stasisHO and rapidly reverts to normal values after delivery following pla­ 4. Systemic lupus erythematosus (SLE) centa separation.8! Placenta is rich in PAI_182 Patients with autoimmune diseases (SLE, and PAI_2.83 These inhibitors pass into the cir­ rheumatoid arthritis, scleroderma) are prone culation84.85 leading to a depressed fibrinolytic to venous and arterial thrombosis.11 0 Such risk activity. has been found to be related to an acquired autoantibody termed lupus anticoagulant or 2. Metabolic disorders LA which is present in a moderate (10-15%) Human obesity is affected by a higher preva­ percentage of these patients.82 LA consists of lence of arterial and venous thrombosis.86 IgG or IgM antibodies against phospholipids There are several reports showing that obese which in vivo act as a thrombogenic factor subjects have a depressed fibrinolysis as despite their in vitro anticoagulant activity.111 shown by a low spontaneous plasma fibrino­ Patients with SLE tend to have a depressed lytic activity and defective fibrinolytic spontaneous fibrinolytic activity of the blood response to venous stasis.H7 -89 Increased levels and to respond poorly to fibrinolytic stimuli 164 M. PANDOLFI AND A. AL-RUSHOOD such as venous stasis.112-114 Defective fibrino­ embolism and women taking p-pills have been lysis seems to correlate with the severity of the found to have an impaired response to fibrino­ disease since it is absent in patients with mild lytic stimuli such as venous stasis.126.127 How­ forms of SLE.115 The reason for depressed ever, in some women the depression of fibrinolytic activity seems mainly to be in fibrinolysis is still present one year after ces­ increased levels of inhibitors of plasminogen sation of p-pill intake, a fact suggesting a pre­ activation.11 4 Concomitant increased von Wil­ existent depression of fibrinolysis as pre­ lebrand factor levels seem to indicate an viously suspected in these patients.1 28 endothelial cell dysfunction in patients with lupus anticoagulant.11 4 However a recent Comment report failed to show that patients with SLE While our knowledge about the fibrinolytic and thrombosis have a fibrinolysislower than system has increased in the last few decades, controls.11 6 our understanding of its main role in patho­ physiology has remained at the stage of an 5. Malignancies assumption formulated in the mid 1950s, i.e. The thrombotic tendency generally observed that fibrinolysis prevents thrombotic occlu­ in malignant diseases has been attributed to sion of blood vessels and promotes vascular the release of thromboplastic substances from recanalisation.129 The persisting uncertainty the tumour.117 However, tumoural cells are depends on the fact that such a role is very dif­ known to produce fibrinolytic agents. For ficult to prove. The pathogenesis of throm­ example in vitro cultures of carcinoma of the bosis is widely multifactorial and therefore ovary have been found to produce an agent notoriously elusive. And, as regards the fac­ immunologically identical to U_PA118 while tor haemostasis, thrombotic occlusions have melanoma cells produce an activator indiffer­ been linked not only to depressed fibrinolysis entiable from t-PA.ll9 Tendency to throm­ but also to platelet hyperaggregability, defi­ bosis. notwithstanding, the presence of ciency in antithrombin III, increased levels of tumoural plasminogen activator may be fibrinogen, coagulation factor V, VII, VIII/30 explained by recent studies showing that deficiency of protein C or of its cofactor pro­ patients with malignancy have an increased tein S.l3l Finally, formation or dissolution plasma levels of t-PA inhibitor/20.121 a charac­ fibrin in the organism results from the inter­ teristic which is shared by patients with idio­ play of two complex systems, coagulation and pathic venous thrombosis (see above). fibrinolysis, each involving a vast number of activators and inhibitors. Such systems are 6. Miscellaneous conditions efficientlybuffered and do not usually decom­ In Beh�et's syndrome one third of the patients pensate following the decrease of one or more develop venous thrombosis.1 22 These patients components. This situation, unlike the action have been found to have a depressed blood of a defective enzyme on a given metabolic fibrinolysisl23.124 and to release low amounts of pathway, makes the consequence of fibrino­ plasminogen activator following vasogenic lytic disorders especially arduous to identify. stimuli as injection of DDAVP, a vasopressin The assumed role of fibrinolysis in the analogue.1 23 pathogenesis of other changes which are far In 12 cases of thrombotic thrombocyto­ more time consuming than thrombosis such as penic purpura plasminogen activator activity arteriosclerosis may well remain impossible to was found to be unmeasurably low but the prove. Astrup's hypothesis of an equilibrium levels of t-PA antigen were normal.I25 The between fibrinformation and fibrinolysis pre­ finding could be explained by the presence in vailing in the whole vascular tree32 however all 12 cases examined of an inhibitor directed appealing to our 'physiological common to t-PA and u-PA. Low levels of protein C sense' is probably destined to remain at the antigen presumably had a contributory action stage of hypothesis for the foreseeable future. to the decreased activity. A disturbing point is what one may call the Oral contraceptives are known to be associ­ 'bias of the positive result'. While embarking ated with an increased risk for thrombo- upon a study on fibrinolysis and vascular FIBRINOLYSIS AND ISCHAEMIA 165 occlusion it is unavoidable for the investigator gen activation. In: Progress in chemical fibrinoly­ to entertain a certain hope that a connection sis and thrombolysis. (Davidson JF, Rowan RM, Samama MM, Desnoyers PC eds), New York: between decreased fibrinolysis and throm­ Raven Press 1978: 167-81. 2 bosis or tendency to thrombosis is going to be Raum D, Marcus D, Alper CA, Levey R, Taylor found. Even if such expectation does not, as it PD, Starzl TE: Synthesis of human plasminogen should not, influence the results it may well by the liver. Science 1980,208: 1036-7. 3 dissuade the continuation of the study, or dis­ Wallen P, Bcrgsdorf N, Ranby M: Purification and identification of two structural variants of porcine courage publication if negative results are tissue plasminogen activators by affinity adsorp­ obtained. In this way the reviewer, faced by tion on fibrin. Biochem Biophys Acta 1982, 719: 318-28. an unbalanced body of evidence, is likely to 4 add his voice to an artificial consensus. 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Nature 1976, 261: 595-7. patients with fresh coronary occlusion133 1 0 Pandolfi M and Lantz E: Partial purification and document angiographically that i.v. adminis­ characterisation of keratokinase, the fibrinolytic tration of t-PA has a thrombolytic effect. activator of the cornea. Exp Eye Res 1979, 29: Some clinical cases are singularly convincing. 563-71. 11 For example, it is difficult not to connect two Kluft C: New prospects in the activation of fibrinoly­ sis. In: Synthetic substrates in clinical blood coag­ unusual conditions, i.e. widespread throm­ ulation assay. (Lijnen RH, Collen D, Verstreate bosis in young subjects and high plasma levels M eds), The Hagues: Martinus Nijhof Publishers , 1980: 113-22. of fibrinolyticinhibitors. 2 1 22 Indirect evidence 12 of the antithrombotic role of plasminogen Kluft C, Dooijewaard G, Emeis JJ: Role of the con­ tact system in fibrinolysis. 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