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.