J Clin Pathol: first published as 10.1136/jcp.17.5.520 on 1 September 1964. Downloaded from J. clin. Path. (1964), 17, 520 The fibrinolytic mechanism in haemostasis: A review J. L. STAFFORD From the Haematology Department, St. George's Hospital, London Circulating blood must remain fluid: if it does not, forces engaged in this endless yet beneficial conflict. the culminating thrombosis is a pathological event There is one further point to be borne in mind, with definable sequelae. It is unlikely, on teleo- intravascular thrombosis in pathology is primarily logical grounds, that such a defensive mechanism a venous phenomenon with occlusive effects on a should exist only in moments of peril. Hence a moving stream, whereas the minor wear-and-tear general if tacit assumption has developed that thrombotic episodes acknowledged to be incidental clotting is not an episodic but a continuous process to everyday life occur largely in the capillary bed, (Macfarlane, 1945; Roos, 1957) which normally is parts of which, intermittently, may be shunted out never allowed to progress to a physical end-point of the general circulation and thus become stagnant. unless vascular integrity is in jeopardy. But if the The physiological significance of fibrinogen maintenance of fluidity, in circumstances which appears to depend solely on its polymerization to permit the possibility of clotting, is a physiological fibrin followed by gelation and subsequent con- necessity, then one must conceive a homeostatic densation (clot retraction). This chain reaction is system in which equilibrium is maintained by the governed, and the fluidity of blood maintained, by balance of equal yet opposing forces (Astrup, 1962). two proteolytic enzymes acting in opposition, It is in this context of a continuous physiological thrombin and plasmin, each derived from a naturallycopyright. requirement, as distinct from episodic pathological circulating plasma precursor prothrombin or changes, that fibrinolysis must bejudged. Moreover, plasminogen (Figure 1). we are dealing with a biological system dependent Study of the clinical effects of enhanced poly- upon protein 'activity' which can be expressed only merization is relatively simple because a clot can be as a resultant of these balanced opposing forces: seen and felt. The opposite is not so, for fibrinogeno- the function of single protein moieties cannot be lysis in vivo (degradation of fibrinogen while still in measured in isolation. solution in contrast to destruction of fibrin) can It is important to appreciate that haemostasis is only be assessed in terms of haemostatic failure:http://jcp.bmj.com/ governed, also, by the effects of both time and minimal enhancement is probably a natural event motion: in physiology, the persistence of free flow for which there is some evidence of diurnal variation must directly influence the sequence of events. (Fearnley, Balmforth, and Fearnley, 1957), but Study in vitro can never simulate the interplay of grades of severity are difficult to define until absolute on September 27, 2021 by guest. Protected * RCALU\~:~ PLATE LETS $prothrombin .... ...~~~~~~.:.. .....clo IBRINOGEN ~~~~~~~~~~retraction FIG. 1. Intrinsic haemostasis. The chain reaction of PLASMIN fibrinogen conversion is influenced by calcium andplatelets, and governed by the opposing effects of thrombin and plasminogen plasmin. 520 J Clin Pathol: first published as 10.1136/jcp.17.5.520 on 1 September 1964. Downloaded from The fibrinolytic mechanism in haemostasis: A review 521 reduction in circulating fibrinogen concentration not prolong the half-life although manifestly becomes measureable. Such excessive fibrinolysis altering intrinsic coagulation sequences. can, however, be observed in two different patho- logical contexts: enhancement of the lytic mechanism THE VASCULAR MILIEU may lead to systemic defibrination and thence to bleeding or, in contrast, actual thrombosis may be Whilst it is convenient to discuss fibrinolysis or restricted and even, in suitable circumstances, coagulation as apparently distinct processes, it is corrected. axiomatic that the physiological significance of the one mechanism can be judged only in terms of the SURVIVAL OF FIBRINOGEN other: and any apparent pathological enhancement of either mechanism must also be viewed in the For the purpose of this review it has been necessary possible context of simultaneous retardation of the to assume that the elaboration of fibrin and the other. process of its dissolution occur constantly, any such Figure 2 shows that each intrinsic system is conception implying a perpetual consumption of the governed by the interaction of globulins in biological principal substrate. The biological half-life of solution and these, in turn, are influenced by their fibrinogen seems to be shorter than that of most relative molecular concentration and their proximity plasma proteins (this may also be true of pro- to metallic ions and to cell and vessel surfaces. In thrombin, factors V, VIII, and less readily assayable certain circumstances, to these features must be clotting proteins); the fibrinogen half-life has been added the effect of flow rate and, should fibrinogen estimated in man to be four to six days (Madden ever polymerize, the apparently specific yet selective and Gould, 1952; Hammond and Verel, 1959) and attraction of the surface so formed for some of the somewhat less in dogs (Lewis, Ferguson, and moieties taking part, whereby their local effect is Schoenfeld, 1961) and rabbits (Cohen, Holloway, concentrated. Matthews, and McFarlane, 1956). This method of assessment may not be valid, however, as isotopic FACTORS TAKING PART copyright. labelling of fibrinogen and its re-introduction into the blood stream demonstrably leads to sequestra- Plasmin and thrombin are formed whenever tion: moreover, Lewis et al. (1961) have shown that impairment of vascular integrity permits the entry systemic administration of coumarin or heparin does of pre-formed tissue activators, 'extrinsic activation'. Vessel wall source of activator 9plasminogen http://jcp.bmj.com/ * Fibrinogen-rich, cell-poor plasmatic 'clear zone'. ........................................................................................................................................................ ............................................ *. .. A.., *:*.............................*.l.........*............, Physiological Lamin&irflow I......Axial~~~~~~~~~ccelll distribution.:i t i u i n ...................................:..:, ............... ........... r::..::.. ....... ::::::.x......{ ................................................................................. .................... ................................................... free. flow. ......................... I Platelet-rich intermediate zone I t -. I on September 27, 2021 by guest. Protected Cell and vessel Variable concentrations Lipoprotein l. surface adsorption of clotting and lytic macromolecules of calcium ions globulin factors I WJmhi .......NRWX - Specific surface adsorption IIIIIIIIIII B Pathological of interacting proteins FI.RIN Platelet surface adherence POLY ~~~~~~........occlusion Endothelial disease ..n 1111 I Extrinsic, tissue, E m~ activating factors FIG. 2. The effect ofenvironment on the haemostatic equilibrium. A A theoretical venule or capillary, free from the influence of turbulence or pulsatile flow. B A similar sized vessel in w,iich occlusion, endothelial disease, or encroachment by tissue factors may alter the floiv pattern. J Clin Pathol: first published as 10.1136/jcp.17.5.520 on 1 September 1964. Downloaded from 522 J. L. Stafford If factors normally in equilibriur n within the lysis, or influence the stability of the fibrinogen vascular tree are in any way stimul; ated, 'intrinsic molecule during its polymerization. These include activation', this is assumed to be iniitiated by the ionic calcium, the globulin fibrin-stabilizing factor so-called contact factors (XII anId XI) when (Lorand, 1961; Laki, 1962) and the ubiquitous thrombin is formed, and by the relea,se of activator platelets (Figure 4). Each of these acts upon clot substances from the vessel wall when(ever plasmino- generation or the formation and function of plasmin; gen is to be converted to plasmin. each may also influence the vessel wall in its Intrinsic activation of fibrinolysis or coagulation release of plasminogen activator or in its association each comprises three preparatory phaases leading to with the contact factors. They represent the lowest the establishment of potent proteolyt;ic enzymes: in common multiples of the coagulation-fibrinolysin a moving stream this may be ephenneral but with equation. stagnation the effect can be explosive and, through Any constant interplay between lysis and co- autocatalysis, progressive within the Ilimits imposed agulation must employ either a retarding mechanism only by the local concentration of precursors which halts fibrinogen polymerization before the (Figure 3). It must be emphasized that this discussion complexed molecules come out of solution- takes no account of any encroaci hrment of the degradation of fibrin monomer-or means whereby circulation by tissue fluids, this being relevant only the fibrin polymer is immediately degraded before it in the pathological context of vasccular damage. becomes large enough to attract platelet adherence There is no convincing evidence to implicate or to obstruct flow. These events, which are occurring extrinsic factors in natural intravas scular homeo-