Subarachnoid haemorrhage due to a ruptured cerebral aneurysm is a dramatic event in neuro-surgery and one of the most destructive. Its management is complicated by the risks of rebleeding and cerebral vasospasm and their sequelae. Rebleeding and vasospasm rarely occur before three days after the primary bleed.'2 Angiographic vasospasm is seen most often 10 to 17 days after bleeding.3 Because of the brain's vulnerability during spasm many surgeons prefer to wait until two weeks after the primary bleed to obliterate the aneurysm.4 Sano and Saito5 reported fatal postoperative vasospasm in patients operated upon on days 4 and 7 after a haemorrhage. However, the 'spasm period' coincides with the time when rebleeding is most likely. The incidence of rebleeding is highest at the end of the first week and at the beginning of the second after the primary bleed, and the mortality after the first recurrence is reported to be between 43 % and 64 %. 6 Thus most surgeons accept
healthy menstruation the blood which is dis-charged does not coagulate; in the irregular or unhealthy it does....' This observation on the non-coagulability of menstrual blood was made by John Hunter in 1794.1 A similar observation was made by Bell in 19122 on the composition of menstrual blood found in patients with haematocolpos.
Fibrinolysis inhibitors are of value in the control of severe overdosage with fibrinolytic agents. The discussion so far has been mainly on the use of fibrinolytic inhibitors to reduce or arrest local bleeding in the absence of an increase in systemic fibrinolytic activity. There are still other clinical applications of antifibrinolytic drugs that are worth mentioning, since furthei research in these areas may prove rewarding.
Most human tissues contain fibrinolytic activators. The alimentary tract organs, however, were not considered to be a site of importance and were not included in a comprehensive survey of human necropsy tissues studied by Albrechtsen.1 But since Cox, Poller, and Thomson2 found local organ fibrinolysis in the stomach and free plasmin in gastric vein blood there has been much interest in the possible role of fibrinolysis in gastrointestinal bleeding. There is also some evidence that similar influences might contribute to bleeding at other sites in the alimentary tract. complementary studies from other centres using a variety of different techniques and approaches.4-8 In a subsequent study from Manchester9 the fibrinolytic potential of the stomach was found in all subjects. Stimulation was applied to the stomach wall by controlled manipulation at laparotomy. There was a gradation of activity. Fig. 1 shows the shortening of the euglobulin lysis time in serial
Blood plasma contains a number of proteins capable of inhibiting the activation of plasminogen and the action of plasmin. Except for urokinase, the nature and action of plasminogen inhibitors are not yet fully understood. Inhibitors of plasmin, on the other hand, are fairly well defined and their clinical significance recognised. Although there are a number of plasmin inhibitors in plasma-for example, onl-antitrypsin, inter-cr-inhibitor, antithrombin III, and Cl-inactivator-only two, 0Y2-antiplasmin and 0c2-macroglobulin, appear to be important in vivo. 0X2-Antiplasmin (see D Collen at page 24) is a specific inhibitor of plasmin which binds the enzyme instantly and irreversibly in a stoichiometric manner (1:1). Its molar concentration in plasma is about 65% of that of plasminogen. Thus on complete activation of plasminogen in plasma only two-thirds of the resulting plasmin is inactivated by oC2-antiplasmin. The remainder is taken care of primarily by 0X2-macroglobulin. This inhibitor differs greatly from OY2-antiplasmin. It is present in plasma in a much higher concentration, has very broad specificity (binds most of the proteases), and has a progressive action. It is generally accepted that the o2-macroglobulin-enzyme complex is formed in two stages-firstly, there is a proteolytic cleavage of M2-macroglobulin by the enzyme and, secondly, a conformational change of the modified inhibitor which traps the enzyme. Owing to steric hindrance, access
When tissue is damaged one reaction is the initiation of the haemostatic mechanism. This involves initially platelet interaction with the damaged vessel walls, platelet aggregation and release at the sites of damage, and subsequent local fibrin formation due to the activation of the coagulation cascade after the 'release' of various factors from the activated platelets -namely, Ca++ ions and phospholipid (PF3). In trauma or disease in man the injury to tissue directly and indirectly can invoke a similar mechanism and, if the stimulus is very strong, the normally protective haemostatic mechanism is activated to such an extent that serious destruction of platelets and significant fibrin formation may occur both at the site of injury and also in normal tissue. In order to limit the spread of fibrin the fibrinolytic mechanism is activated along with or as a consequence of fibrin formation. This 'pathological' activation of the physiological haemostatic process has been called intravascular coagulation and fibrinolysis (ICF), a term which is considered by some to be synonymous with the diffuse intravascular coagulation syndrome (DIC). Either term has been used to define the explosive and sometimes fatal activation of the platelet/coagulation sequence as a complication of infections, malignancy, trauma, and immune complex disease in man.1 A similar sequence may also complicate abnormal events in pregnancyfor example, abruptio placentae and septic abortion. In each instance the platelet, coagulation, fibrinolysis activation is the sequel to tissue damage or the introduction into the blood of a 'trigger'. Experimentally various triggers have been found to produce ICF/DIC in animals which is almost identical to that seen as a complication of disease in man.2 'Direct' triggers in the form of tissue thromboplastin or snake venoms have been described which activate the coagulation cascade directly.1 'Indirect' triggers, endotoxin and immune complexes, require an interaction with coagulation proteins (XII) or platelets/white cells before activating the platelet/ fibrin interaction. Further these indirect triggers may also first produce tissue or vessel wall damage, invoking a direct activation as well as an indirect effect. While the ICF/DIC syndrome is considered as a separate entity from conventional forms of arterial and venous thrombosis the pathophysiology of both is similar and may represent only a variable expression of the degree of activation.3 Whatever the trigger the sequence of events leads to platelet activation in the vessel wall or in the circulating blood leading to destruction of circulating platelets and eventual thrombocytopenia. If the stimulus is sufficient local or diffuse activation of the coagulation cascade (directly or indirectly) leads to thrombin formation or the conversion of fibrinogen to fibrin. The resultant reaction may be mild and detectable only by laboratory tests or may be so strong that both platelets and coagulation factors are consumed, leading to a tendency to abnormal bleeding (consumption coagulopathy) or to the widespread dissemination of fibrin with significant irreversible tissue damage (DIC) (Fig. 1). An acute stimulus (amniotic fluid embolism) can produce this reaction in minutes while a chronic one (for example, dead fetus syndrome, malignancy) the evolution of change may take some weeks.
The growth of a tumour, like that of any normal tissue structure, depends on its vascular supply. Malignant tumours possess coagulative properties that cause deposition of fibrin around them. Such fibrin is a necessary matrix for proliferating tumour vessels. As in wound repair, old residual fibrin must afterwards be removed. This is done by the fibrinolytic system which, in tumours, is initiated by a tumour-plasminogen activator. This enzyme has recently attracted increasing attention.
Severe generalised haemorrhage associated with plasma proteolytic activity after thoracic surgery, operations for hyperplasia or carcinoma of the prostate, gastrointestinal or pancreatic resection, and other operations was reported in the early 1950s.1-3 Such plasma proteolytic activity is usually part of a disseminated intravascular coagulation syndrome. Sometimes, however, the local fibrinolytic activity in the area of the operation or trauma disturbs haemostasis and wound healing. This activity is not usually pathological but is a physiological one in different tissues and body fluids.
The coagulation and fibrinolytic enzyme systems oppose each other in the haemostatic process. Coagulation occurs, of necessity, rapidly and explosively so that a site of vessel damage causing blood loss can be rapidly sealed. The fibrinolytic process, on the other hand, serves as a repair system to remove fibrin deposits which might otherwise cause permanent vascular occlusion. This must occur slowly so that vascular repair and re-endothelialisation can take place before the fibrin is removed. Therefore there is an elaborate system of inhibitors of plasminogen activator and plasmin in the circulation to prevent hyperplasminaemia and the indiscriminate digestion of fibrinogen. Additionally, thrombolysis is determined by the binding and spatial relationship between fibrin, Lys-plasminogen, and activator. In this way selective fibrin digestion can occur without systemic proteolytic activity. The structure of fibrin is also important in determining the rate of fibrinolysis. In cross-linked fibrin the normally susceptible alpha-chain has become polymerised to alpha-polymer, which is inaccessible and resistant to plasmin action.' In this situation the beta-chain is digested first and the polymerised fibrin is much more robust than the non-crosslinked material.2 There are two major situations where the healthy physiological balance between coagulation and fibrinolysis may be lost, leading to a need for antifibrinolytic therapy. Firstly, unopposed fibrinolytic activity may be excessive so that forming or formed fibrin is digested by plasmin before a firm haemostatic plug is produced. Secondly, in the presence of a coagulation defect such as haemophilia the fibrin may be so inadequate in amount that physiological fibrinolytic activity may be sufficient to start haemorrhage. Several causes, however, may operate together to cause haemorrhage. For instance, in the presence of defective small vessel constriction or low-grade disseminated intravascular coagulation the action of the normal fibrinolytic response may be sufficient to initiate haemorrhage. In this review I outline the mechanism of action of the antifibrinolytic drugs and then consider the clinical situations in which they might be expected to be beneficial. Others will discuss the pharmacology and detailed clinical indications for the drug.
The fibrinolytic enzyme system is designed to release the protease plasmin from its inactive precursor plasminogen and to localise its action to the site of its physiological substrate fibrin. The basic components of the system are, therefore, plasminogen and plasmin; agents, collectively termed plasminogen activators, which convert plasminogen to plasmin; and inhibitors of activators or plasmin which ensure that proteolysis of other susceptible proteins does not take place. This review considers the structure and properties of plasminogen and plasmin and the processes involved in the activation of plasminogen, and outlines their relationship to recent concepts of thrombolysis
In a systematic search for a substance with antifibrinolytic properties Okamoto and his group in Japan found that several mercapto-and aminocarbonic acids were active.Of these substances epsilon-aminocaproic acid (EACA) had the strongest antifibrinolytic effect.1 2 The Japanese workers described it as a plasmin inhibitor in vitro and useful in inhibiting proteolytic enzymes in vivo.They gave EACA in a dose of 10-20 g a day by mouth or intravenously to over 100 patients and observed no toxic effects.Their investigation did not include any metabolic studies.EACA has since been widely used and its mode of action and pharmacokinetics intensively studied.In a continued search for more potent antifibrinolytic components p-aminomethyl cyclohexane ,arboxylic acid (AMCHA) was found to be more potent than EACA.3This compound contains two stereoisomers.Independently Melander et al.4 and Okamoto et al.5 found that only the trans-form was antifibrinolytically active.The antifibrinolytically active form was called tranexamic acid (AMCA).It is 6-10 times stronger than EACA and is now used more widely.Its pharmacokinetics have been the subject of several studies.This paper surveys the pharmacology and toxicology of EACA and AMCA. PharmacokineticsAMINOCAPROIC ACID (EACA)
A common symptom of myasthenia gravis is eyelid ptosis. Often, the edrophonium test is negative, particularly in ocular myasthenia gravis. Myasthenic weakness is often improved by cold. We applied ice packs to the eye in 10 myasthenic patients and 7 disease controls. Eight of 10 patients with myasthenia gravis improved, whereas none of the controls improved. The ice pack test is useful in the diagnosis of myasthenia gravis.
Many proteases have been described as activators of plasminogen. To simplify and limit my discussion I have divided them into the following groups. (1) Primary activators-those which by their location, mode of release, and/or affinity for other components of the fibrinolytic reaction seem specially adapted for intravascular fibrinolysis. This group consists of endothelial activator; blood activator; cadaveric activator; urokinase; and, perhaps, leucoprotease. (2) Intermediate activators-those with normally an extravascular iole in fibrinolysis associated with pathophysiological mechanisms such as inflammation, healing, new growth, and immune reactions. The group includes proteases from leucocytes; from epithelial cells in sites such as cornea and cervix uteri; and from cells in culture, both normal and malignant. (3) Non-specific activators-proteases which do not normally play a part in the digestion of fibrin but which can in vitro activate plasminogen. Trypsin is an example of these. (4) Heterologous activators such as streptokinase.
a number of common features.Fig. 1 shows the major features of a sequence of digestive reactions and products formed withwhich most of theseworkers would now agree.The conservation of both the NH2-terminal amino-acids1617 of the Ao-chains suggests that the initial lysis of the Aa-chain takes place at their carboxy ends.Peptides of about 40 000 molecular weight are released rather rapidly, leaving the NH2-terminal remnant of the Ao-chain disulphide bonded to intact BP and y chains.The next reaction involves the removal of peptides 10 copyright.
Fibrinolysis is a basic defence mechanism of the organism designed to control the deposition of fibrin in the vascular system and elsewhere. This fibrin polymer deposition is regulated by the fibrinolytic system which acts on the insoluble protein and by splitting a limited number of peptide bonds renders it soluble.
Cold-reactive lymphocytotoxic antibodies are present in the serum of most patients with systemic lupus erythematosus (SLE) (Mittal et al., 1970; Terasaki et al., 1970). They appear to be equally cytotoxic for autologous and heterologous lymphocytes (Stastny and Ziff, 1971). Studies of the nature of these antibodies showed that their cytotoxic effect is temperature-dependent and maximal at 15°C, that their immunoglobulin class is IgM, and that they are equally reactive with T and B lymphocytes (Winfield et al., 1975a). Studies of the clinical significance of cold-reactive lymphocytotoxic antibodies in SLE have shown a consistent association with neuropsychiatric complications (Butler et al., 1972; Bluestein and Zvaifier, 1976; Bresnihan et al., 1977b). In other respects, however, clinical studies have been inconclusive, which may partly be related to the retrospective nature of most series. Previous studies have suggested an association between cold-reactive lymphocytotoxic antibodies and lymphopenia (Winfield et al., 1975b; Utsinger, 1976). A detailed prospective clinical analysis of SLE began at Hammersmith Hospital in 1973. In all, 50 patients have been investigated, and their clinical features have been described elsewhere (Grigor et al., 1978). This report relates the clinical features in these patients to the presence of lymphocytotoxic antibodies.
The diversity of immunoglobulin (Ig) molecules and antigen-specific receptors on lymphoid cells, the activation processes during the immune response, the clonal propagation of cells stimulated by antigens, and the sophisticated control mechanisms in the immune system are unparalleled in other biological systems (see A. R. Williamson at page 76, and P. C. L. Beverley at page 59). The emergence of early lymphoid precursors is nevertheless likely to be governed by developmental programmes similar to those observed in haemopoietic precursors and other differentiating cell types. The primary purpose of this paper is to summarise some of the salient observations about the development of the earliest identifiable human lymphoid precursors.
The discovery of the LE cell phenomenon (Hargraves et al., 1948) has had particularly far-reaching effects beyond the immediate clinical field of rheumatology. It was, firstly, a timely spur urging research on the underlying causes of the systemic diseases of connective tissue into the then untrodden immunological paths that are now highways accommodating an ever-increasing army of investigators with ever-increasing expectations. It was also the seed (to change the metaphor) that engendered in the minds of those connected with laboratory investigation of patients the conviction that the more precisely the specificity of autoantibodies such as the LE cell factor can be defined the greater their discriminant value for diagnosis and prognosis and the better the chance of gaining insight into the underlying immunopathology, not to say aetiology. The extent to which these expectations about the role of anti-nuclear antibodies have been realised in the intervening decades is ripe for consideration.
I will concentrate on recent work that has improved our understanding of the earliest phases of lymphocyte maturation, since this work provides a basis for the analysis of various forms of immunodeficiency. However, the reasons for interest in primary lymphocyte differentiation extend beyond a consideration of immunodeficiency. According to the clonal selection theory, which has received considerable support from experimental work, the broad range of foreign antigens which may enter the body are recognised by a repertoire of lymphocytes, each specific for a particular antigen. There is evidence that this repertoire of lymphocytes is acquired during the primary differentiation of lymphocytes that occurs in ontogeny. In addition, although the mechanisms of tolerance to 'self' antigens are poorly understood studies on lymphocyte ontogeny may provide important clues. Lymphocytes, like other blood cells, belong to a renewal system and production of new lymphocytes is not confined to ontogeny. Hence, in discussing the primary differentiation of lymphocytes, sites of lymphocyte production in the adult must also be considered.
