J. clin. Path., 23, Suppl. (Roy. Coll. Path.), 4, 102-109 Coagulation and fibrinolysis after injury J Clin Pathol: first published as 10.1136/jcp.s3-4.1.102 on 1 January 1970. Downloaded from P. T. FLUTE From King's College Hospital Medical School, London The direct and indirect effects of injury are to The reactions proceed in a stepwise manner. Each stimulate coagulation and fibrinolysis, almost enzyme, distinguished for description from its immediately, in direct proportion to the severity inactive precursor by the suffix a, has for its sub- of the trauma, and with effects which are both strate the next proenzyme in the sequence. The local and remote from the site of damage. A original proposals have been modified as addi- series ofblood changes follows in quick succession tional information has become available based on and may lead to a phase of apparent hypocoagul- studies with individual factors purified copyright. by ability and reduced fibrinolysis, although even chemical and immunological methods and no at this stage there is evidence of continued doubt more changes are to come (Davie, Hougie, stimulation of both systems. It is important to and Lundblad, 1969). examine the mechanism of these changes in order Pathways of stimulation which are intrinsic to understand, and to be prepared to counter, and extrinsic to the blood have been recognized. the sudden haemostatic failure or thrombo- Contact of blood with a foreign surface initiates embolism which may result. the intrinsic pathway by conversion of Hageman The accelerated blood clotting after injury is factor (XII) to an enzyme (XIIa). In turn factorshttp://jcp.bmj.com/ easy to see. William Hewson, describing the XI and IX are activated. Activated Christmas killing of sheep in 1772, observed that 'the blood factor (IXa) can convert factor X to Xa and this which issued last coagulated first'. Stimulation reaction proceeds faster when IXa forms a dis- of fibrinolysis is less readily appreciated but the sociable complex with antihaemophilic globulin unusually fluid character of the blood at necropsy (VIII), phospholipid, and calcium (Hougie, in cases of violent death was commented on by and John Hunter Morgagni (1769) by (1794). on October 3, 2021 by guest. Protected XI] CONTACT The frequent succession of a 'positive' phase of HAEANm/ hypercoagulability and a 'negative' phase of hypocoagulability was described by Wooldridge XI in a series of papers beginning in 1886. P.TA XlIl To examine the process further it will be neces- lX sary to outline current concepts of blood coagula- CHRISTMAS XIa tion and fibrinolysis before describing the changes x > yTISSUE observed, discussing their mechanism, and their i possible significance. STUART PROTHROMBIN Xa Blood Coagulation FIBRI-_G Ila THROMBIN In 1964 it was proposed that the conversion of the soluble protein fibrinogen to insoluble fibrin FIBRIN was tne cuimination ot a cascauce vmaciariane, 1964) or waterfall (Davie and Ratnoff, 1964) of proenzyme to enzyme transformations (Fig. 1). Fig. 1 A hypothetical scheme ofblood coagulation. Coagulation andfibrinolysis after injury 103 Denson, and Biggs, 1967). Foreign surfaces are with the lysosomes (Lack and Ali, 1964), and their J Clin Pathol: first published as 10.1136/jcp.s3-4.1.102 on 1 January 1970. Downloaded from known to include silica compounds, ellagic acid, entry into the blood in states of tissue damage sodium stearate, uric acid, human skin, and provides an analogy for the extrinsic pathway of collagen but the precise circumstances under blood coagulation. A soluble activator of plas- which such activation occurs in vivo are unknown. minogen may be derived directly from vascular The particular physical properties which give endothelial cells (Warren, 1964) or generated in coagulant activity to a surface are also undefined, the blood. Activator is formed when human although the importance of water wettability and plasma at acid pH and reduced ionic strength is surface negative charge have been postulated incubated with kaolin, an effect which is strikingly (Nossel, Rubin, Drillings, and Hsieh, 1968). reduced in the absence of Hageman factor The extrinsic pathway, independent of factors (Niewiarowski and Prou-Wartelle, 1959; Iatridis VIII, IX, XI, and XII, is stimulated when co- and Ferguson, 1961). It has also been shown that agulants from tissue microsomes enter the blood some Hageman factor-deficient subjects fail to to form a complex with factor VII and calcium, respond to physical exertion or venous occlusion also for the activation of factor X. by the normal increase in circulating activator A complex ofXa, V, phospholipid, and calcium (Iatridis, latridis, and Ferguson, 1966). However, converts prothrombin to thrombin, an enzyme Hageman factor does not appear to act directly which splits specific fibrinopeptides from fibrino- but to catalyse the formation of a plasminogen gen to convert it to fibrin (Laki and Gladner, activator from a precursor, distinguishable from 1964). Thrombin has other important roles in the other known substrates of Hageman factor haemostasis. Trace amounts activate fibrin- (Ogston, Ogston, Ratnoff, and Forbes, 1969). stabilizing factor (XIII) (Laki and Gladner, 1964), This is analogous to the intrinsic mechanism of provoke the platelet aggregation, and release blood coagulation. reactions which provide phospholipid catalysts In purified solution plasmin digests many of the for coagulation and other biologically active coagulation factors, including fibrinogen, ac- materials (Hellem and Stormorken, 1969), and tivates certain components of complement, convert factor VIII (Rapaport, Schiffman, Patch, inactivates peptide hormones, hydrolyses im- and Ames, 1963) and factor V (Ware and Seegers, munoglobulins, and digests even collagen. In 1948) to more reactive forms. Thus factor VIII plasma, however, a great excess of antiplasmins previously exposed to thrombin will increase the normally prevents the expression of all proteolyticcopyright. rate of action of IXa on factor X some 20 times. activities other than the digestion of fibrin. It has Large amounts of thrombin destroy factor VIII been suggested that this specificity for fibrin is and factor V which are usually almost completely conferred by the site of action of the activator. removed during coagulation of human blood in Plasmin formed in the presence of fibrin appears the test tube. to be protected from antiplasmins which would The relative importance of the intrinsic and otherwise be completely inhibitory (Sherry, 1968). extrinsic systems is an area of considerable doubt. Alternatively, circulating plasmin-antiplasmin Defects of either system alone may result in an complexes may dissociate in the presence of fibrin http://jcp.bmj.com/ increased tendency to haemorrhage while neither (Ambrus and Markus, 1960). In both hypotheses, clearly protects against thrombosis. The patient which are not mutually exclusive, the presence of in whom factor XII was discovered, John Hage- man, recently died of pulmonary embolism after a fracture. It is difficult to envisage circumstances where damage to tissues could stimulate one CONTACT pathway without affecting the other, and the on October 3, 2021 by guest. Protected distinction loses some of its importance now that Xii similar intrinsic and extrinsic stimuli have been recognized for fibrinolysis. Xlla x TISSUE Blood Fibrinolysis ACTIVATOR Fibrinolytic activity depends on plasmin, a protease of broad specificity, which can be generated from plasminogen, a globulin with a PLASMINOGEN- >- PLASMIN distribution in the body similar to that of fibrino- gen. A variety of activators (Fig. 2) achieve the conversion by opening a specific argininyl- FIBRIN - --- FIBRIN valyl bond in the plasminogen molecule (Sum- DEGRADATION maria, Hsieh, and Robbins, 1967). PRODUCTS Insoluble activators of plasminogen are found in most body tissues (Albrechtsen, 1957)associated Fig. 2 A hypothetical scheme ofbloodfibrinolysis. P. T. Flute 104 fibrin determines any proteolytic action ofplasmin (Wessler and Yin, 1968a). The intravenous in-J Clin Pathol: first published as 10.1136/jcp.s3-4.1.102 on 1 January 1970. Downloaded from at all in the very inhibitory environment of fusion of normal human serum, but not of plasma plasma. protected from surface contact, induces in rabbits a transient hypercoagulable state during which massive thrombosis develops in large vascular segments containing stagnant blood. The pheno- Blood Coagulation after Injury menon is still observed when the static blood is far removed from the site of infusion and the Although the natural stimulus for coagulation production of thrombi has been shown to depend and for fibrinolysis is not known with any pre- on the presence in an area of stasis of activated cision it is clear that both systems respond to factors, namely, XIIa, XIa, and IXa. Thrombosis similar intrinsic and extrinsic stimuli in vitro and is not produced by stasis alone, or by activated the same is likely to be true in vivo. There are many factors alone, but by the combination of the two. examples of human disease where tissue damage In addition suggestive evidence has been obtained can be shown to stimulate both systems. After in animals that increases in factor VIII may pre- injury direct tissue damage, damage to the dispose to, though not initiate, thrombosis cellular elements ofthe blood, shock and haemor- (Penick, Dejanov, Reddick, and Roberts, 1966). rhage, hypoxia, infection, and fat embolism It is important that the factors are present