thrombosis and embolism injury - from bmj and acp · thrombosis is frequent in injured patients. it...

J. clin. Path., 23, Suppl. (Roy. Coll. Path.), 4, 86-101

Thrombosis and embolism after injury

S. SEVITTFrom the Birmingham Accident Hospital

Thrombosis is frequent in injured patients. Ittakes different forms, and at least one of them,deep vein thrombosis in the lower limbs, is acommon cause of morbidity and death throughembolic detachment. The different kinds may be

Fig. 1 Platelet-fibrin 'building block' of enlargingthrombi. The pale zone is composed of closely packedplatelets and is surrounded by a dark rim offibrin.This extends into a peripheral network trapping redcells and leucocytes. PTAH x 240.

classified as follows, namely, local thrombosis,deep vein thrombosis, pulmonary microem-bolism, glomerular microthrombosis, allied tothe Schwartzman reaction, occasional cases ofarterial thrombosis, and rarely, abacterial vege-tative endocarditis.Thrombi form in flowing blood and are

layered structures, unlike blood clots which formin static blood. They contain platelets, fibrin,red cells, and leucocytes, or a variable mixture,the differences depending on size, genesis, age,and venous or arterial location; but whatever theorigin, the building blocks of enlarging thrombiare closely packed clumps of platelets withnarrow fibrin borders (Fig. 1). Two main pro-cesses are involved, namely, coagulation andplatelet aggregation. These are interlinked andlocal release of thrombin is probably the keyfactor; thrombin promotes platelet clumping at alow concentration and fibrin formation at a higherconcentration. Further, the release of substancesfrom platelets can set in motion the coagulationprocess.

Local Thrombosis and Haemostasis

Thrombosis is frequent as a direct response toinjury. In burned skin, for example, small venousthrombi may become prominent in the subdermisand subcutaneous tissue. Generally, they consistof platelet masses, many applied to the intima(Fig. 2), strands of fibrin, red cells, and someleucocytes. Usually they become visible a day ortwo after burning though they probably beginearlier, during the period of burn oedema. Localinflammatory changes may be visible in the veinwall. This thrombotic or thrombophlebiticcondition has to be distinguished from that ofstasis in venules and capillaries of the heat-affected dermis, which is the result of gross and

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Fig. 2 Small thrombosed vein in the deep dermisof burned skin. Burn three days previoutsly. Note thepale platelet clumps, including an extensive rim ofplatelets lining the intima, below and to the right.PTAH x 480.

rapid permeability of the minute vessels (Sevitt,1949). Histologically, stasis is manifest as dis-tended vessels packed with red cells and withlittle or no fibrin or platelets, at least as seen bylight microscopy.Thrombosis also occurs locally after other

kinds of injury, including mechanical andelectrical trauma; and direct trauma to endo-thelium is probably the cause after venepunctureor catheterization. An unusual form is thrombosisof the axillary or subclavian vein which is said tobe due to its nipping between the clavicle and thefirst rib.The process following direct trauma is

similar to that found in haemostasis. In both,platelet masses accumulate on the injured intimaand later fibrin forms. The event is probablytriggered off by the exposure of subendothelialareas to the flowing blood. Platelets adhere to thedamaged area with subsequent build up of a multi-layered mass of clumped platelets. The adhesionphenomenon is probably related to the formationof a fine film of adsorbed plasma protein as

found when platelets adhere to glass, whilst theplatelet clumping or aggregation is due to theexposure of basement membrane or collagenfibres. Collagen is well established as a potentaggregating substance. The adhesion and sub-

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sequent clumping of platelets are the basic initialprocesses in the cessation of bleeding and inthrombosis of vessels injured in continuity. Theprocess was first observed in vivo by Jones in 1851who noted that the injured vessels becameblocked 'by a mass composed apparently ofcolourless corpuscles and fibrin'. This was con-firmed by Zahn (1875). The role of plateletswas identified by Bizzozero (1886) and Welch(1899), who also found that platelets accumulatedbefore leucocytes and preceded the formation offibrin. Thus, the basic processes have been knownfor a hundred years or more.Four stages may be distinguished, namely,

platelet adherence, platelet aggregation. plateletdegranulation, and platelet disruption or rhexis.The first and second are probably reversible, butthe latter two are associated with the formationof fibrin and the transformation of the plateletplug to a mixed fibrin-red-cell-leucocyte mass andextension of the thrombus.The fine structure can be related to biochemical

processes set in motion by the clumping platelets.Electron microscopy (French, 1965; Poole, 1964)has shown that soon after injury platelets adhereto the sites of defective endothelium, at firstloosely, but as they increase in number they swelland become closely packed into a mosaic andcome to form obstructive masses. Parts maybreak off intermittently and become embolic.These are the 'white bodies' demonstrated bycine microphotography in vessels around injuredareas (Robb, 1963) and burned skin, and observedby Jones (1851) many years ago. In small veins,they probably contribute to the phenomenon ofpulmonary microembolism (vide infra).At this stage, the platelet membranes are in-

tact. Interspaces about 200 A wide separateadjoining cells, but they are occupied by anamorphous material with fine bridges betweenthe platelet surfaces. This probably containsfibrinogen. Platelet granules and other organellesare first unaltered and fibrin is absent. This isprobably a reversible stage, individual plateletshaving the possibility of returning to the bloodstream. Then, platelet degranulation occurs, atfirst at the edges of the clump, and this probablysets in motion a local biochemical chain processwhich produces further platelet aggregation anddegranulation, culminating in the formation offibrin and the disruption of the platelets. In thedegranulation process, platelet granules andmitochondria are lost, though the vesicles remain;the manner by which the granules discharge theircontents is uncertain, though local fusion betweenthe boundary membranes of platelets andgranules has been found, which suggests a directdischarge to the exterior (Poole, 1964). Degranu-lation is believed to be the morphological ex-pression of the platelet-release phenomenonoriginally described by Grette (1962), wherebyadenosine diphosphate (ADP), serotonin, cate-cholamines, platelet factor 3 (PF3), platelet

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factor 4 (PF4), and other substances are released.Adenosine diphosphate and adrenaline are nowknown to promote platelet aggregation, oneenhancing the effect of the other. Platelet factors3 and 4 are known to be capable of triggering theextrinsic and intrinsic coagulation mechanismsrespectively, thereby releasing thrombin, and thiscan produce further clumping of platelets andtheir degranulation as well as the transformationof fibrinogen to fibrin. Notwithstanding recentstudies, much of the intermediary processes isnot fully understood.

After degranulation the platelets become vir-tually empty sacs within intact membranes, butthey remain distinct for a time. Later they dis-integrate. Fine fibrin strands appear, first at theedges of the platelet clump where degranulationbegan and where the platelets are in contact withthe plasma, and then around and within thehaemostatic or thrombotic plug. The plug formswithin a few minutes of injury, and degranulationand fibrin formation are present by 30 minutes.However, accounts differ and some workersreport a quicker sequence of events. Within a fewhours, fibrin considerably increases and many redcells are now present (Weiner and Spiro, 1962).By 24 hours, most platelets have disintegratedand few are recognizable in the oldest part of thethrombus, though new clumps may have appearedin adjoining areas. This is probably the ex-planation of the appearance in Fig. 2, wheremany platelets and little fibrin is present; theburn was three days old. The plug is unstablebefore the appearance of fibrin but becomesconverted into a relatively stable thrombus by itsbinding by fibrin.The sequential changes in the original thrombus

nidus and its transformation into a fibrin-redcell mass indicate a dynamic process in thrombo-genesis. Its lesson goes beyond that of haemo-stasis and points to the need for serial studies inall other forms of thrombi to decide their originand evolution. This has special relevance to deepvein thrombi, since the nature of their nidi isuncertain.

Pulmonary Embolism and Deep Vein Thrombosis

These are common complications in injuredpatients, but they are also well recognized inorthopaedic, gynaecological, general surgical,and obstetric patients and certain medical subjectssuch as those with congestive cardiac failure.Consequently, the thrombogenic factors arelikely to be common ones and not restricted tospecific general or local effects of trauma, suchas the release of tissue thromboplastin. Thethrombotic process is abacterial and non-inflam-matory, and the distinction drawn betweenso-called thrombophlebitis and phlebothrombosis(deep vein thrombosis) is not justified. Inflam-

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matory changes in the vein wall are secondary tothe thrombosis. In only a minority of cases dothe thrombi produce symptoms or signs referableto the limbs, such as pain or swelling. Most casesof thrombosis are silent and this explains thefrequency of unheralded embolism, that is, em-bolism not preceded by limb signs. For a detailedaccount of the subject see Hume, Sevitt, andThomas (1970).

PULMONARY EMBOLISMDeath from embolism in patients with fracturedhips or other injuries is familiar to surgeons.However, the incidence of fatal embolism isgreatly underestimated clinically; some say thatonly 10% of fatal cases are diagnosed during life.

Dissection of the pulmonary arteries revealedmajor emboli in 20% of 468 patients reachingnecropsy after a wide variety of injuries (Sevittand Gallagher, 1961). This corresponded to afrequency of about 1 % fatal embolism amongthose admitted to hospital for longer than a dayor two. Embolism was relatively common inthose over 50 years old and was the most frequentcause of death in the elderly injured. This picturehas been improved considerably by the institutionof routine oral anticoagulant prophylaxis formany groups of injured patients (Sevitt andGallagher, 1959; Sevitt, 1962; Sevitt, 1968).Before prophylaxis, embolism was particularlycommon '(46-60%) in elderly subjects dyingwith a fractured femur or tibia, was frequent inthose with a fractured pelvis (27 %) or spine (14 %),but less common in other subjects. Even youngbattle casualties have a not inconsiderable risk,as fatal embolism was found in 62% of over1,000 such subjects, mostly in those with lowerlimb injuries (Hamilton and Angevine, 1946).The importance of age, and also duration of

bed rest, for embolism was demonstrated among250 subjects who reached necropsy after roadaccidents (Sevitt, 1968b). Major emboli werefound in 19 subjects, but 17 were among the 60subjects over 45 years old who lived more thanfour days at bed rest, an incidence in this group of28% major embolism. This is in accord withthe frequency of deep vein thrombi and its rela-tionship to age and duration of bed rest. Thegroup of patients with fractured hips is growingin importance because the injury is common; thenumber of elderly persons at risk is increasingand they have a high rate of thrombosis andembolism. Their frequency of embolism is about20 times the overall rate found in general hospitals.The differences in the frequency of embolism inthose with different injuries is only indirectlyrelated to the nature or the location of the injury:an increasing risk of deep vein thrombosis largelydepends on increasing age and duration of bedrest, and then differing rates of thrombusdetachment become significant. Major embolismis also not uncommon in medical, surgical, and

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other non-traumatic cases (McLachlin and Pater-son, 1951; Gibbs, 1957; Roberts, 1963). Speciallung studies have revealed an incidence of over60%, evidence of repeated embolism, since thefigure includes cases with recent, organizing, orold organizing emboli, or a mixture of cases(Braconier, 1967; Freiman, Suyemoto, andWessler, 1965).

Major embolism, that is, embolism judged tohave caused or contributed to death, is largelydetermined by the extent of blockage of thepulmonary arterial tree. At necropsy it is con-veniently divided into: (1) a large bifurcationembolus, or large separate emboli blocking bothhilar arteries; (2) a large embolus in one mainartery with or without emboli in lobar branches,or large emboli in lobar arteries of both lungs;and (3) multiple small emboli within central andperipheral arteries of both lungs. Estimation ofthe significance of the emboli found is often amatter of judgment and experience based on aproper dissection of the pulmonary arterial tree,but blockage of more than half the cross-sectionalarterial bed is generally accepted as potentiallylethal in man. Of course, the patient's age andhealth, and especially the strength of the heart,

Fig. 3 The layered structure of a deep vein thrombus.Note the thin valve cusp in the middle and the thickenedvein wall below. Multiple small platelet foci with fibrinrims are present in the thrombas to the right of thecusp. Picromallory x 24.

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are also important in determining life or death.These must be taken into account.Minor emboli, those judged to be subclinical

or certainly non-fatal, are either one or two piecesof thrombus in a lobar artery or sublobar branchor one or a few fine calibre thrombi lodged cen-trally or peripherally.The source of major and minor macro-emboli

is of course thrombi in deep veins of the lowerlimbs: detachment and embolism represent an'accident' in their life history. Subsequent eventsinclude lysis or disintegration of the emboli, theirmural contraction and reduction to fibrous orfibrofatty (atheromatous) plaques, and organiccanalization of obstructive emboli with the for-mation of fibro-endothelial lined channels andalso bronchopulmonary anastomoses.

DEEP VEIN THROMBOSISVenous dissection studies at necropsy revealeddeep vein thrombi in the lower limbs in 65% of125 injured patients, higher (80%) in certaingroups such as the elderly, dying with limbfractures after bed rest (Sevitt and Gallagher,1961). The high frequencies are not the result ofprocesses in moribund subjects since they wereconfirmed in vivo by venographic studies(Borgstrom, Greitz, van der Linden, Molin, andRudics, 1965; Freeark, Boswick, and Fardin,1967). Studies of medical, surgical, and othernecropsies (McLachlin and Paterson, 1951;Gibbs, 1957; Roberts, 1963) also revealed a highincidence of deep vein thrombi, ranging from 36to 60%. The relationship to advancing age andduration of bed rest or other immobility supportsthe old contention that venous stasis of the lowerlimbs is of major pathogenetic importance.

Structure andgrowth ofthrombusThe thrombi have a laminated structure bothcircumferentially and longitudinally (Fig. 3). Thismeans that the layers formed successively and thatthe thrombus grew by an additive process.Numerous red cells trapped in a fibrin mesh maydominate the histological picture, but foci ofclosely packed platelets, each fringed by fibrinand surrounded by granular leucocytes, arepresent in most regions (Fig. 1). The red cellmasses are laminated, with seams of fibrinbetween them or connecting them with leucocyteand platelet zones. The platelet masses vary insize and number; they often connect with eachother in a coralline fashion, and are particularlyprominent in actively propagating areas andespecially at the thrombus head. The individualplatelets, though closely packed, do not seem tobe fused; at the histological level their outlinesare preserved. Electron microscopy has not beenreported but the unusual pulmonary embolusreported by Levene and Levene (1957) was formedof closely approximated spherical bodies re-sembling platelets, though they were not well

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preserved. The close fringing by fibrin, oftencondensed and well defined, is an importantfeature. Similar structures form a major part ofarterial and cardiac thrombi; they are found inmany experimental thrombi, especially thoseproduced by direct trauma (vide infra); they arealso formed when flowing blood is shuntedextracorporeally through a tube (Mustard,Murphy, Rowsell, and Downie, 1962), and invitro by rotating a column of blood in a closedring of plastic tubing (Chandler, 1958; Poole,1959).As in haemostatic plugs, the intimacy between

the aggregates and the bordering fibrin is the keyto thrombus growth, whilst the laminationindicates the manner of growth. The structurepoints to the release of a fibrin-forming substancefrom the clumped platelets, and a platelet-clumping substance during fibrin formation.Thrombin release could account for both (videinfra).Thrombus growth is illustrated in Figure 4. At

first, growth is by propagation in the direction ofthe venous stream through the deposition ofsuccessive layers. By this additive process, theprimary microscopic valve-cusp thrombus be-comes visible (Fig. 5). The addition of furtherlayers, both longitudinally and circumferentially,increases the length and diameter of the thrombus(Fig. 6). Contraction helps to prevent venousblockage; serum is squeezed out and a relativelydry, firm, and condensed tubular structure forms.Such recent. propagating thrombi lie in the centreof the venous stream, unattached to the wall of thevein except at its point (or points) of origin where

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Fig. 4 Diagram illustrating the propagation ofdeepvein thrombifrom a nidus in a valve pocket (A) andthe deposition ofsuccessive layers offibrin, platelets,etc (B and C). Retrograde extension occurs whenthere is venous blockage from propagation (D).

Fig. 5 Small primary thrombus in a valve pocketin the common femoral vein.

organization and fixation to the wall begin. Thisexplains the danger of detachment and thefrequency of embolism. With further propagation,venous obstruction may occur, and this oftenleads to retrograde thrombosis back to the nexttributary (Fig. 4). This is probably due to thediffusion of activated coagulation factors fromthe thrombus. Even this retrograde extensionoccurs in a laminar fashion.

Thus, deep vein thrombi consist of a centrallydirected propagating head, an elongating body,one or two points of original attachment, andsometimes a peripheral retrograde tail. The headis not a fixed part as asserted by some, but it growsand changes as new material is deposited on itssurface from the flowing blood, whilst the bodyis made up of the successive deposits which onceformed the head.

Propagation may cease at any time, especiallywhen venous stasis abates, and a venous flowadequate to dilute and wash away recent productsof thrombosis, is restored. Later, thrombosis mayrecommence and then fresh coagula are depositedon organizing or even organized material. This isa common event.

Primary sites ofthrombosisThe anatomy of the lower venous tree and thedynamics of a slowed venous stream decide wherethrombi begin to form, especially in the hori-zontal position of bed rest. Thrombi may beginin the leg or thigh or both.

Macroscopically, the early manifestation is oneor more small thrombi in the pockets of valvecusps (Fig. 5) or in saccules, often at vein junc-tions. These may be found in deep veins of thepelvis, thigh, and leg. Six main primary sites oforigin have been recognized (Sevitt, 1959; Sevittand Gallagher, 1961). These are shown in Fig. 7:(1) the iliac vein, generally the external iliac vein;(2) the common femoral vein, including themouths of the medial and lateral circumflex

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Thrombosis and embolism alter injury

tributaries and the termination of the superficialfemoral vein; (3) the termination of the deepfemoral vein, often at a valve cusp guarding itsostium; (4) the popliteal vein, distal to the ad-ductor ring and at a relatively large valve; (5) theposterior tibial veins; and (6) the intramuscularveins of the calf, particularly the soleal veins.Thrombosis at one site is independent of throm-bosis elsewhere and thrombi may arise in one,two, or more of them. Their extension in the legor thigh or both produces a variety of thrombuspatterns in the lower venous tree. Thrombosis isgenerally bilateral though the location and dis-

Fig. 6 Deep vein thrombas in the common femoralvein taking origin from valve pockets in the super-ficial and deep femoral veins, and propagatingcentrally beyond the inguinal ligament (above). Notealso the smaller independent thrombits in the deepfemoral vein (right).

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tribution of thrombi in the two limbs may differ.Thrombi in calf veins are probably the mostfrequent and earliest manifestation, and there isevidence that independent thigh vein thrombiform somewhat later in many subjects (Gibbs,1957; Sevitt and Gallagher, 1961).The sites of election of thrombi in the face of a

slowed venous stream seem to depend on adisturbance of normal laminar blood flow atangulations, bends, tributaries, and valves. Tur-bulence is produced, a phenomenon similar tothe eddies at the edge of a river at a bend, and thedirection of flow at the periphery may even bereversed from that in the centre. Flow studies inexcised vein segments (Cotton and Clark, 1965)showed that when perfusion was from below thestream eddied at the free borders of valve cusps;when Indian ink was injected into the valvepockets, it lay in a stagnant pool with little move-ment or diffusion into the moving perfusate.Turbulent flow produces silting of formedelements, especially platelets, and their depositionon the wall at eddy zones, as demonstrated inextracorporeal shunts (Mustard et al 1962).Likely favourite sites for eddies are valve pockets,especially large ones, the dilated sinuses of thesoleal veins, the termination of the posteriortibial veins when compressed by the tendinousorigin of the soleus muscle, the common femoralvein near the inguinal ligament because of themultiple streams of inflow, the external iliac veins

1 External iliac 4 Popliteal2 Common femoral 5 Posterior tibials3 Profunda femoral 6 Soleal

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2 22 3 3 2

4 ~~~~~~4

5 5

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Fig. 7 Diagram ofprimary sites ofdeep veinthrombosis. The six main sites in the thigh and calfveins are independent of each other, althouighthrombosis is frequent at two or more ofthem.

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because of the acute change in flow direction, andthe left limb more than the right because of com-pression of the left common iliac vein by theright artery. Thus venous anatomy and distur-bances of flow promoted by stasis decide theprimary sites of deep vein thrombosis.

Time of onset of thrombosisA connexion between confinement to bed andvenous thrombosis has been known for a longtime and has received support from necropsydissections for deep vein thrombi (Gibbs, 1957;Sevitt and Gallagher, 1961; Roberts, 1963).Fresh thrombi were not found within a day ofbed rest, but thereafter the frequency rose andoften reached high levels among those whosuccumbed after a week or more of bed rest.Thus, in injured and burned patients, deep veinthrombi were seen in 19% of those who diedwithin three days of injury, in 47% who suc-cumbed during the next four days, and in 75 to90% of those dying later (Sevitt and Gallagher,1961).The absence of thrombi on the first day, their

relative infrequency during the first few days, andthe subsequent rise in incidence indicate that thefactors giving rise to thrombi are not present orare not sufficient in the early post-traumaticperiod, but develop or become sufficient later.To some extent, studies in vivo (Flanc, Kakkar,and Clarke, 1968) in surgical cases are in conflictwith necropsy findings, since many of the cases ofthrombosis were detected during or soon afteroperation. Thrombi were diagnosed and locatedby limb scanning after preoperative injection of1251-labelled fibrinogen, supplemented by veno-graphy in many cases. An increased radioactivitywas found in one or both legs in more than 50%of the subjects and three time patterns wererecognized, namely, an early transient rise, anearly sustained rise, and a late rise in radio-activity. Venograms were normal in those with atransient increase after operation and thismay havebeen due to blood pooling in soleal sinuses orminor thrombi lysing quickly. Leaving theseaside, the incidence of thrombosis confirmed byvenography was 35 % and half of the cases weredetected on return from the operating theatre.The apparent discrepancy between this study andvenous dissection at necropsy requires investiga-tion. Perhaps the radioactive method is insuffi-ciently selective or venous dissection is in-sufficiently sensitive to detect recent and perhapsminor thrombi in calf veins.

Hypothesis ofpathogenesis ofdeep vein thrombosisThe haematological factors responsible are notspecially related to injury since deep vein throm-bosis is not uncommon in medical and otherpatients. The absence of a recognizable lesion inthe intima predisposing to venous thrombosis isin contrast with those necessary for the formationof a haemostatic plug or an arterial thrombus.

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Consequently, an explanation is required for theinitiation of a thrombus nidus on normal intima.The selective foci of origin, especially valvepockets, depend on the production of local eddycurrents promoted by a slowed venous stream,with consequent local silting of formed elements,including platelets.

Subsequent events are likely to be complex,involving platelet clumping, the platelet-releasephenomenon, the failure of dilution of locallyreleased substances, and the formation of fibrin,but the key seems to be the local generation ofthrombin with its dual ability to aggregate plate-lets and transform fibrinogen to fibrin. Thethrombin must be formed locally but cannot bewashed away because of the flow disturbance.Two methods of its formation are possible,namely, (1) through thrombogenic factors broughtfrom a distance, and (2) by local formation ofthrombogenic substances. Local formation seemsmore likely. It can be explained through the workof Wessler and his colleagues (see Wessler, 1962)on the production of venous thrombi underconditions of stasis following the injection ofserum into the general circulation. The serumfactors found responsible were those involved inthe early stage of intrinsic coagulation, namely,activated factors XII-Xl or XII-XI-IX. Con-sequently, the carriage of activated prozoagulantfactors from afar could initiate the coagulationmechanism in stagnant pools such as valvepockets. This hypothesis presupposes a continualor at least intermittent activation of these pro-coagulant factors in the vascular system and anormal mechanism for their removal. The latterhas been demonstrated, the liver and reticulo-endothelial system being largely responsible,but the former is still theoretical. The possibilityis worth considering that atheromatous lesionsin the lower aorta and major arteries to the lowerlimbs contribute to the initiation process byactivating procoagulant factors in the bloodflowing over them. This would help to explain thesusceptibility of middle-aged and elderly subjectsto deep vein thrombi, but it is not the wholeexplanation, since young subjects without signi-ficant atheroma may also develop deep veinthrombi.An alternative or supplementary mechanism

is the local initiation of platelet aggregationthrough the local release of ADP from red cellsor leucocytes silted by eddies into valve pockets.Thrombin generation might then follow throughplatelet degranulation and the release ofthrombo-plastic PF3 with consequent activation of theextrinsic clotting mechanism. Against the in-volvement of this pathway are the reports ofvenous thromboembolism in patients with con-genital deficiency of factor VII. Further, againstthis mechanism also are the experiments (Stuartand Thomas, 1967) which failed to producevenous thrombi under conditions of stasis afterinjecting large doses of ADP, and also the un-

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certainty concerning the increased availability ofplatelet factor 3 induced by ADP action. On theother hand, release of PF4 may be involved,since inter alia it can precipitate fibrinogen andproduce evidence of intravascular coagulationwhen given in vivo.The final outcome is determined by the balance

between thrombogenic and fibrinolytic mech-anisms. Favouring thrombosis is the demon-stration (Nilsson, 1968) that little fibrinolyticactivity develops in the veins of the leg after theproduction of stasis, and that in injured subjectsthere is a relatively prolonged period of inhibitedfibrinolysis following the early transient activation(Innes and Sevitt, 1964). In favourable circum-stances, the thrombus nidus, once formed, isstabilized or strengthened by fibrin throughfurther release of thrombin, and growth occursthrough the deposition on the nidus of successiveand alternative layers of aggregated platelets andfibrin (Fig. 4). Soon this becomes the propagatinghead. The original nidus is transformed into astructure containing much fibrin, many red cells,and few, if any, platelet clumps. This explains themixed histological structure of many small valve-

Fig. 8a Histology from a femoral valve pocketthrombus. A fibrin-red cell condensed structure,adherent to the intima at the apex of the pocket.Valve cusp on the left. No platelet clumps visiblehistologically. Picromallory x 40.

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pocket thrombi and the absence or infrequencyof platelet collections near the valve-pocket apex(Fig. 8a) and in others the presence of plateletclumps in this zone (Fig. 8b). In this process andsubsequent growth, thrombus contraction andlocal release of serum containing thrombinprobably play an important role, although this islikely to be potentiated by the chain reactioninvolving the release of platelet-aggregating sub-stances (ADP and adrenaline) and coagulationactivators (PF3 and PF4) from clumped degranu-lating platelets. A fuller account of this postulatedmechanism is given elsewhere (Hume et al, 1970).

Pulmonary Microembolism

Microscopic lung thrombi have been known formany years although, until recently, they havereceived less attention than large thromboemboli.Morphologically, two kinds can be broadly dis-tinguished (Eeles and Sevitt, 1967), namely, (1)arterial microthrombi (micro-arterial) found inlung vessels about 0.25 to 1-00 mm in diameter

Fig. 8b Apex of another femoral valve pocketthrombus. Valve cusp is above and to the left, andthe vein wall is below. This shows several elongatedoval pale foci of clumped platelets surrounded bynarrow dark rims offibrin, as well as many red cells.Picromallory x 120.

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(Fig. 9), and (2) capillary-arteriolar microthrombi(capillary microthrombi) mostly in vessels 20 tolOO,u in diameter (Figs. lOa and b). Repeatedattacks of microembolism are now believed tobe an important cause of pulmonary hypertensionof insidious onset.

ARTERIAL MICROTHROMBIMost arterial microthrombi are structurally likemacroscopic emboli; they contain many red cellsand a variable mixture of fibrin, platelets, andleucocytes (Fig. 9). Some are seen in the processof organization or already organized. They werefound in the lungs of 12.4% of injured patientsand 21 .2% of burned subjects, usually one or twoper section histologically (Eeles and Sevitt, 1967).Like macroscopic emboli, they occur in manysubjects other than the injured. For example,Brenner (1935) found them in the lungs of 19out of 100 unselected necropsies. Macroscopicthromboemboli are also present in some patients.In injured patients, the incidence is related to ageand survival time: arterial microthrombi wereuncommon in those with short survival, but theirfrequency rose as survival time increased (Fig. 11,bottom), and was highest (20 to 30%) in thoseover 40 years old who survived, mostly at bedrest, for longer than a week. Large emboli werealso seen in some cases, and dissection of the

Fig. 9 Recent arterial microthrombus in a lung.H&E x 9.

Fig. lOb Lung capillary microthrombus showing aFig. lOa Capillary microthrombi in the lung. mixed fibrin-granular (platelet) structure. H & E xH & E. x 75. 400.

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lower limb veins revealed deep vein thrombi as apotential source of lung thrombi in nearly everysubject. Clearly, these arterial microthrombi arethe microscopic counterpart of large thrombo-emboli: they originate as deep vein thrombi,become detached and carried to the lungs.The condition is more complicated in many

burned subjects. Many later-appearing thrombican be explained by deep vein thrombosis, butthe early appearance after burning of arterialmicrothrombi in many severely burned patients(and in some injured subjects) cannot be explainedon this basis. The thrombi in them may representthe process of capillary microthrombosis (videinfra) occurring in larger vessels, or an additionalembolic source of thrombi such as small throm-bosed veins in burned skin or an injured area.

CAPILLARY MICROTHROMBI IN THE LUNGSThese generally have a different appearance fromarterial microthrombi (Figs. lOa and b). Theypresent with an eosinophilic condensed fibrillaryor granular structure, some like aggregatedplatelets, others with a mixed fibrin-plateletstructure, and some largely fibrinous in appear-ance. The majority are found in thin-walled

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interstitial vessels, some clearly in musculararteries and others in alveolar capillaries. Someare mural, but others are occlusive.

Microthrombi have been known for manyyears in burned subjects (Hayem, 1889; Pack,1926; Sevitt, 1957), and arefound in patients dyingafter severe injury (Eeles and Sevitt, 1967). Theyhave also been described in the lungs of animalsafter experimental haemorrhage (Crowell andRead, 1955; Turpini and Stefanini, 1959; Robb,1963; Hardaway, 1968), after various shock-like states in animals and man (Blaisdell, Lim,Amberg, Choy, Hall, and Thomas, 1966; Good-man, Lim, Blaisdell, Hall, and Thomas, 1968),and in rabbits after endotoxin shock (Thomas,1964). Electron microscopy ofthe lungs ofshockeddogs has confirmed that the microthrombi, intheir early stage, consist mainly of platelet plugs(Goodman et al, 1968), and there is experimentalevidence that they are formed outside the lung,that is, they are microemboli from the venouscirculation.Necropsy studies (Eeles and Sevitt, 1967)

showed capillary microemboli in the lungs of25.4% of injured patients. This was a minimalestimate since only unequivocal evidence ofthrombosis before death was accepted. Thrombiwere most frequent in those with severe injury orhaemorrhage. Of course, transfused blood mighthave played a part either through platelet debris(Jenevein and Weiss, 1964) or by activation ofprocoagulant factors from storage in glass.However, microthrombi were also found in thosewithout blood loss or transfusion, which indicatesthat tissue damage is also important. Whenrelated to survival period, thrombi were alreadyquite common within three hours of injury,became more frequent and numerous during thenext day or two, being found in 60% of subjectsdying between 12 and 48 hours after injury, andthereafter declined (Fig. 11, top). This was incontrast to the later appearance of arterialmicrothrombi in the lungs of the same subjects(vide supra). The early flood of thrombi must herelated to a phase of microthrombogenesis andthe ebb to subsequent thrombolysis. Embolismfrom the venous circulation is the likely explana-tion, and the slower stream of the venous flowcompared with the arterial is probably importantin their formation.

- I I I I Pathogenesis ofcapillary microemboliThe appearance after injury of capillary micro-thrombi in the lungs seems related to aggregation

0 3 12 46 7 14 >14 of platelets and activation of blood coagulationHours Da in the venous circulation. However, primary and

SURVIVAL MME secondary processes are somewhat blurred at

Frequency related to survival time after present and a number of problemsare not settled.-ap (. api,lary).andarterial Quickened blood clotting after severe haemor-mbi in the lungs of a series of injured rhage was first recognized by William Hewson inVote the early dominance of capillary 1772, though it was not invariable. Speededmbi and the latet appecrance of arterial clotting by haemorrhage and adrenaline wasmbi. studied in a series of classical papers by Cannon

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and his colleagues (Cannon and Gray, 1914;Cannon and Mendenhall, 1914; Gray and Lunt,1914). This phase of hypercoagulability is nowknown to be an important initial component ofthe complex coagulative and fibrinolytic res-ponses to injury, haemorrhage, operation, andother noxious stimuli (Warren, Amdur, Belko,and Baker, 1950; Smith, Hartwick, and Regan,1957; Turpini and Stefanini, 1959; Bergentz andNilsson, 1961; Arturson and Wallenius, 1964;Innes and Sevitt, 1964; Attar, Kirby, Masaitis,Mansberger, and Cowley, 1966; Rutherford,West, and Hardaway, 1966; Leandoer, 1968;Leandoer, Bergentz, and Nilsson, 1968). Earlyactivation of the coagulation mechanism occurs,since severe haemorrhage shortened the prolongedclotting time induced by intravenous heparin,peptone, and protamine (Shafiroff, Doubilet,Siffert, and Co Tui, 1943), and acceleratedintrinsic thromboplastin generation (Turpini andStefanini, 1959). A thrombotic accelerator,possibly thrombin, appears transiently in theblood.

Serial studies on injured patients by Innes andSevitt (1964) demonstrated a phase of speededclotting and activated fibrinolysis dominating thefirst few hours after severe trauma, soon followedby slower clotting and reduced fibrinolysis (Fig.12). The main fibrinolytic changes have beenconfirmed (Borowiecki and Sharp, 1969), and thereduced fibrinolytic activity seems due both todepletion of plasminogen and the appearance ofan inhibitor. These changes are associated with areduction in various plasma clotting factors,including prothrombin, factors V and VII, andof platelets, which indicates their consumptionduring acute thrombogenesis. Experimentally,the changes can be prevented by prior treatmentof the animals with heparin. This is important,because it indicates that their disappearance isthrough consumption and not to active fibrino-lysis, though that is also present for a time. Ofspecial interest is the fall in blood plateletsbeginning soon after trauma and continuing forone to three days, when the lowest counts arefound; after this the platelet count rises steadilyto levels of thrombocytosis during the next oneto three weeks (Fig. 13). The falling platelet countmay be accompanied by a moderate fall in plasmafibrinogen concentration. Low fibrinogen levelsmay occasionally occur, but they are unusual andtransient.The continued pulmonary microthrombosis

during the first two days is in accord with thefalling level of platelets which in turn, can beexplained by in-vivo clumping, consumption,and disruption during microthrombogenesis.Thus, the major period of microthrombogenesis,when capillary microthrombi are most frequent,is manifest in the blood as a period of hypo-coagulability characterized by a fall in platelets,various plasma clotting factors, and often aprolonged coagulation time. A reduced pro-

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thrombin consumption after clotting and theacquisition of antiheparin properties bytheplasmaare also present (Innes and Sevitt, 1964), and thelatter is consistent with the appearance of plateletfactor 4 in the blood (vide infra). Later, thefibrinogen and factor VIII levels of the plasmarise, the former often reaching high levels two tofour weeks after trauma.The trigger mechanism responsible for setting

off the coagulation and fibrinolytic sequences areprobably neurohumoral or humoral in origin,involving sympathetic overactivity and adrenalinesecretion. How these act is unknown, thoughvenous endothelium is a known source of plas-minogen activator.Whatever the trigger mechanism, it is likely

that the early activation of coagulation and plate-let clumping set up a temporary chain reactionthrough the appearance of intermediary coagula-tion products and factors released from platelets,a process with similarities to that postulated inthe origin of deep vein thrombi. The findings ofBrinkhous and Penick (1955) indicate that theintrinsic system of coagulation is activated, andthat its activation is necessary for the develop-

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Fig. 12 Serial platelet counts, prothrombin time,clotting time and diluted-bloodfibrinolysis time in apatient during the first 24 hours after severe injury.The horizontal lines represent limits of normality.Note the early transient phase ofspeeded clottingand fibrinolysis, the early fall in the platelet count,and the slightly prolonged prothrombin time.

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* Severely Injuredo Moderotely Injured

. t _-- . . * * . * * . ,- 0 1 2 4 6 8 10 12

Days after Trauma

Fig. 13 Serial platelet counts in a series of injuredsubjects. The count falls on the day of injury andcontinues to fallfor one to three days occasionallyalmost reaching thrombocytopenic levels. Then thecount rises, often reaching levels ofthrombocytosis during the next week or two.

ment of thrombocytopenia. After severe freezingof the skin in dogs, the factor VIII level and plate-let count fell, but the platelet count remainednormal in haemophilic dogs similarly treated.Platelet factor 4 may be an important inter-mediary in the chain reaction: it is rapidlyreleased during platelet aggregation in vivo(Niewiarowski, Lipinski, Farbiszweski, and Pop-lawski, 1968; Niewiarowski, Poplawski, Lipin'ski,and Farbiszewski, 1968); when infused intorabbits, clotting time rapidly shortens, the bloodplatelet count falls and other effects suggestive ofclotting activation and intravascular plateletaggregation are found (Farbiszewski, Lipin'ski,Niewiarowski, and Poplawski, 1968). Certainly,release of PF4 explains the appearance of anti-heparin activity in plasma found during the firsthours after injury (Innes and Sevitt, 1964), andprobably also the heparin resistance of plasmapostoperatively and in subjects with thrombosisor embolisrh.The explosive chain reaction is brought to an

end presumably by protective and inhibitorymechanisms. These include the removal of ac-tivated clotting factors by the liver and reticulo-endothelial system, the action of antithrombinand other inhibitors.

Significance and importance of capillary micro-emboliSome workers (Pack, 1926; Wartman, 1962)have postulated that these are of obstructiveimportance in burns, and it has also been sug-gested that they are responsible for the rise inpulmonary artery pressure in some injuredsubjects (Hardaway, 1968). Blaisdell et al (1966)claimed they were responsible for acute cardio-respiratory disturbance and early death in somesubjects after emergency operations on the aorta.Humoral-mediated effects are possible. Thomas,Stein, and their coworkers (Thomas, 1964; Stein,Tanabe, Khan, and Thomas, 1965; Thomas, Ta-nabe, Khan, and Stein, 1965) found broncho-constriction after experimental lung embolismand related this to the release of serotonin fromplatelets; lung vasoconstriction was also possible.Consequently, embolization of microthrombi tothe lungs after injury and burns might accountfor certain early respiratory effects, such aspolypnoea after extensive burning (Sevitt, 1957),and contribute to certain ventilation-perfusionanomalies in injured subjects.A breakdown in the homeostatic balance

between hypercoagulability and microthrombosison the one hand and thrombolysis on the other,has been postulated to explain 'irreversibleshock' in dogs bled to severe hypotension andthen unable to respond beneficially to subsequentre-infusion of blood. Thrombi in various organsincluding the lungs were said to be responsible(Crowell and Read, 1955; Turpini and Stefanini,1959; Hardaway, 1962) and heparin and'fibrinolysin' were said to be beneficial. Heparintherapy prevented the appearance of micro-thrombi after experimental shock (Robb, 1963;Goodman et al, 1968), prolonged the survivaltime of lethally burned dogs (Elrod, McCleery,and Ball, 1951; Johansson, 1961), and increasedthe survival rate in severely bled animals afterreturn of the blood (Crowell and Read, 1955:Hardaway, 1962). However, others found thatthere was little protection offered by heparin inhaemorrhagic shock or that it even increased themortality (Smith, Grace, and Hussey, 1958;Schumer and Lee, 1964).

Glomerular Microthrombosis

Necropsy studies (Sevitt, 1956; Innes and Sevitt,1964) have shown that glomerular microthrombidevelop in some burned and injured patients. Inburned subjects, the condition was known toWertheim in 1867, but had been largely neglected,

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They were seen (Sevitt, 1956) in 9.3 % of 86burned patients studied for renal failure andtubular necrosis; and in another study (Innes andSevitt, 1964), in 5X3 % of those with burns and in3X8 % of injured cases. They present as eosino-philic, oval or elongated condensed masses oftentaking the shape of or distending glomerularcapillaries (Fig. 14). They stain prominently forfibrin in Mallory and PTAH preparations and arePAS-positive. Platelets are difficult to distinguishby light microscopy, though their presence maybe transitory, preceding fibrin deposition, as hasbeen claimed for glomerular thrombi in theShwartzman reaction. The condition is minor inthe majority of injured subjects affected, whenless than 2% of glomeruli are involved, but ittends to be more extensive in most burned sub-jects when 10 to 20% of glomeruli or morecontain thrombi. Even in such cases, few capil-laries per glomerulus are affected but an occa-sional glomerulus is packed with thrombi. Pre-sumably most of these cases are subclinical. Inburned subjects, the frequency seems to beassociated with short survival and the develop-ment of tubular necrosis and was particularlyfrequent among the elderly who died withtubular necrosis during the second day afterburning (Sevitt, 1956). The thrombi are probablytemporary since they are uncommon in patientssurviving longer.

Occasionally, an injured or burned patient isfound with many thrombi affecting the greatmajority of glomeruli: then tubular necrosis andrenal haemorrhages may be present. Figure 15shows the 'flea-bitten' haemorrhagic appearance

*~_i,;::... . .-_wL g szk.,F~j. ,... C!-,sFig. 14 Glomerular microthrombosis in an injuredpatient. PTAH x 75.

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of the kidneys in such a case, a rare phenomenon.Such cases could be responsible for an unusualform of acute posttraumatic uraemia. Of course,glomerular microthrombosis is absent in most ofthose dying with renal failure.Glomerular microthrombi may occur in subjects

with or without lung microthrombi, and thecondition is certainly much less frequent thanpulmonary microthrombosis. Small thrombi areabsent or scarce in other organs: this does notsupport an embolic origin so that the glomerularthrombi are probably formed locally within thekidney. Though an association with glomerularfat embolism has been suggested, the conditionsare only occasionally related; when they areassociated, fat emboli are numerous but micro-thrombi are few.

PATHOGENESISThe origin and mechanism of glomerular micro-thrombosis is obscure. Acute coagulative changesmay be involved and the possibility that thethrombi are preceded by platelets must be takeninto account. Also worthy of consideration is thepossibility that the substance reacting for fibrinin the glomerular capillaries is the result of para-coagulation offibrinogen rather than true clotting.This non-enzymatic process is a property ofplatelet factor 4 which might be involved. Theindependence of glomerular microthrombosisfrom that in the lungs or other organs points tocoagulative or other changes localized to the renalblood flow.Glomerular microthrombosis is a central feature

Fig. 15 'Flea-bitten' haemorrhagic kidneys from ayoung man who died a day after a severe head injury.(Many microthrombi were present in most glomeruli,and also extensive tubular necrosis and haemorrhagicttbular areas.)

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of the generalized Shwartzman reaction precipi-tated by two properly spaced injections ofbacterial endotoxin or other procedure, and itsappearance after injury or burning might re-present this mysterious state in man. Glomerularthrombosis in burned patients who died fromsepticaemia due to Serratia marcescens (Graber,Tumbusch, Rudnicki, and Vogel, 1960), or otherbacteria including Ps. pyocyanea (Innes andSevitt, 1964), could be accounted for by pre-cipitation of the Shwartzman phenomenon bybacterial endotoxin. However, neither bacterianor their toxins are essential for this reaction,which can be provoked in pregnant animals by aspecial diet. Consequently, the possibility arisesthat injury itself might trigger off the phenomenonin particular subjects. This would explain itsappearance within a day of trauma in occasionalsubjects, though it would not explain why theyand others, are susceptible. Perhaps, some peopleare already sensitized by previous infection orotherwise 'prepared' in some way, and traumasets in motion endocrine, coagulative, or otherchanges which precipitate the reaction.

Arterial Thrombosis

Fortunately this is an unusual phenomenon in theabsence of direct trauma. Nevertheless, a numberof unequivocal cases involving large or importantvessels have been reported (Sevitt, 1966). Theseinclude acute cases of extensive recent coronaryartery thrombosis with recent myocardial in-farction in a young woman with largeburns (Cole,1963) and of fresh coronary artery thrombi in anextensively burned young soldier (Stevens, 1965).In these patients atheroma was minimal. Othercases in the literature are referred to by Cole(1963). Coronary artery thrombosis has also beenfound at necropsy in occasional burned or injuredpatients (Sevitt, 1966). Most ofthem were middle-aged or elderly and had atheromatous disease ofthe affected vessel and elsewhere. Consequently,other explanations, that the thrombosis wascoincidental or preceded the injury, and perhapseven caused the accident, was plausible. This ismuch less likely in the young people, and sincethey indicate that the phenomenon was preci-pitated by burning or other trauma, the possibilityor even probability, cannot be excluded in thosewith coronary atheroma. A unique case of intra-vascular clotting in a previously healthy child witha small burn was referred to by Wilson, Mac-gregor, and Stewart (1938): thrombosis was foundin the intracranial venous sinuses and Rolandicveins, and also in the arteries of the lower limbsfrom the lower abdominal aorta downwards.Other burned subjects, developing thrombosis ofcerebral veins and venous sinuses, have beenreported (Sevitt, 1957), and lateral sinus throm-bosis is occasionally found in injured subjects

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without head trauma. Furthermore, infarction ofthe kidney related to thrombosis of a renal arterybranch is seen occasionally in patients withoutdirect trauma to the organ (Fig. 16). These findingsare unusual and their explanation is difficult. Inthose developing arterial thrombi, the post-traumatic hypercoagulable phase may have in-volved the arterial circulation, which ordinarilyseems to escape from microthrombogenesis. Insuch cases, the arterial thrombosis might beconsidered as one kind of breakdown in thehomeostatic balance between posttraumatichypercoagulability, thrombosis, and fibrinolysis.

Abacterial Vegetative Endocarditis

This is the most uncommon form ofposttraumaticthrombosis but it is found in occasional cases.

CASEA 23-year-old male was admitted with a fracturedpelvis and a minor cerebral contusion. Two dayslater, he became pyrexial with laboured, rapidbreathing and chest pain. Fat embolism was sus-pected but was not confirmed at necropsy.

Fig. 16 Recent white infarct at upper pole of kidneyrelated to thrombosis ofa renal artery branch.Injutred patient, but no trauma to the infarctedkidney.

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Tracheostomy and artificial ventilation withoxygen were carried out because of a low arterialP02. He remained cyanosed; P02 remained low.Radiological lung opacities developed. Cardiacarrest occurred twice and he died seven days afterinjury.Necropsy confirmed the fractured pelvis and

cerebral contusion. Also present were a severeinterstitial pneumonitis with hyaline membraneformation, probably related to the oxygen therapy;thrombosis in a lateral sinus, in femoral and iliacveins,and multiple small pulmonary emboli; acutegastric and duodenal ulcers; and a central area ofnecrosis in the anterior pituitary gland, probablyrelated to cerebral contusion. The heart weighed312 g; a few epicardial petechiae and streaks ofsubendocardial haemorrhage over the anteriorpapillary muscle were present. Both the mitraland tricuspid valves showed recent vegetativeendocarditis with numbers of pale, firm irregularcrumbling vegetations lightly attached to thecontact points of the cusps (Fig. 17). They weremore numerous and larger in the mitral valve,measuring up to 1 cm long. Culture grew a fewatypical Bact. coli, regarded as a contaminant.Myocardium and coronary vessels were natural.Histology of the vegetations showed that theywere formed of fused platelet eosinophilic massesembedded in a fibrin network; no organisms wereseen.The pathogenesis of this lesion is unknown. It

is well recognized in uninjured patients underseveral names, including non-bacterial thromboticendocarditis, cachetic endocarditis, endocarditissimplex, and degenerative verrucal endocardiosis.It is distinct from the atypical verrucous endo-carditis (Libman-Sacks) which is associated withacute disseminated lupus erythematosus. Factorsconsidered to play a role are allergy, vitamin C

Fig. 17 Vegetative endocarditis involving the mzitralcusps (see text).

deficiency, haemodynamic trauma to valves, andpreexisting valvular deformity. None of theseseem to have been involved in the present case.

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