Ischaemic enterocolitis: expression intravascular

Gut, 1971, 12, 912-917

Ischaemic enterocolitis: an expression of theintravascular coagulation syndromeR. WHITEHEAD

From the Department ofPathology, Radcliffe Infirmary, Oxford

SUMMARY In 20 cases of ischaemic enterocolitis unassociated with lesions of major vessels, freshthrombi were found in the small vessels of the bowel wall and were widespread in other tissues. Thecapillaries of the renal glomeruli and vessels in the lung were the commonest sites. Pseudo-mem-branous enterocolitis is shown to be an early or more slowly evolving but identical entity to otherforms of so-called ischaemic enterocolitis. This is a condition which includes ischaemic enterocolitis,postoperative enterocolitis, necrotizing enterocolitis, and probably some cases of clostridial andstaphylococcal enterocolitis. It is due to an episode of intravascular coagulation occurring prin-cipally in the gut wall but also elsewhere.

When the intestine is deprived of an adequate bloodsupply a surprisingly wide variety of clinical andpathological states may result. Exclusion of thosecases manifestly due to lesions of the vessels sup-plying the intestine still leaves a large group of casessimilarly characterized by ischaemic necrosis inwhich neither arterial nor venous obstruction can bedemonstrated. Terminology pertaining to these isconfused and poorly defined and under the headingof ischaemic enterocolitis (Goulston and McGovern,1965) and ischaemic colitis, group 1 gangrenous(Marston, Pheils, Thomas, and Morson, 1966), areincluded cases previously entitled haemorrhagicenterocolitis (Wilson and Qualheim, 1954), necroti-zing colitis (Killingback and Williams, 1961),Clostridium welchii colitis (Tate, Thompson, andWillis, 1965), uraemic colitis, postoperative entero-colitis, staphylococcal enterocolitis, and pseudo-membranous enterocolitis although Goulston andMcGovern regard this as a separate entity.Those cases which for the purpose of this paper are

called 'ischaemic enterocolitis' have no specialtendency to involve only the splenic flexure, some-times involving the whole of the large bowel and partof the small bowel. Although commoner in old agenoage group is exempt. Clinically there is usually asudden onset of diarrhoea, sometimes containingblood, in severely ill patients in a terminal state, inshock, or in the postoperative period, and recoveryis uncommon. By contrast ischaemic colitis due tomajor vascular occlusion or narrowing is commonlysegmental and involves the splenic flexure andReceived for publication 29 July 1971.

neighbouring colon. Concomitant small intestinallesions and rectal lesions are rare except in specialcircumstances and the patients are nearly always inthe older age groups and commonly have othermanifestations of vascular insufficiency. Clinicallythere is bloody diarrhoea in an otherwise fairlyhealthy patient and recovery with or withoutstricture formation is not infrequent.

In the absence of vascular occlusion or narrowingthe lesions in ischaemic enterocolitis have beenattributed to splanchnic hypoperfusion secondary tohypotension or vasoconstriction. One of the more orless characteristic histological features is, however,thrombosis of mucosal and submucosal vessels, and,whilst these have been regarded as a secondaryphenomenon, the possibility that local thrombosis isprimary must be considered. After noting thepresence of disseminated thrombosis in cases ofischaemic enterocolitis coming to necropsy and inview of recent evidence for intravascular coagulationas a cause for other haemorrhagic lesions of thegastrointestinal tract, including pseudo-membra-nous colitis (Margaretten and McKay, 1971), agroup of cases of ischaemic enterocolitis was studiedin detail for the presence of disseminated thrombosis.

Material and Methods

Twenty cases of ischaemic enterocolitis wereselected fromri the necropsy records of the RadcliffeInfirmary between 1948 and 1968 from materialpreviously filed under the heading of ischaemiccolitis or uraemic enterocolitis, pseudo-mem-

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Ischaemic enterocolitis: an expression of the intravascular coagulation syndrome

branous enterocolitis, postoperative enterocolitis,and staphylococcal enterocolitis. Only those in whichthe absence of major vascular pathology wasspecifically noted were included, othersbeingrejectedbecause of inadequate macroscopic descriptions orincompatible histological appearances. In each caseseveral sections of affected intestine and sectionsfrom at least six other tissues or organs, includinglungs and kidney, were stained by the haematoxylinand eosin, Lendrum's MSB, and picro-Mallorymethods. They were examined for the presence ofrecent thrombi. As a control similarly preparedsections of lung and kidney from 10 unselected caseswhich had recently come to necropsy were alsoexamined.

Results

No thrombi were found in the control cases. The siteof involvement of the bowel and the location ofthrombi in other organs and tissues in the cases ofischaemic enterocolitis is indicated in Table I.

MACROSCOPIC APPEARANCES OF THEINTESTINEFrom the outside the bowel affected may appearunremarkable or dilated and slightly injected butmay be somewhat reddened or darker. The ap-pearance of obvious intestinal gangrene, such as isassociated with mesenteric vascular occlusion orstrangulation of the bowel, was not a feature in thisseries, but in one case there was a full-thicknessischaemic necrosis of the caecum with perforationand peritonitis. Internally the affected mucosaappears reddened and haemorrhagic and the in-testinal contents may be red and bloody or darker inolder lesions. Redness appears to be due to hyperae-mia and ulceration which may be superficial pin-point, or deeper and transverse, longitudinal orserpiginous. The ulcers have necrotic raggedmargins and there may be extensive areas of com-plete ulcerative loss ofmucosa. Adherent or sloughedmembranous material of yellow necrotic appearanceis sometimes seen and a distinctive appearance whichmay be generalized throughout the bowel is that ofmultiple discrete dome-shaped or less regularmembranous plaques scattered over a diffuselyhyperaemic background. It is this type of case whichis often referred to as pseudo-membranous entero-colitis.

HISTOLOGICAL APPEARANCES OF THEINTESTINEThe earliest lesion appears to be thrombosisinvolving the capillary plexuses high up in theintestinal mucosa (Fig. 1). These are present before

there is mucosal necrosis and serial sections haveproved that they are not just lesions at the edge ofmembranous plaques or larger lesions. Later there isnecrosis of the superficial layers of the mucosa withoedema and haemorrhages and an acute inflam-matory infiltrate in the lamina propria with extensionof the thrombosis to involve submucosal vessels (Fig.2). The appearances in so called pseudo-membranouscases (Fig. 3) suggests a slower evolution. Super-ficial capillary thrombi are present and in patchesthe superficial mucosa becomes necrotic. The oedemaand inflammatory infiltrate seem to obstruct themouths of glands causing mucus retention andcystic dilatation in their deeper parts. Plaques of

Fig. 1 Thrombosed apical capillary loop. Mucosaotherwise shows only early postmortem change and anon-specific inflammatory infiltrate (MSB x 80).

Fig. 2 Extensive mucosal capillary thrombosis withextension to submucosa. Upper layers of mucosa showischaemic necrosis (MSB x 30).

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Case No. Age Sex Bowel Symptoms Bowel Involvement Site of Thrombi in Comments and CoexistentOther Organs Disease

F

F

F

M

M

M

Bloody diarhoea for6 daysBloody diarrhoea for6 daysDiarrhoea for 7 days

Mild diarrhoea for 8daysDiarrhoea for 11daysDiarrhoea (profuse)12 hours

69 M Abdominal pain andvomiting 2 days

52 M None

64 F Diarrhoea for 2 days

65 F Diarrhoea for 1 day

43 M Bloody diarrhoea

92 F Diarrhoea for 5 days

67 M Bloody diarrhoea for12 days

41 F Diarrhoea for 18days

58 M Abdominaldistension

Large bowel

Terminal ileum andlarge bowelTerminal ileum andlarge bowel; rectumsparedLarge bowel (partlypseudo-membranous)Descending andsigmoid colonIleum, caecum,ascending and trans-verse colon; descen-ding, pelvic colon,and rectum sparedIleum and largebowel; sparing ofrectum belowcarcinomaLarge bowel; pelviccolon and rectumspared

Ileum and largebowelLarge bowel

Jejunum, ileum, andlarge bowel; rectumspared (caecalperforation)Pelvic colon

Ileum and caecum

Terminal ileum andlarge bowel (partlypseudo-membranous)

Terminal ileum andlarge bowel (largelypseudo-membranous)

59 M Mild diarrhoea Ascending colon(partly pseudo-membranous)

10 M None Terminal ileum andlarge bowel

M

F

Bloody diarrhoea for Ileum and large6 hours bowelDiarrhoea for 10 days Large bowel

(completely pseudo-membranous)

38 F Bloody diarrhoea for Terminal ileum and2 days large bowel

Lung, kidney, l

Kidney, endoc

Lung

Kidney, heart,endocardiumKidney, adreni

Lung, kidney, apancreas, thyr(lymph nodes

Adrenal, pancithyroid

heart Carcinoma of ovary, bilateralhydronephrosis, uraemia

:ardium Chronic pyelonephritis, uraemia

Congestive heart failure, chronicrespiratory disease

and Myocardial infarction, severeheart failure, terminal uraemia

al Prostatectomy: Staphylococcusaureus cultured at necropsy

adrenal, Partial gastrectomy for duodenal*oid, ulcer, numerous Gram-positive

cocci in bowel mucosa

:reas, Transverse colostomy forobstruction-carcinoma of recto-sigmoid

Kidney, brain, Chronic focal glomerulo-pancreas nephritis; hypertension, uraemia

(renal capillary thrombi inotherwise normal glomeruli)

Lung, kidney Purulent pericarditis

Lungs, adrenal Gastroenterostomy and vagotemyfor duodenal ulcer

Kidney, thrombi in Empyema following injury tocavernous haeman- chest; staphylococci grown atgioma of liver necropsy from empyema and gut;

early peritonitisLung Arthroplasty for fractured neck of

femurLung, kidney Acute on chronic pyelonephritis,

chronic paraphimosis andbalanitis

Lung, kidney Infective diarrhoea with restof family; sudden collapsediarrhoea became worseAspergillus pneumonia at necropsy

Lung, kidney Suppurative bronchopneumoniafollowing influenza;Staphylococcus aureus culturedat necropsy from lungs andbowel

Lungs, endocardium, Vascular nephrosclerosisand aortic valve uraemia

Lung, kidney Aplastic anaemia;thrombocytopenia and systemicmoniliasis.

Lung, adrenal Proliferativeglomerulonephritis

Lung, kidney, heart Skin graft for pressure soresfollowing fractured femur;thrombosis of subclavianartery

Lung, kidney Mitral valvotomy

Table Site of involvement ofbowel and of thrombi in other organs and tissues.

membranes on the surface consist of fibrin, in- necrosis. Extensive submucosal venous thrombiflammatory cells, mucus, and necrotic epithelium. occur and other vessels exhibit typical ballooningSuch lesions are seen throughout the colon in pseudo- and red cell sludging. The inflammatory infiltrate maymembranous cases and intervening mucosa is be pronounced and a 'phlegmonous' picture is nothyperaemic but intact and yet will exhibit occasional uncommon. Ulceration often extends into thecapillary thrombi. Isolated lesions essentially similar submucosa and may involve the inner muscle layersoccur in later cases in which there is more advanced and very rarely full-thickness necrosis of the bowel

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Ischaemic enterocolitis: an expression of the intravascular coagulation syndrome

Fig. 3 Mixed fibrinoid, mucus and inflammatory cell Fig. 5 Thrombus in pulmonary vein and neighbouringsuperficial plaques with typical ballooning of deeper capillaries (MSB x 108).parts ofglands in so-called pseudo-membranousenterocolitis (MSB x 18 ).

Fig. 4 Capillary thrombi in glomerulus (MSB x 270). Fig. 6 Detail of capillary thrombi in lung (MSBx 270).

wall is seen. Thrombosis of small veins outside thebowel wall in the mesentery may also be present andwas seen in two cases.

Sometimes colonies of organisms can be seenwithin the superficial necrotic tissues and in three ofthese Staphylococcus aureus had been cultured fromthe postmortem bowel. By and large the mostsevere lesions were seen in those cases with thelongest history or those with an abrupt onset ofsevere shock, diarrhoea, and rapid death, eg, thefulminant cases. Those with a longer history and

mild bowel symptoms were more likely to showsuperficial bowel mucosa involvement and includedthose with 'pseudo-membranous' lesions.

HISTOLOGICAL FINDINGS IN OTHERTISSUESIn all cases examined fibrin thrombi giving apositive staining reaction with the MSB and picro-Mallory methods were found in the vessels of otherorgans. In some cases thrombi were frequent but inothers they were found only after a thorough search.

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Fig. 7 Thrombosed adrenal vessels and haemorrhagicnecrosis (darker zones) (H and E x 20).

Capillary thrombosis in the kidney glomeruli (Fig. 4)and thrombi in capillaries, small veins, and arteries inthe lungs (Figs. 5 and 6) were the commonest findingsby far, but thrombi were seen in a wide variety ofother tissues, including, brain, heart, and liver.Larger vessels were sometimes involved and althoughthese were usually veins in one case there wasspontaneous thrombosis of the subclavian artery.Fibrin thrombi were also seen on the mural endo-cardium of the heart and on the aortic valves(presenting at necropsy as thrombotic endocarditis).It is of interest that in four cases the adrenal veinsand sinusoids showed thrombosis and in one this wasextensive and accompanied by early haemorrhagicnecrosis of the Waterhouse-Friderichsen type (Fig.7).

Discussion

The watershed area between the area of supply by thesuperior and inferior mesenteric vessels is the regionof the splenic flexure (Griffiths, 1956). This is thearea most commonly made ischaemic when there isocclusion or narrowing of the mesenteric vessels.The comparative rarity of ischaemic lesions in spiteof the relatively common finding of such vascularpathology at necropsy speaks highly for the richanastomotic network of vessels supplying theintestine. The correlation between ischaemia of thegut of this zonal type and arterial disease is notalways good (Dick, Graff, McGregg, Peters, andSarner, 1967) and the position is clearly analogous tocoronary artery disease and myocardial lesions.Single vessel thrombosis in an otherwise healthycoronary circulation produces infarction in some

cases whereas widespread atheroma in others isassociated with a relatively normal muscle. Thistype of gut ischaemia seems to be a problem distinctfrom the entity of ischaemic enterocolitis not onlyon pathological grounds but also on the clinicalgrounds already outlined.

Pathologically there is apparently no pattern ofdistribution determined by the blood supply ofmajor vessels and in early pseudo-membranous casestypical lesions and relatively normal mucosa occurside by side. Ischaemia occurring initially at capillarylevel would explain this pattern of involvement. Thisfinding is typical of all the cases of ischaemicenterocolitis examined and it is clear that thepseudo-membranous enterocolitis and ischaemicenterocolitis of McGovern and Goulston (1965) andGoulston and McGovern (1965) are the same entitybut of a different stage of evolution and severity.The presence of occasional lesions in the mesen-

teric veins of some of these cases also suggests arelationship with so-called primary mesenteric veinthrombosis. There is little doubt that once ischaemicnecrosis is established bacterial invasion is quick tofollow and secondary invasion by organisms alreadyin the bowel may be responsible for at least somecases of Clostridial and staphylococcal entero-colitis.The pattern of distribution of thrombi in the gut

wall, kidney, and lung capillaries, and in otherorgans closely parallels that seen in intravascularcoagulation experimentally induced by thrombininfusions (McKay, Linder, and Cruse, 1971). Thesite of thrombosis can be modified by using otheragents in conjunction with thrombin, eg, epsilon-aminocaproic acid, histamine, serotonin, steroids,adrenalin and noradrenalin, and depends on the stateof activation or inhibition of the fibrinolyticmechanism, the adequacy of renal glomerularfiltration, and the integrity of the reticuloendothelialsystem. It is clear that many of the factors which canprecipitate intravascular coagulation often operate inpatients with ischaemic enterocolitis and includeendothelial damage due to prolonged hypotension,tissue damage after surgical operations, malignancy,infection, shock, and Gram-negative endotoxaemia.

It is now widely recognized that the generalizedSchwartzman reaction is but a manifestation ofintravascular coagulation initiated by injection ofbacterial endotoxin (Evenson and Hjort, 1970). ASchwartzman-like phenomenon localized to vesselsin certain organs may also be responsible for quitedistinct clinical entities, eg, the Waterhouse-Friderichsen syndrome (Lo, Hitzig, and Frick, 1971),and it is of interest that in one out of four casesshowing adrenal thrombi in this series there wasearly haemorrhagic parenchymal necrosis. The

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factor or combination of factors which cause more orless localization of the coagulation to one or otherorgans in human disease are yet to be determined.

Perhaps the best evidence for intravascularcoagulation during life is the presence of freshthrombi in postmortem tissues. Coagulation studiesusing postmortem blood are valueless but corrob-orative evidence of intravascular coagulation wouldbe possible if these cases were investigated duringlife. Then depletion of coagulation factors andplatelets and the presence of fibrin degradationproducts would be significant, especially if arterio-venous differences in the levels of these factors wereshown to occur across the involved bowel. These arethe lines along which further investigation might leadto those factors which indicate and localize theprocess of coagulation to the bowel. It is clear thatthe closest cooperation between physician, surgeon,and pathologist is needed in this endeavour.ReferencesDick, A. P., Graff, R., McGregg, D., Peters, N., and Sarner, M.

(1967). An arteriographic study of mesenteric arterial disease:large vessel changes. Gut, 8, 206-220.

Evanson, S. A., and Hjort, (1970). Pathogenesis of disseminatedintravascular coagulation. Plenary scientific contributions.XIIIth International Congress of Haematology, pp. 109-120,Lehmanns, Munich.

Goulston, S. J. M., and McGovern, V. J. (1965). Pseudo-membranouscolitis. Gut, 6, 207-212.

Griffiths, J. D. (1956). Surgical anatomy of the blood supply of thedistal colon. Ann. roy. coll. Surg., 19, 241-256.

Killingback, M. J., and Williams, K. L. (1961). Necrotizing colitis.Brit. J. Surg., 49, 175-185.

Lo, S. S., Hitzig, W. H., and Frick, P. G. (1971). Clinical experiencewith anticoagulant therapy in the management ofdisseminatedintravascular coagulation in children. Acta haemat. (Basel), 45,1-16.

Margaretten, W., and McKay, D. G. (1971). Thrombotic ulcerationof the gastrointestinal tract. Arch. intern. Med., 127, 250-253.

Marston, A., Pheils, M. T., Thomas, M. L., and Morson, B. C.(1966). Ischaemic colitis. Gut, 7, 1-15.

McGovern, V. J., and Goulston, S. J. M. (1965). Ischaemic entero-colitis. Gut, 6, 213-220.

McKay, D. G., Linder, M. M., and Cruse, V. K. (1971). Mechanismsof thrombosis of the microcirculation. Amer. J. Path., 63,231-241.

Tate, G. T., Thompson, H., and Willis, A. T. (1965). Clostridiumwelchii colitis. Brit. J. Surg., 52, 194-197.

Wilson, R., and Qualheim, R. E. (1954). A form of acute hemor-rhagic enterocolitis affecting chronically ill individuals.Gastroenterology, 27, 431-444.


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Ischaemic enterocolitis: expression intravascular