disseminated intravascular coagulation as a consequence of ... · it has been suggested that...

Journal of Neurology, Neurosurgery, and Psychiatry, 1974, 37, 241-248

Disseminated intravascular coagulation as aconsequence of cerebral damageF. E. PRESTON, R. G. MALIA, M. J. SWORN,W. R. TIMPERLEY, AND E. K. BLACKBURN

From the Departments of Haematology and Neuropathology, United Sheffield Hospitals,and the Department ofPathology, University of Sheffield, Sheffield

SYNOPSIS Three cases with intracranial lesions developed evidence of disseminated intravascularcoagulation which was confirmed at necropsy. The factors engendering this state, including release ofpotent thromboplastin from neural tissue are discussed and the danger of this intermediary mechan-ism of disease increasing the mortality of intracranial disease is demonstrated. Careful haemato-logical investigation of all patients with intracranial disease is therefore advised, especially if theymanifest evidence of a bleeding tendency.

It has been suggested that disseminated intra-vascular coagulation (DIC) is an importantintermediary mechanism of disease and death(McKay, 1965). Many clinical entities have beenrelated causally to intravascular coagulation(Nalbandian et al., 1971) and many agents shownto be capable of initiating, promoting, andmodifying the effects of DIC (McKay, 1965;Hardaway, 1966; Preston et al., 1972b).Whatever the initiating agent, the manifesta-

tions of DIC are similar in many respects, pre-senting a spectrum ofclinicopathological changeswith variable degrees of shock, haemorrhagicdiathesis, and parenchymal necrosis, the latteroccurring in many different organs (McKay,1965).

In presenting this series of cases we wish todemonstrate the causal relationship of intra-cerebral lesions to consumption coagulopathy,

to adduce evidence for the ability of such lesionsto induce DIC, and to stress the danger of thisintermediary mechanism of disease in increasingthe morbidity and mortality of intracraniallesions.

CASE 1

A 38 year old man with a two year history of rightchronic otitis media presented with neck stiffness of10 days' duration. He was drowsy, had nystagmus onlooking to the right, ataxia of his upper limbs, drag-ging of his right leg, marked neck stiffness, and a puru-

lent discharge from his right ear. The haemoglobin(Hb) level was 17-0 g/100 ml. Examination of hiscerebrospinal fluid revealed 141 white cells/cu. mm,9000 of which were lymphocytes. A ventriculogramwith iophendylate revealed a space occupying lesionin the right posterior fossa. A right cerebellar abscesswas found at operation and the abscess and its cap-

sule were removed. Pus from the ear and abscess

TABLE 1SUMMARY OF MAIN HAEMATOLOGICAL FINDINGS IN EACH CASE

Case no. Hb WBC Platelets FDPs FDPs Prothrombin Thrombin Fibrinogen(glMO ml.) (h.d.) (/pJ.) in serum in urine time time (mg/100 ml.)

(jsg/ml.) (pg/ml.) (sec) (sec)

1 12-2 18,000 50,000 80 10 17 (12) 9 (6) 2502 3-4 9,000 16,000 80 5 22 (11) 60 (6) 1503 7-2 11,000 45,000 80 - 18 (12) 6 (6)Normal 0-20 2 5 200-400

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F. E. Preston, R. G. Malia, M. J. Sworn, W. R. Timperley, and E. K. Blackburn

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FIG. 1. Case 1. Section ofparietal lobe. Occlusion ofsmall vessels by fibrin. H and E, x 600.

revealed heavy growths of Proteus vulgaris and treat-ment with penicillin, streptomycin, and sulphon-amides was instituted. The day after the operation hewas alert and moving all four limbs but by the nextday he was oliguric with macroscopic haematuria.His blood urea concentration was 310 mg/100 ml.,Hb 12 2 g/100 ml., and burr cells were noted in ablood film. The results of further haematologicalinvestigations are shown in Table 1. Peritonealdialysis was performed for five days, by which timethe blood urea was 150 mg/100 ml. On the seventhpostoperative day his respiratory rate suddenly fellto 6/minute and the blood pressure rose rapidly to170/110 mmHg. Ventricular puncture revealed onlyblood and necrotic tissue, while insertion of a drainand Spitz-Holter valve into the left cerebral ven-tricle with decompression of the posterior fossaresulted in no improvement in his clinical state. Hedied the day after this operation.At post-mortem examination the brain (weight

1,410 g) was swollen, more so on the right than theleft. Approximately two-thirds of the right cerebellarhemisphere had been removed surgically. A largehaemorrhage was present in the centre of the rightcerebral hemisphere in the region of the internalcapsule and basal ganglia. The haemorrhage had

FIG. 2. Case 1. Section ofpituitary gland. Clumps offibrin in small blood-vessels. H and E, x 600.

ruptured into the ventricles, which were full of bloodclot. Linear haemorrhages were also present in themid-brain, presumably as a result of cerebral swell-ing. The only other macroscopic abnormalities notedwere that the heart weighed 425 g with evidence ofmarked left ventricular hypertrophy and that therenal calices and pelves and ureters contained alarge amount of recent blood clot and brownishdebris. Sections of the brain confirmed that thecerebellar abscess had been removed completely.

Histologically, clumps of fibrin were seen in manysmall vessels of arteriolar or capillary size in thebrain (Fig. 1). The pituitary gland showed thepresence of aggregates of fibrin within one capillary,but no infarcts were seen (Fig. 2). Many arteriolesand capillaries within the kidneys contained plugs offibrin which appeared to be of various ages (Fig. 3),some showing evidence of organization with in-growth of fibroblasts; others being more recent with agranular appearance and no evidence of organiza-tion. Some glomeruli showed areas of infarction withrelease of fibrin and cells into the glomerular spaces.An occasional glomerulus was totally infarcted;again the infarcts appeared to be of various ages,some showing evidence of organization. A few small

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taining partially organized area of infarction andmasses offibrin. H and E, x 600.

areas of recent haemorrhage and infarction were seenin the renal medulla. There was erythrophagocytosisof red cells by hepatic Kupfer cells; an occasionalvessel in the portal tracts contained plugs of fibrin.In the lungs, several small and medium sized vesselscontained plugs of fibrin (Fig. 4) and a few smallhaemorrhages were evident within the alveolar wallspaces. All other organs appeared normal.

CASE 2

A 9 year old girl was admitted after a roadtraffic accident. She had frontal scalp haematomasand she responded to painful stimuli only. Bothpupils were equal and reacted to light. Four hourslater her left pupil was larger than the right and itbecame unreactive to light. An intracranial echogramshowed a 4 mm shift of the midline structures fromleft to right and a burr hole revealed a thin subduralclot in the left temporal region and contusion of thelateral aspect of the temporal lobe. She was treatedwith intravenous mannitol and soon moved all fourlimbs. Five days later she developed convulsivemovements and the left pupil became dilated and un-reactive to light. Carotid arteriograms showed a

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FIG. 4. Case 1. Section of lung. Occlusion ofa blood-vessel in an alveolar wall by a mass offibrin. H and E,x 600.

shift of the anterior cerebral artery to the right. Aleft temporal decompression was performed withslight clinical improvement but the next day shedeveloped profuse gastrointestinal bleeding. In-vestigations revealed a haemoglobin level of 8-0 g/100 ml., a platelet count of 68,000/cu. mm, andmarked polychromasia of red cells in the blood film.She was treated initially with intravenous infusion offresh blood and heparin and later with streptokinasebut continued to bleed into her gastrointestinaltract. Barium studies failed to reveal any localizedgastrointestinal lesion. The next day results were asfollows: Hb 6-1 g/100 ml., reticulocytes 40/, platelets75,000/cu. mm, prothrombin time 17 seconds (con-trol 13 seconds), thrombin time 8 seconds (control 7seconds), and fibrinogen 150 mg/100 ml. Her serumand urinary fibrin/fibrinogen degradation products(FDPs) were 80 jig/ml. and 2,000 ,ug/24 hours re-spectively. During the following two days her Hblevel progressively fell to 3-4 g/l00 ml. and theplatelet count to 16,000/cu. mm. The 1-stage pro-thrombin time was markedly prolonged at 22seconds, as was the thrombin time at 60 seconds. Therelevant investigations are summarized in Table 1.On the eighth day after admission she developed

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FIG. 5. Case 2. Coronalsection through frontal lobe.Area of contusion and areasof early necrosis in corticalgrey matter.

FIG. 6. Case 2. Coronalsection through the posteriorparietal region of the brain.Numerous areas of earlyinfarction in the cortical greymatter.

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FIG. 7. Case 2. Section of cerebral cortex. Occlusionofa small artery by masses offibrin. H and E, x 600.

acute oliguric renal failure and died the followingday.At necropsy, numerous petechiae were noted in

the skin, particularly over the abdomen and thorax.The brain was swollen with herniation into the de-compression site. There was superficial contusion ofthe lateral aspect of the left temporal lobe and of theposterolateral and inferior aspects of the left frontallobe (Fig. 5). Some contused temporal lobe had beenremoved surgically. Coronal sections through thebrain showed numerous areas of haemorrhagicinfarction involving the cortex of both cerebralhemispheres. These infarcts were of variable size andpatchy in distribution. The depths of the sulciappeared to be most severely affected (Fig. 6). Thedistribution of the infarcts involved the territory ofall major cerebral vessels about equally, and thepatterns suggested occlusion of multiple smallvessels. Histologically, fibrin plugs were noted inlarge numbers of small vessels of arteriolar orcapillary size from all areas of the cerebral hemi-spheres (Fig. 7). The vessels penetrating the brain be-tween the gyri were particularly involved, and adja-cent areas of both cortex and white matter showedevidence of recent infarction. Many neurones in theaffected areas had lost their nuclei and cytoplasmic

FIG. 8. Case 2. Section ofkidney. A glomerulus con1-taining masses offibrin within the capillaries. H and E,x 600.

structures and others were seen in various stages ofacute degeneration. There was marked vacuolationof the surrounding neuropil and of the adjacentwhite matter, with acute swelling of both astrocytesand oligodendrocytes. Many capillaries in the in-farcted areas showed evidence of recent haemorrhage.The vessels of several systemic organs also showedevidence of fibrin plugging. The kidneys in particularshowed a large amount of this with occlusion ofmany glomerular arterioles and capillaries (Fig. 8)and affected glomeruli showing areas of partial orcomplete infarction. Fibrin was present in manytubules. The lungs contained a few recent haemor-rhages, both within the pleura and in the alveolarsepta and again many small vessels showed evidenceof fibrin plugging. Fibrin plugs were also present inthe small vessels of the gastrointestinal tract and ofthe bladder. Petechial haemorrhages were seen in theterritory of affected vessels.

CASE 3

A 26 year old man was admitted after being foundunconscious at the bottom of the stairs after drinkingheavily. He was restless, showed violent movementsof the right arm and both legs, and was incontinent

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of urine. The left pupil was larger than the right, butboth pupils reacted to light. He was treated conserva-tively, but in view of deterioration in his respirationthree days after admission he was artificially ven-tilated. Twelve days after admission he showed atendency to bleed easily from venepuncture sites.Results of investigations were Hb 10 5 g/100 ml.(compared with 17 9 g/100 ml. on admission),platelets 45,000/cu. mm, 1-stage prothrombin time18 seconds (control 12 seconds), thrombin time 6seconds (control 6 seconds), and serum FDP's80 ALg/ml. On the same day he developed oliguricrenal failure, passing only 74 ml. of urine with aplasma urea of 480 mg/100 ml. He was treated byperitoneal dialysis and intravenous heparin-3,000units four hourly, which was subsequently increasedto 5,000 units four hourly. On this therapy his Hblevel fell to 8 0 g/100 ml. over the following four days,but his platelet count rose to 90,000 per cu. mm.Microcytes and polychromasia were evident in theblood film during this period. His plasma urea pro-gressively fell to 175 mg/100 ml. and serum electro-lytes were within normal limits. Peritoneal dialysiswas therefore discontinued. At this time he developeda staphyloccal chest infection and his peritoneal fluidshowed a profuse growth of coliforms and Pseudo-monas aeruginosa. He died on the 17th day afteradmission, the platelet count on this day being45,000/cu. mm. Results of other haematologicalinvestigations are shown in Table 1.At necropsy there were numerous purpuric

haemorrhages on the back, chest, and limbs withpitting oedema of both ankles. The peritoneum con-tained slightly turbid fluid. There was a large leftsided haemorrhagic fibrinous pleural effusion. Sec-tion of the partially collapsed lower lobe of the leftlung showed the presence of an abscess measuring3 cm in diameter. There was evidence of broncho-pneumonia in both lungs. Staphylococcus pyogeneswas grown from the abscess at postmortem. Thestomach, duodenum, small intestine, and largeintestine showed the presence of numerous smallhaemorrhages in the mucosa. There was also evidenceof multiple small bleeding points in the retro-peritoneal pelvic fat. The bladder mucosa showed afew small petechial haemorrhages. Section of theswollen brain showed an area of necrosis surroundedby recent haemorrhage, in the centre of the corpuscallosum. The necrotic area measured 1 cm indiameter. There was an irregular tear in the uppersurface of the corpus callosum just anterior to thenecrotic area. An area of contusion 1 cm in diameterwas seen in the grey matter on the inferior aspect ofthe left frontal lobe just anterior to the temporalpole. The temporal lobes on both sides showednumerous small petechial haemorrhages in the grey

and white matter. A few similar areas were also seenin the parietal and occipital lobes. All petechialhaemorrhages appeared to be of very recent origin.

Histologically, the area of necrosis and tearing inthe corpus callosum showed foamy histiocytes andbreakdown of myelin and axons. This damage pre-sumably dated from the original head injury.Petechial haemorrhages in the grey and white matter,however, were clearly more recent in origin andvessels within the territory of the haemorrhages wereshown to contain fibrin plugs. Microscopical examin-ation of the midbrain showed several small areas offibre disruption with the presence of focal accumula-tion of foamy histiocytes. Some neurones in the areashowed evidence of chromatolysis. This also pre-sumably dated from the original injury. The kidneyscontained fibrin strands and globules within manytubules and a few plugs of fibrin were s en inglomerular capillaries. An occasional partiallyinfarcted glomerulus was present. Recent petechialhaemorrhages in the bladder and intestinal mucosawere confirmed histologically and again an occasionalvessel contained a fibrin plug. The retroperitonealhaemorrhage also appeared to be of recent origin.Both lungs showed evidence of severe haemorrhagicbronchopneumonia and numerous colonies of grampositive cocci were seen. A few vessels containedfibrin aggregates.

DISCUSSION

It has been suggested that throughout life thereis continual deposition of fibrin on endotheliumwhich has been damaged by the stresses of thecirculation (Fearnley, 1965). After repair thefibrin is removed by the action of the fibrinolyticenzyme system, thus serving to maintain thepatency of the vascular tree. There is therefore adelicately balanced equilibrium between thecoagulation and fibrinolytic enzyme systems(Nolf, 1908). Increased deposition of fibrin maybe a consequence of impaired fibrinolysis or theresult of excessive concentrations of coagulantsubstances within the circulation. Many of therecognized syndromes of disseminated intra-vascular coagulation (DIC) stem from the rapidrelease of thromboplastic substances into thecirculating blood. The widespread deposition offibrin is usually associated with a secondaryfibrinolytic response resulting in the generationof increased concentrations of fibrin degradationproducts.Although Graham and Adams (1971) have

described cerebral ischaemic damage in associa-

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Disseminated intravascular coagulation as a consequence of cerebral damage

TABLE 2DISTRIBUTION OF FIBRIN IN VARIOUS TISSUES EXAMINED*

Organ Case I Case 2 Case 3

Brain 2 3 2Heart 1 0 0Kidney 2 3 1Liver 2 0 0Gastrointestinal tract 0 2 1Bladder 0 2 1Pituitary 1 0 0Lung 2 3 1

* The degree of involvement is graded 0 to 3 (negative to heavy). Nofibrin was seen in the adrenals, thyroid, spleen, or pancreas of any case.

tion with fatal head injuries, there have been sur-prisingly few reports of DIC complicating braindamage. Cerebral tissue has marked thrombo-plastic activity; indeed, it is used as a source oftissue thromboplastin in the Quick one-stageprothrombin test. The three patients described inthis study developed clinical and haematologicalfeatures of DIC apparently as a consequence ofdamage to the brain. A possible additional factorin the first patient was the presence of a cerebralabscess. A variety of abnormalities of thecoagulation mechanism have been described as aconsequence of bacterial infection and it hasbeen suggested that they may be a reflection ofintravascular coagulation (Goldenfarb et al.,1970; Preston et al., in press).The diagnosis of DIC was made on the basis

of thrombocytopenia, prolongation of thrombinand prothrombin times, and elevation of serumfibrin degradation products (FDP). A bleedingdiathesis, as evidenced by generalized bruisingand excessive bleeding from venepuncture siteswas observed in each patient. The abnormalbleeding state which accompanies DIC resultsfrom the consumption of clotting factors andplatelets together with the anticoagulant proper-ties of the FDP's (Marder and Shulman, 1969;Larrieu et al., 1972).

It is of considerable interest that renal failureoccurred in all three patients and that intra-glomerular fibrin was demonstrated in each caseby histological exa'mination of''ne'cropsy material.There has been much recent discussion on therole of intraglomerular fibrin in the patho-genesis of various renal disorders and Clarkson

et al. (1970) have expressed the view that intra-glomerular coagulation plays an important rolein the production of acute renal failure. Theincreased concentrations of urinary FDPs intwo of the three patients were considered toreflect lysis of intraglomerular fibrin.The haematological diagnosis of DIC was

subsequently confirmed by histological examina-tion of necropsy material. Cerebral and renalvessels were involved in all three patients, gastro-intestinal and bladder vessels in two, and hepaticinvolvement was noted in one patient (Table 2).The organ distribution of fibrin which occurs inDIC is incompletely understood but Regoecziand Brain (1969) have demonstrated that animportant factor, at least in the experimentalanimal, is the rate of fibrin formation and thatthis dictates the actual dimensions of the in-soluble fibrin strands.A disturbing feature of two of the cases

described here is the relatively trivial head injurywhich precipitated the profound disturbances ofthe coagulation fibrinolytic mechanism. The out-come, in this group of patients, illustrates thegrave prognosis when this syndrome occurs as aconsequence of cerebral damage. Clearly, earlydiagnosis is vital and we believe that earlyheparin therapy may be of value in the manage-ment of this type of patient. There is also a needfor a carefully controlled investigation of thissyndrome in a larger series of cases with damageto the nervous system, as it seems likely that it isfar more common than is at present realized. Itmay also be that intravascular coagulation playsa more widespread and important role in otherneurological states such as the occurrence of'little strokes' previously thought to be largelyassociated with atheroma of the carotid arteries.

We would like to thank Mr. J. Hardman and Mr.A. A. Jefferson, of the Department of Neurosurgery,United Sheffield Hospitals, for their permission touse clinical information on their cases; Dr. A. J.Coup, of the Department of Pathology, SheffieldUniversity, for permission to use case 1 on which heperformed the postmortem examination, TheDepartment of Medical Illustration, United SheffieldHospitals, for their help with the photography, andMr. K. Horton, Chief Technician in the Departmentof Neuropathology, for his technical help.

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REFERENCES

Clarkson, A. R., MacDonald, M. K., Fuster, V., Cash, J. D.,and Robson, J. S. (1970). Glomerular coagulation in acuteischaemic renal failure. Quarterly Journal of Medicine, 39,585-599.

Fearnley, G. R. (1965). Fibrinolysis. Arnold: London.Goldenfarb, P. B., Zucker, S., Corrigan, J. J., Jr., and

Cathey, M. H. (1970). The coagulation mechanism in acutebacterial infection. British Journal of Haematology, 18,643-652.

Graham, D. I., and Adams, J. H. (1971). Ischaemic braindamage in fatal head injuries. Lancet, 1, 265-266.

Hardaway, R. M. (1966). Syndromes of Disseminated Intra-vascular Coagulation. Thomas: Springfield, Ill.

Larrieu, M. J., Rigollot, C., and Marder, V. J. (1972). Com-parative effects of fibrinogen degradation fragments D andE on coagulation. British Journal ofHaematology, 22, 719-733.

McKay, D. G. (1965). Disseminated Intravascular Coagula-tion. Harper and Row: New York.

Marder, V. J., and Shulman, N. R. (1969). High molecularweight derivatives of human fibrinogen produced byplasmin. 2. Mechanism of their anticoagulant activity.Journal of Biological Chemistry, 244, 2120-2124.

Nalbandian, R. M., Henry, R. L., Kessler, D. L., Camp,F. R., Jr., and Wolf, P. L. (1971). Consumption coagulo-pathy: practical principles of diagnosis and management.Human Pathology, 2, 377-388.

Nolf, P. (1908). Contribution a l'etude de la coagulation dusang. 5. La fibrinolyse. Archives Internationales de Physi-ologie, 6, 306-359.

Preston, F. E., Malia, R. G., Sworn, M. J., and Blackburn,E. K. (1972a). Intravascular coagulation and renal failurein E. coli septicaemia. (Abstract.) Journal of ClinicalPathology, 25, 1006-1007.

Preston, F. E., Malia, R. G., Sworn, M. J., and Blackburn,E. K. (1972b). Intravascular coagulation and E. colisepticaemia. Journal of Clinical Pathology, 26, 120-125.

Regoeczi, E., and Brain, M. C. (1969). Organ distribution offibrin in disseminated intravascular coagulation. BritishJournal of Haematology, 17, 73-81.

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