J. clin. Path., 23, Suppl. (Roy. Coll. Path.), 4, 110-120

The significance of coagulative and thromboticchanges after haemorrhage and injury

R. M. HARDAWAYWashington, DC, USA

Haemorrhagic shock may progress under certaincircumstances by the events described in thediagram shown in Figure 1. Normally, arterialblood pressure is adequate: arterioles are open,though with adequate tone; arteriovenous shuntsare closed; and only about 20% of the capillariesare open at any one time. Flow is so good in thefunctioning capillaries that the cells are satisfiedwith about 20% perfusion time. When mast cellslining and adjacent to a closed capillary becomeslightly anoxic, they secrete histamine whichcauses the capillary to open. The histamine isdestroyed in the blood quickly and does notcirculate. When the mast cells are satisfied, theyhalt histamine secretion and the capillary closes.In this way the capillaries take turns in beingperfused. Capillary flow is rapid and the fall inpHalongthecapillaryissmall, perhaps from 7-4 to 7.3.Lactic acid is continuously being excreted inminimal amounts by the cells and carried away bythe capillary flow; normally this is so good thatlactic acid does not accumulate. The sequence ofevents in haemorrhagic shock is as follows.

Phase I: Reversible Haemorrhagic Shock

STAGE 1: VASOCONSTRICTIONInitiated by some shock-producing stress such as ahaemorrhage or trauma, the sudden secretion ofcatecholamines and the high blood levels of theseemergency hormones initiate an intense arteriolarvasoconstriction. This stage is that of compen-sated or partially compensated shock and bloodpressure may be normal. However, the pulse maybe rapid and thready. There is other evidence ofsympathetic stimulation: pale, sweaty skin, rapid,thready pulse, elevation in blood glucose, andgeneral nervousness. These are common clinical

findings associated with shock. The catecholaminelevel in the blood remains high throughout shock,even until death.

STAGE 2: CAPILLARY AND VENULE OPENINGThis might also be called the stage of expansionofthe vascular space by the opening ofcapacitancevessels. It is also the stage of hypercoagulable andstagnant capillary blood. Acidosis is a prominentfeature of this stage. It is easily reversible byvolume administration. As seen in Fig. 1, arteri-olar vasoconstriction with or without a fall inarterial blood pressure results in less volume ofblood flowing through the arteriole. Therefore,capillary flow slows. Parenchymal cells, which areusually satisfied with intermittent perfusion oftheir particular capillary, now find they needlonger and longer perfusion times to maintain anormal metabolism. Mast cells adjacent to eachcapillary provide for this by secreting smallamounts of histamine when they become slightlyanoxic. This causes the opening of that particularcapillary, and keeps it open as long as thehistamine is secreted. The histamine is quicklydestroyed in the bloodstream so that other vesselsare not affected. However, as each capillary andvenule remains open longer in this way, anincreasing proportion of capillaries are open atany one time until, when carried to extreme, theyare nearly all open at once. This particularlyapplies to the abdominal viscera. Because of thetremendous number of capillaries and venules inthe body, a large part of the blood volume isalways in these vessels (capacitance vessels), evenunder normal conditions with only about 20% ofcapillaries open at one time. With the opening ofmany additional capillaries and venules the totalvolume of the vascular space may actually double.This is reflected in extreme congestion of viscera,such as thelung, liver, kidneys, and gastrointestinal

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mucosa. Those who rely on measurements ofblood loss to gauge volume replacement are oftenfooled by this phenomenon. A frequent commentis that more blood was lost than is realized. Thiscapillary and venule expansion has two importanteffects on the shock picture. First, the vascularspace is greatly expanded. This makes even anormal blood volume inadequate to fill it. Thecapillary and venule capacity is so great that verylittle blood is left over to reach the great veins andvenae cavae. Vena caval pressure falls to zero,resulting in a great reduction of venous return tothe right atrium. Then the cardiac output fallsstill further, and also arterial pressure. Second, thelow blood pressure, extremely constricted arteri-oles, open arteriovenous shunts, and many opencapillaries together produce an extremely stagnantcapillary flow. This causes slow delivery ofoxygenand increased anoxic metabolism. With increasedsecretion of lactic acid into the slow-movingcapillary blood, the blood becomes acidic by thetime it reaches the venous end of the capillary. Amarked lactic-acidaemia develops quickly, first inthe venous blood and later also in the arterialblood. The body compensates for the acidaemiaby blowing off CO2 till the excess lactate iseventually removed. In fact, in early shock this

I.

compensatory mechanism may even over-compensate and produce a respiratory alkalosis.However, compensation becomes inadequate asthe lactic acid level continues to increase and thepH falls, producing a true acidosis. This acidosishas a number of effects, including a marked effecton blood coagulability. Its full extent will not berealized if one merely takes the pH of arterialblood, because it is in the veins where it is mostprominent. In addition, certain vascular beds willbe much more affected, that is, where vaso-constriction is worst as in the abdominal viscera.BloodpH levels as low as 6.6 have been recordedhere. Further, arteriovenous shunting may help toraise the venous pH. This may give a false sense ofsecurity. Capillary and tissuepH is probably muchlower. Very important is the tremendous increasein lactic acid which must occur around cellswhich aredeniedperfusion. Anaerobicmetabolism,which soon comes on, increases this. Delicatecellular enzymes cannot work under theseconditions.The effect of this acidosis on blood coagulation

is dramatic. It produces a hypercoagulable state.The silicone clotting time may fall from a normalof 20 to 40 minutes to three to five minutes (Figs. 2,3). The sluggish hypercoagulable blood may not

2.

Vasoconstriction

4.

CapillaryCoagulotion

3.

CopillaryDilatation

Clot Lysis

Fig. 1 Stages in Development of Irreversible ShockDiagram represents a small artery ending in anarteriole with sphincter-like action. Arteriole feedsthree capillaries, each feeding a group of cells.

1 Normal Condition Arterioles fairly widelyopened. Only one capillary is being perfused whileothers rest. Capillaries open in rotation on demand oJthe cells adjacent to them. Constant perfusion notnecessary. Bloodflow through the capillary is rapid.pH drop across the capillary is minimal.

2 Phase I: Shock Vasoconstriction Due tocatecholamine secretion after haemorrhage andtrauma. Arteriole constricts letting less blood through.Hypotension in the artery, capillary flow slowed.

3 Phase II: Shock Capillary Dilatation(Expansion of Vascular Space) All capillaries are openon demand of their cells. Bloodflow through allcapillaries is extremely slow. pH fall across thecapillary is marked.

4 Phase III: Shock-disseminated IntravascularCoagulation Late shock. Haemolysis has aided theslow flowing acid blood in two of the capillaries toclot, stopping perfusion completely in these capillaries.Cells nourished by these capillaries are dying. Bloodflow through the remaining capillary is sluggish.Circulating blood incoagulable.

5 Phase IV: Irreversible Shock Arteriole hasopened somewhat after replacement of blood volume.Capillary clots have been lysed by endogenousfibrinolysin thereby restoring circulation. However,cells supplied by the formerly clotting capillaries arenow dead. This produces areas offocal necrosis and ifwidespread enough, causes tissue and organ failure.

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clot in vivo and the shock may not progress. Purehaemorrhagic shock is almost always reversibleup to the point of death. Of course if the meanarterial pressure drops below a critical point(20 mm Hg), capillary perfusion halts and deathensues. Up to this point, pure haemorrhagicshock responds well to adequate treatment.

However, many factors are possibly presentwhich can initiate in vivo coagulation in this

>6O0

4 )-4 CONTROLLED HYPOTENSION>TBLEED TRANSFUSION

Fig. 2 Silicone clotting times of dogs subjected tohaemorrhagic shock. Bleeding produced a decrease inclotting time. The dogs which later developed aprolonged clotting time (over 35 minutes) all died as

noted by the crosses. Those which did not all survived,as noted by the circles. Two typical animals are

shown by the lines.

Fig 3. Thromboelastograms of the blood of a dogsubjected to haemorrhagic shock. The record at the topwas taken before haemorrhage and shows a normalclotting configuration consisting of a spike followed bya torpedo shape. The spike or straight line portiondenotes fluid blood. The torpedo shape beneathdenotes rapidity offormation andfirmness of the clot.

The second recording (just below) was taken afterhaemorrhage and shows an almost complete absenceof the spike showing that the blood clotted almostimmediately. The increased width of the torpedo shapedenotes rapid and firm clotting.

The third recording (below) taken after two hours ofshock shows only a straight line. The blood did notclot during the recording (about two hours).

112

dangerously susceptible blood. If the oligaemia isnot corrected by adding to the volume (more thana normal blood volume is required) and if it isaided by even a mild amount of trauma, infection,haemolysis, or other clot-initiating factors, theshock may enter the next stage, that of dissemi-nated intravascular coagulation.

STAGE 3: DISSEMINATED INTRAVASCULARCOAGULATIONThis stage is roughly equivalent to 'refractory'shock, that is, shock which is resistant to treat-ment but is still reversible. Many capillariesbecome occluded by clotted blood (Fig. 1). Thestage is ushered in by the sudden appearance ofincoagulable or hypocoagulable blood. Clinically,widespread oozing of blood from wounds maysuddenly appear. Previously adequate haemo-stasis seems to become inadequate. It may beimpossible to stop the bleeding by ligature,pressure, or other means. The coagulation withincapillaries has two important consequences. First,the widespread coagulation of large quantities ofblood in the expanded capillary bed uses up largequantities of clotting factors, thereby leaving theremaining unclotted blood deficient in clottingfactors andhencehypocoagulable or incoagulable.Second, fibrin formed by disseminated intra-vascular coagulation may deposit on any surface,including red cells. This may involve a thick coatof fibrin (Figs. 4, 5, 6) or cause cells to sticktogether into small thrombi. The thrombi occludethe first capillary or small vessel they come to. Orthey may form in situ in a small vessel (Fig. 7).Capillary coagulation may completely halt localperfusion, cutting off all nutrition and stoppingthe removal of acid cellular metabolites. Theseincrease around the cells quickly creating such amarked local acidosis that the pH falls to levels.incompatible with cell enzyme activity; metab-olism soon stops and the cells die. Prothrombintime and partial thromboplastin time becomeprolonged. Platelets decline markedly. This suddenonset of incoagulability denotes the onset ofdisseminated intravascular coagulation and,therefore, is a sign of a very poor prognosis. Deathof dogs which exhibit a prolonged siliconeclotting time is almost certain (Fig. 2). Similarly, aprolonged silicone clotting time after extracor-poreal circulation is correlated with a fataloutcome.

Phase II: Irreversible Haemorrhagic Shock

This is the stage of tissue death and necrosis. Theonset of this important stage is impossible todetermine. Clinically, it should never be assumedto have taken place and energetic treatmentshould continue. Its actual time of onset is not asharp line; death of cells begins on a small scale

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The significance of coagulative and thrombotic changes after haemorrhage and injury

Fig. 4 Small vessel in a patient dying of multiple j -Vtrauma. Section is stained by PTAH and aniline-eosin /i #which renders fibrin blue-black, while allowing red "';cells to remain red. A normal red cell is seen in thecentre, and above it (right hand arrow) anotherwhich has taken on an additional bluish hue. The , *;other arrow shows a larger globule with a haemo-globin centre and a blue-black coating. At the top are Fig. 5 Central vein of the adrenal gland containing aa cluster of heavily staining globular clots. x 700. globular clot. The amorphous, poorly staining centreFibrin formed in the flowing blood may deposit on any and three trapperd cells are seen. H & E, x 360.surface including the surface of red cells. From a 50-year-old man who died after acute

pancreatitis with renal failu(re and profound shock.

Fig. 6 A microthrombus in a small myocardial vesselof a 60-year-old woman dying from haemorrhagic Fig. 7 Fresh microthrombus in a glomerulus of ashock. Note the surrounding oedema but with 75-year-old man dying from septic shock secondary tonormally preserved myocardial fibres. H & E, x 350. Pseudomonas pneumonia. H & E, x 192.

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and progresses. The determination of bloodenzyme levels such as LDH, SGOT, and SGPTmay be an index of the onset and progress oftissue necrosis. Death of the whole organism mayensue when cell death in vital organs is sufficientto be incompatible with function. The amount ofnecrosis required for organ failure will vary withthe original health of the organ. As much asthree-quartersofnormal kidneys may be destroyedwith adequate function; but if kidneys are alreadydiseased, death of only a small number of cellswill be enough to produce renal failure. The sameprinciple applies to other organs. However, underproper conditions of supportive treatment (suchas an artificial kidney) the remaining living cells(kidney or liver) may multiply and reconstitute anadequate amount of parenchyma to produceadequate organ function; the organism may thensurvive.

If capillaries remain occluded for an hour or so,the cells nourished undergo changes which rapidlybecome irreversible. Lack of oxygen results inanaerobic metabolism with increased lactic-acidproduction; lack of perfusion increases acidmetabolites, and cellular enzymes cannot functionat a low pH. It becomes impossible to maintaindifferentials across the cell membrane: potassiumthen leaves the cell and sodium enters it. The cellsbecome unable to metabolize raw materials andmetabolism stops. Soon, certain changes can

114

be noted by electron microscopy, first affectingmitochondria, and later focal necrosis in certainareas can be noted by light microscopy. Largeareas of necrosis can be tolerated in many organswithout death of the whole organism, but ifenough tissue dies in certain vital organs, thatorgan fails. Hepatic failure is perhaps mostcommon and the earliest in onset (Fig. 8). It isheralded by a dramatic fall in the blood glucoselevel, which up to this time has been high due tothe effect of catecholamine secretion. Failure ofthe kidneys is evidenced by persistent anuria; upto this time, urine flow has been reduced or onlytransiently halted. There may be evidence of heartfailure with a rising central venous pressure evenwithout volume administration (Fig. 9). Gastro-intestinal necrosis may be denoted by the onset ofmelaena. Focal areas of necrosis in the pancreasmay liberate trypsin which, if it gainsaccesstotheblood stream, results in further clotting. Lungtissue does not usually become necrotic, perhapsbecause of the availability of oxygen and therelatively low metabolic requirements of itsconnective tissue and endothelium. However,thrombosis may produce a severe picture ofhaemorrhage into alveoli leading to deathfrom respiratory failure. The picture is thatofhaemorrhagic infarction. Death of the organismmay follow from any or all of these organ failures.A review of the cases of the 'crush syndrome' in

Fig. 9 Microinfarct of the myocardium. Patient diedFig. 8 Liver of a dog dying of endotoxin shock. Note of Gram-negative septicaemia. There were manymarked congestion and centrilobular necrosis. H & E, globular clots in various tissues, including the heart.x 110. H & E, x 110.

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Fig. 10 On the left are three blood samples taken_ rom a dog subjected to 100 blows of a padded mallet

on one thigh. Blood in tube A was drawn before the,- t ig.11trauma, in t obeB 30 minutes later, and in tube C 48

80 -. . \ Dhours after the trauma. Note that haemolysis, which was,70 | \only slight soon after the trauma, had increased markedly

60 | \ lengtheningtbythe end of two days. This is thought to be due toabsorption ofhaematoma and ecchymosis probably vialymphatics. If no haemolysed blood had beenabsorbed, the mild haemolysis shown in tube B wouldave disappeared completely in a few hours. On the

m rO| ight are two tubes ofblood drawn before (A') and after(B') the administration of 20 ml of autogenous blood.. m \ which had been frozen and thawed. Note that the

g amount of haemolysis 48 hours after trauma andA ..---*Baimmediately after the administration of 20 ml of

haemolysed blood is about the same.

>180 Fig. _1 Silicone clotting times in groups of dogs.o80 Dogs subjected to haemorrhagic shock alone show ai70 decrease in silicone clotting time with a subsequent

16URSlengthening at the end of the shock period into ais50 borderline zone of 55 minutes. Three groups of dogs44 =givenhaemolysed blood without any shock130 2 procedure, show varying changes according to dosage120 of haemolysed blood but all are within the normal

(/1 11 0

W0range by four hours. Dogs given SO and 100 ml of1890 haemolysed blood showed a transient but dramatic

6.El Fig. 12Averageprolongation of silicone-clotting times at 30 minutes70

13 5 _13 6 _ 60 pafter administration of the lysed blood. In dogs given60

m _and100 ml, the 30-minute samples often did not clot in a

so_' ' F1-J'6 week. Dogs subjected to a haemorrhagic shock after40 L a L administration of 20 ml of haemolysed blood showedPatietan immediate lengthening of clotting time character-30 istic in the dogs given SO or 100 ml of haemolysed2 0 blood, but instead of returning to normal levels'0 within four hours, there was a further increase in0INITIAL 30 Min, 4clotting time. This prolonged clotting time at the end

HOURS ~~~~~~~~ofa shock period is characteristic of irreversibility.HOURS ~~~~~~~Thus, the initial shortening of clotting time afterhaemorrhage is converted to a marked prolongationby prior administration of 20 ml of lysed blood

245 ~~~ ~ ~ ~ ~ ~ ~ ~~~~~-haemolysed blood alone; .- 20 ml130 haemolysed blood and shock --- shock alone.

24 -AVERAGE PROTHROMBIN TIMES AND PARTIAL110 THROMBOPLASTIN TIMES IN VARIOUS 120

GROUPS2 2 -1 10

PT~-100

20- PTT-90 PTT

18 -Sec.-80

16- 70 Fig. 12 Average prothrombin and partial thr.ombo-plastin times in various groups ofpatients and normal

14 -60 people. In unshocked patients the prothrombin times13.5 ~~13.6 and partial thromboplastin times are normal. In early

43.9 445

- ~~~~~~~~50haemorrhagic shock these tend to be shortened. This12 may indicate a hypercoagulability which may

38,8 -40 predispose toward disseminated intravascular coagula-106 ~~~~~~~~tionand the development of a clotting defect. In

IC :o' refractoryt

ist i

29 Normal 29 Refractory l4Non Shock 14 Early Hemorrhagic pohobntm n ata hobpatntmPeopletshc Pains SokPtes indicating a clotting defect.

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the literature reveals several with a haemorrhagicdiathesis. Bywaters (1942) noted that haemor-rhage could be either internal or external and wasthe most common complication of this syndrome.The mechanism of this haemorrhagic diathesiswas not then known. Because of the similarity ofthis syndrome to the incompatible transfusionsyndrome, the possibility arose that the haemor-rhagic phenomena in both might be due to thesame mechanism.There was a clinical impression that patients

with soft-tissue injury did not tolerate haemor-rhage as well as uninjured subjects. Simplehaemorrhage was tolerated quite well by dogs andcaused neither death nor evidence of disseminatedintravascular coagulation as indicated by the lackof change in the clotting mechanism. Therefore,it was thought that dogs with injury to one limbcaused by multiple blows to the thigh (underanaesthesia) with a rubber hammer might be moresusceptible to haemorrhagic shock, due perhaps tothe liberation of tissue thromboplastin into theblood stream. This was tried but proved not tobe the case. The animals were not apt to die eventhough they incurred both trauma and a degree ofhaernorrhagic shock which was not fatal. This wasunexpected and some explanation was sought.Then thework ofBorgstrom, Gelm, and Zederfeldt(1959) came to our attention and seemed mostpertinent. They ligated both femoral veins ofrabbits and then administered blows with a malletto one thigh; thrombi formed in the femoral veinsof both the injured and uninjured limbs, theincidence reaching a peak by 48 hours after injury.This indicated stimulation of intravascularcoagulation by a factor or process present at peaklevels at about 48 hours. Our dog experimentswere then repeated allowing a 48-hour intervalbetween trauma and haemorrhage: now theresults were different, death usually resulting fromhaemorrhage which otherwise was not fatal. Instudying blood samples of the dogs, it was notedthat though there was little or no haemolysis onehalf hour after trauma, a marked haemoglobinae-mia developed by 48 hours (Fig. 10). One hundredblows to one thigh resulted in a moderatelyswollen and discoloured tbigh which was not atall disabling two days later. It was not certainwhether the pigment was haemoglobin or myo-globin, but it was surprising that its excretionincreased over a two-day period in the face ofnormal renal output. The effects of an equivalentamount of haemolysis without any trauma werethen investigated. The haemoglobinaemia pro-duced after 48 hours could be roughly duplicatedby removing 20 ml of the animal's blood, freezingit, thawing it, and returning it to the animal. Thisamount of haemolysis had no demonstrable effectalone. In fact, the administration of 100 ml ofautogenous haemolysed blood was also withoutobvious effect. However, other experiments provedthat even the 20 ml dose was capable of producingdramatic effects. The following observations were

made on dogs suffering from haemorrhagic shock(Fig. 11).

1 A small amount (20 ml) of haemolysed blood,given before haemorrhagic shock is produced,causes an increase in mortality of dogs from 13 %to 91%.

2 This lethal effect is due to the stimulation byhaemolysed blood of intravascular coagulation.However, in normal rapid capillary flow, coagu-lation does not take place. A second factor isnecessary, namely, stagnant capillary flow asproduced by arterial hypotension, arteriolarvasoconstriction, and capillary dilatation. All ofthese are produced by an otherwise non-lethalhaemorrhage.

3 The lethal factor of haemolysed blood is aclotting factor (thromboplastin) in red cells.

4 Large amounts (100 ml) of haemolysed bloodalone are harmless, but even a small amount(20 ml) is lethal in the presence of shock.

5 Haemolysed blood causes the conversion offibrinogen to fibrin.

6 Therapeutic 'fibrinolysin' will prevent death inotherwise irreversible haemorrhagic shock eitherproduced by haemorrhage alone or wheninfluenced by haemolysed blood.

7 Endogenous heparin secretion is stimulated bydisseminated intravascular coagulation producedeither by haemorrhage alone, haemolysed bloodalone, or by a combination. It is probably aprotective mechanism.

8 A markedly prolonged silicone clotting timeoccurring during haemorrhagic shock is anaccurate prognostic index of irreversibility.

9 Irreversibility is correlated with a fall in theplasma fibrinogen level when that is due toconsunmption in disseminated intravascularcoagulation.Red cells contain a thromboplastin which

initiates blood coagulation. Hom e- er, fairly large-scale haemolysis is harmless in a normal circula-tion; intravenous injection of distilled water isharmless to normal humans, and the only effectsare transient haemoglobinaemia and haemoglobin-uria. Injection of 100 ml ofautogenous haemolysedblood into normal animals produced no harmfulresults but it did produce a transient, butdramatic, prolongation in silicone clotting time, atransient rise in prothrombin time, a transientrise in endogenous heparin, and a mild andtransient fall in the fibrinogen level. All returnedto normal within four hours. However, whencombined with otherwise non-fatal haemorrhagicshock, even 20 ml ofautogenous haemolysed bloodwas fatal in over 90% of animals. It also produceda significant increase in fibrinogen utilization, andincreased clotting and prothrombin times. Theeffects were progressive over the four-hour shockperiod. The fatal effect of haemolysed blood isattributed to initiation of an episode of dissemi-nated intravascular coagulation. It was not pro-duced by an injection of pure haemoglobin. It ispostulated that the shock-induced stagnant

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capillary circulation, plus the initiation of coagula-tion by haemolysis, caused clotting of the blood inthe microcirculation, and that haemolysis initiatescoagulation by the liberation of red-cell thrombo-plastin. That the toxic effects of haemolysed bloodare due to its stimulation of disseminatedintravascular coagulation is supported by theprotective effect of fibrinolysin. Fibrinolysinadministered during haemorrhagic shock after theadministration of 20 ml of autogenous haemo-lysed blood reduced the mortality from 91 to38%. Fibrinolysin acts by lysing capillary thrombi.

Clinical Studies

Twenty-nine patients in refractory shock were

studied at the Walter Reed shock unit. Alldeveloped a coagulation defect (Figs. 12-15).Table I is a summary of the results. It was notpossible to associate clearly a coagulationabnormality with the shock syndrome in every

case, because of preexisting diseases and/ortherapeutic agents administered before the onsetof shock.

In 22 patients, the coagulation abnormality was

definitely associated with the shock syndrome andno other aetiology was possible. Five had severe

infection, four giving positive blood cultures.Bacteraemia was suspected in the other but blood

culture was negative probably because of anti-biotic therapy.

Coagulation studies were carried out on 130cases of shock at the Third Surgical Hospital inVietnam. The general character of these patientswas different from those at Walter Reed. TheVietnam cases generally had severe oligaemicshock from battle wounds. However, most were

easily restored to a normal condition by trans-fusion and only a few could be regarded as

'refractory' shock, unlike nearly all the cases

studied at the Walter Reed Hospital.Sixty of the 130 cases had coagulation abnor-

malities. In general, these were of two types,

hypercoagulability and hypocoagulability. Evi-dence of hypercoagulability was found in 14subjects with prothrombin times less than 11seconds or partial thromboplastin times below30 seconds (Fig. 12). This may be analogous to thehypercoagulable phase of haemorrhagic shock indogs discussed earlier (Fig. 2). Evidence of hypo-coagulability was found in 46 patients who hadprolonged prothrombin times (over 16 sec) or

partial thromboplastin times (over 75 sec). These,in general, were the most severely shockedpatients. Increasing severity of clotting defects wasassociated with death whilst a rapid spontaneous

repair of the clotting defect was associated withrecovery.

Another group of 45 seriouslywounded patientswere studied at the 93rd Evacuation Hospital in

Patient Plasma Platelet Count Patients Control Clotting Factor AssaysFibrinogen per cmm(mg %) PT PTT PT PTT II V VIII IX X XI XII

1 238 16,500 19-0 60-4 13-2 38-42 228 31,000 16-2 72-8 12-5 37-6 46 59 100 57 543 347 111,000 15-6 49-4 12-5 41-64 359 102,000 13-0 215-8 13-2 42-5 45 66 48 2 17 955 542 265,000 14-5 120-5 13-0 55-06 318 24,000 15-8 255.0 12-3 43-0 50 32 10 37 777 400 99,500 15-8 75-0 13-4 47-4 100 86 59 56 488 235 97,500 17-9 71-6 13-9 44-39 280 16,500 19-3 61-9 14-5 48-210 290 154,000 120-0 180-0 14-9 42-011 650 101,500 25-4 93-4 13-5 48-3 100 63 35 26 1512 320 8,000 22-0 86-2 12.5 41-013 355 8,000 19-0 72-6 13-0 44-3 45 35 67 23 9014 160 29,000 16-2 132-0 13-6 41-615 165 3,000 37-0 263-4 13.3 46-2 23 5 3 6 1816 150 57,000 17-8 277-0 14-3 55.917 355 116,000 15-2 49.0 13-7 44-718 184 13,000 26-4 207-0 13-3 44-9 6 12 54 23 2919 355 110,000 15-2 49-0 14-5 44-820 184 12,500 26-4 207-0 13-5 46-8 6 12 54 23 2921 50 18,000 33-0 240-0 14-1 40.522 605 83,000 14-9 50-5 14-3 46.523 367 3,500 16-0 116-9 13-1 48-224 240 15,500 52-5 107-4 12-9 35-725 525 29,500 16-6 76-6 14-6 48-526 325 140,000 14-4 44-9 14-2 54-727 465 31,000 2-22 86-6 12-8 47-128 436 33,500 17-4 52-0 12-7 47-329 310 12,000 30-6 94-2 14-5 55-5

Average 305 59,000 24-5 119-0 13-5 43-9 46 41 48 38 35 20 50

Table I Clotting factor depletions noted in patients treated in the Walter Reed Hospital shock unit

PT, prothrombin time; PTT, partial thromboplastin time, both in seconds. Factor assays are percentages of normal.

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20 _

80 _ M. D.

18 _ 4070

16 30PTT 6

14 : -2 0PT 50

12 X.

40 - 10 15 Units of Blood ' 1-1 L s°t )Seconds o (mtm_%_

80 L.C.

18 X-4070

is 30

60

14 - 20

s0

12 - -- - 1.t

40

12 24 36 48 60 72Hours

Fig. 13 Serial blood clotting and lactate studies intwo casualties. Patient M.D. retained clottingstability despite rapid transfusion of 15 units of bloodin three hours. He was never significantly hypotensive.Patient L.C. entered the hospital hypotensive withabnormal clotting studies before transfusion. Heillustrates a type of response to transfusion that mightbe seen in factor-deficient individuals.

PT, prothrombin time; PTT, partial thromboplastin time.

Fig. 14 Thromboelastogram on a patient studied inthe shock unit. On admission the blood clotted althoughthe clotting time was somewhat prolonged and the clotnot as firm as normal. However, the patientdeteriorated and the next three thromboelastogramsfailed to show any clotting at all. The patient died thefollowing day.

Fig. 15 On the left are three thromboelastogramsfrom a patient treated on the shock ward. Onadmission (far left) his bloodfailed to coagulate in thethromboelastogram; this improved to normal onsuccessive days and the patient recovered. On theright is a group offour thromboelastograms onanother patient. On admission (left) the blood failedto clot normally and the poor clot lysed due toendogenous fibrinolysin as denoted by the narrowingof the figure below. On subsequent days thethromboelastogram reverted to normal and the patientrecovered.

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The significance of coagulative and thrombotic changes after haemorrhage and injury

Vietnam, 27 of whom showed some clottingdefect. All required transfusion but the multipletransfusions could not account for the clottingdefect.The plasma fibrinogen levels did not vary

greatly during the acute phase of injury andtransfusion and formed no recognizable patternor correlations except for a steady rise beginningone or two days following injury.These patients had at least four different factors

influencing the clotting mechanism: 'shock',multiple transfusions of stored citrated blood,extensive local tissue damage, and tissue (andpossibly thromboplastin) embolization. Eachfactor appears to have a positive correlation withthe clotting defect (Table II).

Significant hypotension (systolic pressure bycuff measurement less than 90 mm Hg for morethan 20 minutes) was associated with a clottingdefect though hypotension during anaesthesia didnot seem to have the same significance (vaso-dilatation) (Tables II and III). The rise in lactateduring an hypotensive episode under anaesthesiawas often slight, indicating better tissue perfusionthan during similar hypotension in an un-anaesthetized patient.Among 34 patients receiving up to 15 units of

blood, the clotting studies were normal in 18 andabnormal in 16 cases (Tables IV and V). Incontrast, each of the 11 patients receiving morethan 15 units ofblood had clotting abnormalities inthe period after injury. Unfortunately, othermajor variables cannot be separated, because all11 had also been hypotensive before anaesthesiaand none had normal postoperative blood oxygentensions.Twenty-one of the 27 patients with clotting

defects suffered blast or high velocity missileinjuries with major long-bone fractures. One ofthe remaining six sustained a severe closedabdominal injury and cardiac arrest duringoperation. Among the 18 patients with no clottingdefects, 14 sustained blast or high velocity missileinjury, but only six had major long-bone fractures,possibly indicating less extensive local damage inthe group with no clotting defects.There was more definite evidence for an

association between embolization and a clottingdefect (Table VI). Excluding patients with chestand abdominal injuries, seven of 19 patients withclotting defects had unexplained preoperativearterial hypoxaemia, and therefore presumedembolization. Only three of 12 patients withoutclotting defect had evidence of embolization. Ifpostoperative hypoxaemia is also considered, andthis has many more variables, only three of the 19subjects with clotting defects retained normalblood oxygen tensions throughout, compared withseven of the 12 without clotting defect.Most of the patients studied had a combination

of the four factors mentioned. Extensive tissuedamage was common in both groups, but theother three factors were less common. Each of the

No Defects ClottingDefect

Total cases 18 27'Shock' 3 3Transfusion > 10 units 1 0Presumed embolization 2 1Shock + transfusion 0 10Shock + embolization 0 3Embolization + transfusion 1 1Shock + embolization + transfusion 0 2None of the above 11 7

Table II Presence or absence of clotting defects in 45patients related to shock, transfusion of more than 10units, and presumed embolization or various combina-tions

No Defects ClottingDefect

Total cases 18 27Hypotensive before anaesthesia 3 20Hypotensive only during anaesthesia 4 2Never hypotensive 11 5

Table III Clotting defects in 45 patients related to theoccurrence ofhypotension

Blood Transfusion (Units Blood) No Defect Clotting Defect

0-15 18 1615 + 0 111

Table IV Defects in 45 patients related to extensivetransfusion'Also hypotensive and hypoxaemic

Blood Transfusion (Units Blood) No Defect Clotting Defect

1- 9 14 1310- 19 4 520- 30 0 430 + 0 5

Table V Presence or absence ofa blood-clotting defectin 45 patients related to the volumes ofblood transfused

Arterial Hypoxaemia No Defect Clotting Defect

Total cases 12 19Preoperative 3 7Postoperative only 2 8No hypoxaemia 7 4

Table VI Patients with and without clotting defectsaccording to presumed embolization (preoperativehypoxaemia)l'Excluding patients with chest or abdominal injury.

three factors, 'shock', extensive transfusion (morethan 10 units of blood in the first 24 hours), andembolization (unexplained preoperative hypox-aemia), was rare in the absence of the other twoand no apparent association with a clotting defectwas seen in these few patients (Table II). All

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combinations which included 'shock', however,were associated with a clotting defect.No pattern of change associated with rapid

transfusion emerged in this series: six normo-tensive patients given 6 to 15 units of blood rapidlyhad normal clotting studies at all times.

Figure 13 illustrates a shortening of clottingtimes during rapid transfusion from initiallyprolonged values, with subsequent prolongationseveral hours after cessation of transfusion. Thiskind of response is seen during temporary replace-ment of depleted clotting factors by transfusedblood or blood products. The pattern is not thatexpected if bank blood were responsible for thebleeding problems often attributed to its use.Shortening of clotting times during rapid trans-fusion with later prolongation was seen in eightpatients.The more expected change, a lengthening of

clotting times with rapid transfusion, was seen insix patients, but the clotting times decreased astransfusion was continued.

Finally, no definite pattern of change infibrinogen levels could be detected. Any changeswere relatively small in the acute phase. Of courseall the patients were transfused with blood withnormal fibrinogen levels. Fibrinogen levels oftenrose to about 1,000 mg per 100 ml on the secondor third day after injury, especially in those withhigh velocity missile injuries. At this time theprothrombin and partial thromboplastin timeswere usually below normal.

In spite of the uncontrolled nature and multi-plicity of the variables in this study, severalconclusions seem warranted. Severely injuredcombat casualties often exhibit clotting abnormali-ties during the acute phase of injury. Thisappearedto be associated with extensive tissue damage,extensive transfusion of stored blood, presumedembolization at the time of injury, and haemor-rhagic hypotension. Of all the factors, hypo-tension seems the most important. Combinationsof factors, especially with prolonged hypotension,increased the likelihood of a clotting defect.Neither the aetiology nor the clinical significanceof the clotting changes was apparent in this studyexcept for an association with severely injuredpatients. Extremely abnormal clotting values wereseen only in the few who died. Clinical bleedingproblems were rare, but when they occurred it isnot justifiable to attribute them to clottingaberrations due to replacement of the patient'sblood with bank blood. Hypoperfusion appearedto be more important in our clinical study andalso experimentally.Most patients studied received stored bank

blood for the treatment of oligaemia and duringsurgery. It is known to differ from normal circulat-ing blood in many ways. In contrast to the situationin large civilian hospitals, the blood used in a fieldmedical unit in a combat zone necessarily travelslong distances, and usually undergoes several shortperiods with little or no refrigeration. Generator

failures, especially during the monsoon season,are expected occurrences and are accompanied byunavoidable variations in blood-bank-refrigeratortemperatures. For these reasons it was of interestto estimate the clotting properties of the bankblood at its point of usage. Blood was drawn fromthe intravenous tubing during the latter half of atransfusion and handled exactly as for arterialsamples except that additional citrate was notadded for the clotting studies. All the bloodstudied was in Fenwal plastic bags said to contain450 ml blood plus 67-5 ml NIH solution A. All theunits of blood were administered throughdisposable field-type blood recipient sets (Fenwalor Burron).The results are summarized in Table VII. Bank

blood, even old bank blood, has a relativelynormal coagulation profile. In most cases it shouldnot contribute to a coagulation defect, but shouldactually help to correct it.

Partial Thromboplastin Prothrombin FibrinogenTime Time (mg %)(sec) (sec)

Old bloodMean 65 18 390Range 55-91 14-23 290-510

Fresh blood 47 13-8 365

Table VII Measurements of bank blood administeredat the 93rd Evacuation Hospital''Old blood' represents 15 units of blood within five days of

expiration, 8 units actually on the day of expiration. 'Fresh blood'represents a single unit of blood given four hours after shedding.All blood used was supplied through the 406th Medical Laboratory(Japan) and its mobile element in Vietnam.

On the basis of our studies, one conclusion canbe surely drawn: definite changes in the bloodclotting values of these young, acutely injuredadults who require blood replacement, cannot beattributed simply to the use of bank blood.

Summary

Severe or refractory shock due to trauma,infection, or other cause is usually associated withan episode of disseminated intravascular coagu-lation as manifested by the rapid development ofa consumptive coagulopathy, and the finding ofmultiple intravascular thrombi associated withareas of focal necrosis in various vital organs.

References

Borgstrom, S., Gelm, L. E., and Zederfeldt, B. (I1959). The formationof vena thrombi following tissue injury. An experimentalstudy in rabbits. Acta chir. scand., Suppl., 247.

Bywaters, E. G. L. (1942). Crushing injury. Brit. med. J., 2, 643-646.

Hardaway, R. M. (1968). Clinical Management of Skock.Thomas, Springfield, Ill.

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