POSTGRAD. MED. J. (1965), 41, 80

ANTE-PARTUM THROMBO-EMBOLISMJ. J. TAYLOR, M.B., B.S. (Lond.)

Senior Registrar in Clinical Pathology, United Birmingham Hospitals.*

WHILST thrombo-embolism is a well recognisedcomplication of the puerperium, ante-partumit is rare. No mention of its management isto be found in standard textbooks. Despitecontroversy concerning the value of anti-coagulant treatment in arterial thromboticdisease, the efficacy of this therapy in venousthrombo-embolism is now well established. Theapparent rarity of this condition in the ante-partum period and its high mortality rate,coupled with the special hazards of anti-coagulant treatment at this time prompt thisreport of two cases, in one of which the outcomefor both mother and baby was favourable andanother where post-mortem cwsarean sectionwas employed.

Pathogenesis of Thrombo-embolismin PregnancyChanges in the BloodFormed elements. During pregnancy both

plasma volume and red cell mass increase.From about the third month onward mildleukocytosis may be found especially in primi-gravide. No consistent change in platelet countor morphology occurs. The result of thesechanges is an increase in the total circulatingnumber of all formed elements.

Coagulation factors. Factor 1 (fibrinogen)rises during the first eight weeks and remainselevated throughout pregnancy. Whilst factorII (prothrombin) may fall a little in the latermonths there is a decreased titre of anti-thrombin and fibrinolysin. Due to the increasein plasma protein in pregnancy there is thusan increased amount of circulating coagulationfactors.

Changes in the VesselsVaricose veins are commonly seen in preg-

nancy, at which time the vulva, 'broad ligamentsand uterus may be severely affected. Withinthe pelvis marked increase in vascularity occursand the cardio-vascular system as a wholeexhibits a hyperdynamic state. It thus seemsunlikely that intimal hypoxia can develop innormal vessels; where there is local pathologyhowever the increased circulation rate may be*Present address: Dept. of Haematology, QueenElizabeth Hospital, Birmingham, 15.

deleterious leading to eddy formation, thecentral core flowing rapidly on, and the peri-pheral lamine suffering varying degrees ofobstruction. Such a hypoxic condition of theintima predisposes to thrombus formation,damaged intimal cells having thromboplasticactivity (O'Brien, 1959).

Experimentally, blood 'between venousligatures remains fluid, but when veins areisolated from their own vascular and nervoussupply thrombosis occurs and is preceded bychanges at the intimal surface. By a silvernitrate technique with flattened intimal pre-parations it has been shown that under suchconditions platelets adhere to and outline theintercellular 'borders. Subsequent viscous meta-morphosis leads to the formation of a mass ofplatelets and fibrin which may be accompaniedby dissolution of the endothelial wall (O'Neill,1947).Aggregation of polymorphs and monocytes

around the platelet clumps leads to theformation of the white-headed or "coralline"(coral-like) thrombus, a description derivedfrom the ramifying nature of the structure soformed. From this further strands of fibrinextend to enmesh red cells and so is formedthe red-tailed thrombus (Poole, 1959). Detach-ment of the latter may give rise to clinicalattacks of embolism.

StasisConclusive proof of stasis in the legs during

pregnancy has been provided by the use ofradio-active sodium (Wright, Osborn andEdmunds, 1950). SeVeral factors contribute,among them the decreased action of the diaph-ragmatic pump, diversion of blood through theplacenta, the obstructive effect of the increasedvolume of pelvic venous return where it entersthe iliac veins, and local uterine pressure onthe intra-abdominal veins, including the inferiorvena cava (Burwell, 1938; Kerr, Scott andSamuel, 1964).When the blood stream slows platelets be-

come more plentiful in the peripheral slower-moving lamina than in the central core; in thisposition they are more accessible for attachmentto the intimal surface, a sequence of eventswhich has been demonstrated cinematographi-cally (Witte and Schricker, 1958).

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Uterine swellingThrombosed pelvic veins may be seen at

operation in the presence of uterine swellings,local sepsis and in pregnancy. Despite thefrequency with which leg vein thrombi canbe demonstrated in fatal cases of embolism itis however likely that emboli can and do arisefrom the pelvic veins in the absence of clinicalor autopsy evidence of leg vein involvement.Role of the Placenta

Trophoblast has a powerful proteolyticaction, and in normal pregnancy deep invasionof decidual and myometrial tissues occurs.Microscopically, penetration of maternal veinsis common, and from time to time portions ofsuch tissue may suffer detachment coming torest in the lungs. Such trophoblastic embolismoccurs more frequently as pregnancy proceeds(Attwood and Park, 1961); trophoblast hasalso been seen in the blood from uterine veins(Douglas, Thomas, Cullen and Morris, 1959),and very rarely chorionic villi may be seen asemboli (Bardawil and Toy, 1959).

Experimental trophoblast emiboli evoke notissue reaction in the lung nor is thrombosisa feature (Park, 1958), suggesting that whilstplacental tissue is a rich source of thrombo-plastin, detached trophoblastic cells do notpossess sufficient activity to initiate localthrombosis or that inhibitory mechanisms maybe operating. The demonstration of fibrinolyticactivity in pulmonary veins (Todd, 1959), butnot in placental tissue (Beller, Goessner andHerschlein, 1962) suggests some local pul-monary mechanism.On rare occasions giant trophoblastic emboli

have caused death in both normal pregnancy(Marcuse, 1954) and in hydatidiform mole(Hughes, 1930; Trotter and Tieche, 1956). Thesyndrome of pulmonary hypertension due torepeated tumour emboli from chorion carci-noma is now well known.Predisposing factors

In most recorded cases to date generallyaccepted predisposing factors (heart disease,anemia, post-operative states, prolonged bedrest, trauma or neoplasm) have been absent.Multiparity, multiple pregnancy and pre-eclampsia have been more commonly associatedthan primiparity. Thrombophlebitis precedesembolism in the majority of cases but theclinical evidence of leg vein involvement issometimes delayed; recurrence of thrombo-phlebitis seems likely in subsequent pregnancies.There may be a racial or geographical factor,embolism being rare in Asians in Asia;

embolism is exceedingly rare in the loweranimals. While thrombophlebitis is commonin pregnancy it may also be a presenting signin systemic infections, blood dyscrasias andcollagen diseases (Barker, 1936a; Miller andDaley, 1946). Superficial thrombophlebitisfailing to respond to phenylibutazone is asinister sign suggesting the Trousseau pheno-menon (Stein, 1955). There is no convincingevidence to date that hormone preparationsplay any part in the genesis of thrombo-embolism in pregnancy.

Case ReportsCase No. 1

Mrs. M.M., aged 28 years, a primigravida marriedfor six years, had been attending her generalpractitioner for ante-natal care. All went well untilearly June 1959, when at the twenty-eighth week ofgestation she developed pain, swelling and tendernessof the right calf associated with prominent tenderveins. Thrombosis with phlebitis was diagnosed anddomiciliary treatment with poultices, 'bed rest, sup-portive dressings and oral penicillin was instituted.She had had no previous illness although she wassubject to recurrent epistaxis. Satisfactory clinicalresolution appeared to occur over the next weekand she became ambulant again.On the 13th July she suddenly developed pleuritic

pain below the right breast and became dyspnceic.Pleurisy was diagnosed but as her condition beganto deteriorate hospital admission was sought on15th July.On Examination in the ambulance by the author

she was a well-covered young woman who appearedin danger of imminent death. Her colour was ashen,profuse sweating was present, the radial pulse wasimpalpable and severe dyspncea was present. It wasimmediately apparent that marked deterioration hadoccurred during the ambulance journey. Adminis-tration of oxygen and the adoption of the supineposition produced considerable relief. At this timethere was no clinical evidence of leg vein thrombosis.Impaired movement, dullness to percussion, decreasedbreath and voice sounds were elicited from the rightlower chest. Central cyanosis was present, the radialpulse was now palpable, regular, 110 per minute,B.P. 110/50 mm. Hg.; she was apyrexial but slightfinger clubbing was noted. The peripheral pulseswere present, equal and not delayed, there was noevidence of pulmonary cedema, no evidence of pre-existing cardiac or respiratory disease was elicitedand no cervical emphysema was detected. Despitethe minimal changes in the ECG it was feltthat she had had a major episode of pulmonaryembolism (Fig. 1), and immediate treatment consistedof continuous oxygen, six-hourly heparin and power-ful analgaesics as required to reduce pain and allowdeeper respirations. A course of systemic tetracyclinewas commenced.

Investigations: WBC 15,700/cu. mm.; ESR (Wester-gren) 78 mm. /hr., SGOT 25 units, SGPT 20 unitsper ml. The fundus uteri corresponded in height toa pregnancy of 34 weeks, the fcetal position wasright occipito-anterior, movements were active andthe heart was easily heard.On this regime she gradually improved until 20th

July when there was a further attack of overt

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FIG. 1.-Case 1.

embolism which again rendered her state critical.Subsequently however, on the same regime, she maderapid progress, ambulation and oral anticoagulanttherapy being introduced and she was allowed homebeing seen weekly for review. On 17th August a furtherepisode of embolism caused her readmission and thereinstituting of heparin therapy by repeated intra-venous injection. There was now a right paravertebralsystolic bruit which was attributed to stenosis of alarge branch of the right pulmonary artery con-sequent on the previous attacks of embolism. Againthere was gradual improvement and on 19th Sep-tember clear amniotic fluid was removed followingthe passage of a Drew-Smythe catheter. Labourbegan six hours after this operation and progressednormally. No heparin was administered followingthe onset of labour and no attempt at heparinreversal was made. Oxygen was given by face maskto relieve cyanosis which was at times severe. Aftera first stage of six and a quarter hours, a spon-taneous delivery of a normal living female infanttook place (weight 5 lbs. 14 ozs., length 19 inches,head circumference 121 inches). The second stagehad lasted sixty five minutes and twenty five minuteslater a normal placenta complete with membraneswas delivered. There was no retroplacental clot andthe total blood loss was within normal limits.

Oral phenindione was commenced twelve hoursafter delivery, breast feeding was not permitted andambulation was begun three days after delivery.Lochia persisted for two weeks and was normal inappearance and volume. By the 26th Septemberthe chest was clinically clear although the bruit wasstill faintly audible on deep inspiration. She wasallowed home on 13th October and continued normalprogress as an out-patient still taking phenindione.Towards the end of November she began to feelunwell, had attacks of shivering and on 28th had aprofuse epistaxis. By 30th November her conditionwas again serious (Temp. 102', rapid shallow res-pirations, cyanosis, increased clubbing, and thick

yellow sputum) and she was thought to have anaspiration pneumonia. Persistent epistaxis which wasdraining into the pharynx ceased after the withdrawalof phenindione (at no time had the one-stage pro-thrombin time exceeded twice the control value).Swinging pyrexia and amphoric breath sounds in theright lower lobe suggested pulmonary abscess.Following surgical advice a prolonged course ofantibiotic treatment ensued with the gradual abate-ment of fever and sputum. Recovery was howeverfurther complicated by the development of a left ilio-femoral thrombosis; this subsided rapidly followinga heparin infusion and her return to normal activitywas unimpeded. Three years later she remains ingood health. During the period described no adversefeatures were discovered in the baby.

Case No. 2A woman collapsed suddenly in a large store.

On arrival at hospital she was found to be dead,but the uterus which was distended to a level betweenthe umbilicus and the xiphisternum contained a livefcetus. Post-mortem casarean section was performedand the baby obtained alive although death followedsix hours later.Necropsy. The body was obese, measuring 5 feet 6

inches in height and weighing 18 stones 3j lbs. Theright lower limb was thicker than the left but therewas no pitting cedema. Internally thrombus waspresent in the right common iliac vein and in theright femoral vein. Portions of the thrombus wereless adherent than others and some portions appearedto have become detached. An impacted thrombuswas present in the left main pulmonary artery.A benign colloid goitre was present, and the uteruscontained many large, soft, sub-serous fibroids show-ing lymphangiomatous degeneration.

Histological examination of the thrombus con-firmed its nature and the absence of decidua ortrophoblast.

DiscussionThe diagnosis of ante-partum pulmonary

embolism is rarely made, but when charac-teristic symptoms and signs occur shouldpresent little difficulty. Atypical presentationssuch as 'pleurisy' (as in Case 1), 'pneumonia',cardiac failure, renal failure, progressive fatigue,syncope and hypotensive episodes occasionallycause confusion (Sevitt and Gallagher, 1961).Rarely pulmonary embolism presents so as toresemble bacterial endocarditis, gastro-intestinal disease or cerebro-vascular disorder(Hamilton and Thompson, 1963). Pulmonaryartery thrombosis rarely arises in the absenceof preceeding cardiac, respiratory or generalmedical disease (e.g. blood dyscrasia).Cardiac infarction occurs in pregnancy

(Magner, 1960) and is sometimes difficult todistinguish from massive pulmonary embolism(Wood, 1956). Shock, severe chest pain, fever,leukocytosis, and an elevated sedimentationrate are common findings in both conditions,the latter also being elevated in normal preg-nancy. High levels of transaminase activity

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may be found in both and in the early difficultstage lactic dehydrogenase activity may bemore helpful.

Evidence of right ventricular stress is pro-vided by the electrocardiogram, but changesmay not develop for several days. Serial recordsare therefore imperative in doubtful cases.Furthermore in pregnancy there is usually aprominent S wave in lead I, and a Q in leadIII which is associated with an inverted T wave,changes due to the rotation of the heart. Whenpulmonary embolism sufficient to cause rightventricular stress occurs, sinus tachycardia, lowvoltages and similar changes to those of normalpregnancy are seen in standard leads. The Qwave in lead III being due to rotation is notreflected in aVF. Occasionally tall peaked Pwaves are seen in lead II. The precordial leadsshow inverted T waves in V1-3 or even furtherwhen there is much rotation. These changesare not dissimilar to those of posterior myo-cardial infarction, transient ST segmentelevations in leads III and aVF being seen inboth occasionally. Skiagrams show variableevidence of infarction but are often of littlevalue in the early stages. Dissecting aneurysm(Schnitker and Bayer, 1944), ruptured esopha-gus (Kennard, 1950), spontaneous pneumo-thorax, and acute pulmonary cedema (Szekelyand Snaith, 1957) are distinguished by theircharacteristic clinical features.

In Case 1 there was no known previousmedical atbnormality and no signs of chronicdisease were elicited on physical examination.The typical appearance of the patient whenfirst seen with the history of thrombophlebitisthree weeks previously immediately suggestedthe diagnosis of thrombogenic pulmonaryembolism. No retrospective evidence in supportof alternative diagnosis was obtained.With general supportive measures alone both

fcetal and maternal mortality rates are alarm-ingly high. Shock occasioned by pulmonaryembolism may be counteracted by pressoramines as first shown by Wolff (1954), and thesuccessful use of this measure in these circum-stances during pregnancy was reported bySilbthorpe (1955). Corticosteroids, if used,would probably also need to be given duringlabour and to the newborn.Even when there is an obvious thrombotic

site in the legs, and although success has beenattributed to venous surgery (e.g. Adamson,Weaver and Jaimet, 1950 case 2), proximallig4tion gives no guarantee of success since theembolic focus may be elsewhere. Inferior venacaval ligation is attended by considerable

dangers (Aird, 1958) and might presentdifficulties in late pregnancy. Paravertebralsympathetic block to relieve spasm is contra-indicated in the course of anticoagulanttreatment owing to the very real risk of retro-peritoneal hemorrhage (Lilly and Lee, 1949).There is now convincing evidence that

properly controlled anticoagulant therapy is amajor advance in treatment. Previously pul-monary embolism in pregnancy had beenattended by high mortality variably assessedas from 15% (Mansell, 1952) to 60% (Ullery,1954). The use of anticoagulant drugs hasreduced maternal mortality to very low levelsbut there exists a hazard to the fcetus. In thenewborn the coagulation mechanism is deficientand in prematurity this disturbance is moremarked. Since coumarin-indanedione drugs acton the liver serious coagulation defects mightbe expected if these drugs pass the placentalbarrier. Schofield (1924) showed that the calvesof cows which had fed on spoiled sweet cloverdeveloped fcetal hlmorrhages, and Quick (1946)and Kraus (1949) showed that transplacentalpassage of dicoumarol occurred (in dogs andrabbits respectively). At least twelve cases offoetal hiemorrhage in man are recorded andother unrecorded cases are known to the author.

In the first reported case (von Syndow, 1947),treated in the last month of pregnancy, severecerebral and subcutaneous fcetal h=morrhageswere present. Quenneville, Barton, McDevittand Wright (1959) described three cases in twoof which the maternal one-stage prothrombintime was depressed below presently acceptablelevels, but even when this test shows less thanaccepted therapeutic levels fcetal hiemorrhagehas still occurred. In the presence of cardiacfailure increased sensitivity to these drugs iscommon (Owren, 1954). Mahairas and Wein-gold (1963) using warfarin sodium in a patientwith cardiac failure of rheumatic origin notedthe prothrombin time to be 'labile' and afteithirteen days' treatment fcetal death occurred.Thymic and retroplacental hamorrhages werefound at autopsy. Further examples are thoseof Sachs and Labate (1949) and Gordon andDean (1955), the latter authors recommendingthe use of the two-stage prothrombin time testas a more adequate procedure. Due to themultiple defect produced by the coumarin-indanedione drugs a test which measures thisoverall effect might be deemed more advisablein pregnancy (e.g. "Thrombotest").Apart from the single case of Mahairas andWeingold (1963) retroplacental haemorrhage hasnot been a feature of anticoagulant treatment

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84 POSTGRADUATE MEDICAL JOURNAL February, 1965

in pregnancy, several series now being available,some of them admittedly small (Yahr, Reichand Eggers, 1945; Logan, O'Driscoll andO'Donoghue, 1951; Mansell, 1952). Barnes andErvin (1946) showed that excessive bleeding isnot a feature of the puerperium, during anti-coagulant treatment and this is now commonexperience. Although labour has been allowedto proceed during full anticoagulant dosage itwould seem wiser to withhold treatment duringlabour and delivery, as in Case 1.No foetal hemorrhage has been recorded

attributable to the use of heparin duringpregnancy, possibly due to its high molecularweight-about 20,000 (Reynolds, 1949). Theonset of heparin action is rapid, the effectprofound, rapid antagonists are available andtransplacental passage is unknown. Coumarin-indanedione drugs are slower in onset, theireffect is less profound on the maternal system,reversal is accomplished less easily and takeslonger, and transplacental passage is wellrecognised, Severe anaphylactic reactions toheparin are now exceedingly rare whereas thenumber of reported incidents with oral anti-coagulants is constantly growing and many ofthese are often fatal. In the absence of acceptedcontra-indications to anticoagulant therapy, orin the situation under discussion where theserisks are outweighed by the danger of furtherfatal embolus, anticoagulant treatment in theantepartum period should be with repeatedintravenous doses of heparin. (Six-hourly dosesof the order of 10,000 units require no super-vision of the clotting mechanism in the absenceof shock; if a continuous heparin infusion isset up then the clotting mechanism should bemonitored either by the whole blood clottingtime or by the quicker and more reliablethrombin clotting time. In either test thetherapeutic ratio in overt pulmonary embolismshould be nearer three than two-Wood, 1956).

Post-partum anticoagulant therapy with theoral type of anticoagulant drug must be con-tinued for an extended period in an attempt toprevent the development of subacute thrombo-embolic pulmonary hypertension (Wood, 1956).A period of at least one year has been recom-mended for this phase of management, but inCase 1 the danger of further epistaxes (to whichshe was particularly prone) and repeatedpneumonic episodes with further lung damagewere thought to outweigh any advantage to begained from long term treatment. Three yearsafter delivery she remains in good health.The possible place of newer anticoagulant

drugs and thrombolytic therapy has not beendiscussed.At a recent Scientific Session of the Royal

College of Obstetricians and Gynaecologists thisproblem received only passing mention and theimpression was gained that pulmonary embo-lism is a result of putting patients to bed. Arecent review of the causes of sudden death inapparently healthy people in Philadelphiasuggests that there may be other factors atwork in obstetric patients; five cases of fatalpulmonary embolism were discovered inwomen in the first trimester of pregnancy(Breckenridge and Ratnoff, 1964). In noneof these cases were any unusual elementspresent in the emboli (Breckenridge, 1964).SummaryTwo new cases of ante-partum thrombo-

embolism are reported, a brief survey of thepathogenesis of this condition is made withspecial reference to pregnancy and the problemsof anticoagulant treatment are discussed.Heparin is at present thought to be the agentof choice in this situation.

I am indebted to Mr. H. Roberts for permission toreport the clinical details of Case 1, and to Mr.G. Billington, H. M. Coroner for the City ofBirmingham, and Dr. D. A. Heath for allowing meto include Case 2.To both Mr. H. Roberts and Dr. C. W. Taylor

I owe sincere thanks for their advice, criticism andencouragement during the preparation of this paper.

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AIRD, I. (1958): Companion in Surgical Studies,London: E. & S. Livingstone.

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