The occurrence of thrombosis and pulmonary embolism in pneumonia

Acta Medica Scandinavica Vol. CXIII, fasc. IV, 1943.

From the Medical Clinic (Director: Professor Sven Ingvar) of the Royal University at Lund (Sweden).

The occurrence of thrombosis and pulmonary embolism in pneumonia.

BY

ERIK ASK-UPMARK, M.D. (Submitted for publication November 25, 1942).

Thc occurrence of venous thrombosis and pulmonary embolism in connection with disorders belonging to the internal medicine has been well established during recent years. I t has even been n-aintained that the incidence of fatal pulmonary embolism should be greater in internal diseases than after surgical interventions (for references see Geissendorfer 1935 and Hultquist 1936). Neveithe- less, theie is a striking disproportion between the numerous surgical investigations dealing with this much dreaded complication and the comparatively feeble interest devoted to the matter by internal authors. The reasons for this difference may be variable but one of them is doubtless the fact that whereas thrombosis and pulmonary embolism, appearing in connection with an operation, may be ascribed to a definitely timed traumatic incidence, the surgical intervention, difficulties in this regard do arise when most internal disorders are about. If, for example, a venous thrombosis should occur during the course of a pulmonary tuberculosis or a valvular lesion of the heart, the chronic nature of these conditions makes i t difficult or impossible to attempt an explanation why the thrombosis should have occurred just at that very moment of the sequence of events. Thcrc are, as a matter of fact, only few internal disorders, complicated by thrombosis-embolism (TE), where it swms

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possible to obtain a definite time table between the primary pathological lesion and the secondary appearance of the coniplication in question. Such disorders are lobar pneumonia, coronary thrombosis and certain instances of pernicious anemia (cases not previously treated, where the onset of the treatment may be selected as the staIt point of the itinerary). The occurrence of TE in connection with lobar pneumonia represents a well established issue (cfr. for example Reimann 1938 and Ingvar 1939). The present study will attempt an analysis of this occurrence of TE in pneumonia with special regard to the chronological point of view. Investigations dealing with the same matter in coronary thrombosis are to be published in another communication.

All instances < 40 years

pneumonias . . . . . . . . . . 979 578

. . . . . . . . . . 475 203 . . . . . . . . . . . . . . . . . . I6 6

I { TE . . . . . . . . . . . . . . . . . . 11 5

2 40 years

401 6

272 10

It will be seen that the percentage of TE in pneumonia was in males about 1.1 yo, in females 3.4 yo. If the various ages are considered the percentage will become: -

< 40 years > 40 years in both sexes ...................... 1.4 % 2.2 % in males .......................... 0.9 % 1.5 % in females .......................... 3 % 3.7 %

Although no undue importance should be applied to these figures on account of the limited size of the available material i t may be presumed that TE is more frequent among older than among

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younger persons afflicted with lobar pneumonia and more common in feniales than in males. This incidence is in accordance with the general experience on the occurrence of TE after surgical operations. A more detailed review of the various observations will be found i n the following table.

Table 2. Sex and age of TE.

The youngest iiian was 17, the oldest 57. The youngest wonian was 26, the oldest 70. In most instances the primary manifestation of' the TE was represented by venous thrombosis but in 8 cases pulmonary embolism was the first lesion t o be observed (in 4 males, agcd 17, 21, 43 and 49 and in 4 feniales, aged 27, 56, 66 and 70, the embolism becoming fatal in two men, agcd 43 and 49 and one woman, aged 66).

With regard to the frequency of TE in the various years concerned by the material the following table will be a brief summary.

Table 3. Incidence in various years of TE.

1916-1920 1 (male) 1921---1925 3 (1 male, 2 females) 1026-1930 5 (3 males, 2 females) 1931-1935 2 (1 male, 1 female, last case 1932) 1936-1940 13 (4 males, 9 females, first case 1938) 1911 3 (1 male, 2 females)

I t should be observed tha t during the last 4 years (1938-41) more (16) instances of TE have been taken to the records than during the preceding 22 years (1916-1937: 11 cases). The most outstanding cause for this remarkable fact seems to be the introduction of specific therapy, by means of which instances have been brought t o survive, who otherwise might have succumbed before their having Ihe opportunity t o develop TE. Thus, in

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1938-1941 there are 16 TE in 353 pneumonias = 4.5 yo; 1916-1937 )) )) 11 T E D 1101 0 = 1 yo.

Specific treatment (serum, chemotherapy or both of them) was applied to 12 out of the 16 instances of TE observed since 1938; i t was applied to none of the 11 cases previously observed. I t might, on the other hand, be surmised that the apparent increase of T E in the pneumonias during the last 4 years be due to an alteration of the material with regard to the age or the sex of the patients afflicted with pneumonia. That such cannot be the case will be seen from the following considerations.

All pneumonias Pneumonias < 40 years Before 1938 . . . . . . . . . . . . . . 1101 499 1938-1941 . . . . . . . . . . . . . . . . 353 182

Before 1938 . . . . . . . . . . . . . . 1101 346 1938-1941 . . . . . . . . . . . . . . . . 353 129

1\11 pneumonias l'emales

The percentage of aged and of women, i. e. of the groups according to table (1) and (2) most severely affected by TE, is obviously the same during the two periods here concerned. On t h e other hand the percentage of aged survivors has most certainly increased during the recent period on account of the introduction of specific treatment; and this seems to be the main reason for the increased percentage of TE in the material since 1938. The question may be raised whcther not the specific therapy in itself may favour the development of TE. An apparent support for this view may be derived from the fact that before 1938 there were 599 pneumonias of less than 40 years of age, including 6 TE (= 1 %), whilst 1938- 1941 there were 182 pneumonias below 40 years including 5 TE (= 2.7 %). But on the one hand the difference is not significant from statistical point of view, and on the other hand a scrutinizing of the primary material will show that in 1938 not all instances were treated with specific therapy: among the 5 TE below 40 years there were thus 2 who did not enjoy the treatment in question! Con- sidering this evidence i t cannot justly be maintained that the specific therapy has increased the occurrence of TE in pneumonias otherwise than indirectly, by augmenting the number of survivors; i t has, on the other hand, not reduced the incidence here discussed.

290 E R I K A S K - U P M A R K .

The number of days elapsed between the onset, viz. the crisis of pneumonia and the clinical onset of the TE, was a subject of particular interest. In some few instances the details about the onset and the course of the illness were less complete and in others the occurrence of irregular features such as migrating pneumonias was liable to obscure the time-table so that only ZOinstances out of the 27 were to be used. In 6 out of these 20 instances there was a lysis instead of a crisis. The observations will be seen in the following table:

Table 4. Clinical onset of TE in pneumonia.

Days after onset of the pneumonia (20 cases): 8-21, on an average 13.4 days u crisis B u u

Case

1 2 3 4 5 6 7 8 9

10 11 12 13 14 15 16 17 18 19 20

Sex, age

lif 43 F 53 1' 33 M 51 M 30 F 66 F 35 M 17 F 51 1' 31 M 21 F 56 1: 38 111 49 F 42 F 47 M 47 F 52 F 27 M 57

Record

79/16 677122 136123

1251 128 364129 667 129

2457131 1625132

304138 670/38

1429138 522139 572139 809/39

2742/39 3020140

701 140 2501141

951141

138

(14 cases), 4-12, on an average 8 days,

lays aftei onset

20 21 19 16 1 4 14 13 10 13 11 12 14 18 9 8

14 11 10 8

14

lays afte: crisis

11 12 12 10

7 8

4 Lysis

I.ysis Lysis

Lysis 5

8 7 7 6

Lysis a

7 Lysis

First sympton

E t '1 I ?' T T

'1' li 'I- T E 11 '1'

'1' '1' T 'I' 1: T

r.:t

E t

Specific treatment

NO

No NO

NO No No No No No No No

Yes, S. Ch. Yes, Ch. Yes, s. Yes, Ch. Yes, Ch. Yes, Ch. Yes, Ch. Yes, Ch.

Yes, S '

1 S = Serum, Ch. = Chemotherapy. 1 In this case the T occurred 10 days after onset of the pneumonia but before

I t will be seen from the table that the first symptom in most instances was represented by T, only in 6 cases by E. As with the postoperative TE i t was found that if T was the first symptom it

the apparently postponed crisis.

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was rare for any E to occur (such was the case only in case 15, where the T antedated the E by one day), whereas if E was the first symptom and the patient did survive a T did appear sooner or later (cases 8, 11, 19). With regard to the clinical diagnosis of T viz. E it was performed along the usual lines with the reservation that only local symptoms were considered conclusive (T: pains in the calf, tenderness below the anterior end of calcaneus or in the deep structures of the calf, oedema, heat and cyanosis; E suddenly appearing pleural pain in the chest, followed by the characteristic bloody (not rust-brown) sputum and eventually by T or by death and autopsy). This restriction on the one hand, the fact that an elevated temperature or pulse often did precede the onset of TE on the other make it obvious that the average time elapsed between the onset of pneumonia and the onset of TE rather should be con- sidcrcd as shorter than the time here indicated, 13.4 days. It was howcver not possible to utilize the behaviour of the temperature in order to determine the onset of TE since i t was found that in the very majority of the cases here concerned the temperature did not reach the normal level between the crisis (or lysis) and the onset of TE, such being the case only in the observations (4), (S), (11) and possibly also (l), and neither was the pulse of conclusive character.

From practical clinical point of view the conclusion seems warranted that the evolution of TE is particularly to be feared in such instances of lobar pneumonia, where the temperature does not attain the normal level in connection with the crisis or the lysis, although i t may occur also if this level is reached. I t was also observed that in some instances [(17), (20) and in a case here not tabled of a woman, aged 261 the pneumonia was to be considered as a recurrence, but since recurrences anyway do occur to a certain extent in lobar pneumonia no conclusions seem to be allowed from this observation. In two instances serum sickness was noted (case 15 and one case not here tabled of a woman aged 52); it did not occur a t the same time as the TE (in case 15 seven days after the TE, in the other case five days prior to the TE). In a t least two instances [cases (17) and (ZO)] typical rashes, induced by the chemotherapy, were present when the TE did appear; the limited size of the material makes it impossible to decide whether this represents a mere accidental coincidence (cfr below).

292 E R I K A S K - C P M A R K .

Comment and discussion.

Whcn attempting to date the occurrence of TE induced by a surgical intervention i t is possible to get a fix starting point for thc sequence of events, as represented b y the operation. Whcn the occurrence of TE in lobar pneumonia is about we have from this point of view the advantage of a sudden onset of the disease, often also of an abrupt crisis. I t is true tha t the classical duration of a pneumonia amounts to one week, whereas the operation is performed in hours, but this difference should not be overemphasized since the tissue injuries established by an operation will not be healed a t the moment when the operation is finished. I t has been established hcyond doubt that the majority of postoperative TEis to heexpected during the second week after the operation, the niaximum on an average being reached on the 10th day. The evidence brought for- ward in the present investigation will apparently represent a most interesting parallel to this phenomenon, since i t has been demonstrated t h a t the average time elapsed between the onset of the discase and the onset of TE was about 13 days. For reasons alrcady indicatcd it may be presumed tha t this interval is, in reality, no t quite so long. If on the other hand the period is considered elapsing 1)ctween the crisis and the onset of TE this period was found t o average 8 days, or possibly some day less if the source of error contained in the general symptoms (temperature etc.) is to be considered. The question may be raised whether the dices of fate with regard to TE have been thrown with the onset, with the course or with the crisis of the pneumonia. Since TE occasionally may be observed to occur before the onset of the crisis and since i t may be met with else in cases finished with lysis the crisis in itself seems to be of less importance, although the resolution of the pneumonia with its absorption of large amounts of organic matter cannot reasonably be discarded in this connection. Most prohahly the whole sequence of events induced by the lobar pneumonia during its course is to be hold responsible for the development of TE; with regard, however, to the desirability to obtain a fixed date with which to work it seems logical t o reckon with the onset of the pneumonia. If this is done we will obtain 13.4 days or somewhat less, say 11-12 days as the average period of time necessitated for the evolution of TE in its clinical sense. Another possibility, perhaps more ade-

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Temperature curves in four instanrrs of lobar pneumonia Symbols E: pulmonary embolism

T: Trombosis S : Serum-reac t ion Roman figures: days of pneumonia ( I onset) D : Serumtreatineiit

: Chemotherapy

quate but a bit more awkward, would be to reckon with the middle day of the pneumonia as the starting point; in this case we may obtain a TE on an average of 9-10 days after this date, i. e. a t exactly the same time as after a surgical intervention. I t may be added that in as much as specific therapy is being used a t an early stage of the pneumonia the duration of the disease willbecome accordingly abbreviated, so that the deductions here necessitated may be avoided; it is instructive to note that in those very cases of the present material (14,15,19) where the duration of the disease did not exceed 2 days the pulmonary embolism did appear already 8-9 days after the onset of the pneumonia.

The striking similarity hence ascertained between the occurrenc of TE after operations and after pneumonia makes i t reasonable

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. ..- .

Temperature curves in four instances of lobar pneumonia Symbols E: pulmonary embolism

T: Thrombosis S : Serum-reaction Roman figures: days of pneumonia ( I onset) - : Serumtreatment

: Chemotherapy

to presume a common pathogenesis. Following the time honoured theses of Virchow, Lubarsch and Aschoff with regard to the evolution of thrombosis we have to consider the alterations brought about by the pneumonia with regard to

1. The haemodynamic conditions, 2. The composition of the blood and 3. The behaviour of the vascular endothelium. ad (1) The main factors responsible for the adequate venous

blood-flow are the muscular tonus, the arterial pulsations and the vis a tergo represented by the beat of the heart. With regard to the muscular tonus its importance has been stressed particularly by Hendei son; investigations by Budelmann and co-workers (1939) as well as earlier by Bock have demonstrated areduction of muscular

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tonus not only during convalescence and generally in bedridden individuals but particularly during infectious disorders and especially in pneumonia (method of Beiglbock and Junk). I t is obvious that this reduction of muscular tonus will be conspicuous not least in the lower extremities of a bedridden patient, for example in the planta pedis, where the veinous basin, supplied with blood from the arterial system described by Ask-Upmark (1938), will be particularly liable to suffer, since its circulation is so very much furthered by thc use of the feet; it is well known that this plantar basin quite often will represent the source of thrombosis (cfr the tenderness on pressure exerted towards calcaneus).

As to the arterial pulsations it is a general arrangement of the veins of the extremities to accompany an artery; as a rule two veins will run along one artery, connected with one another by anastomotic branches around the artery, so that they are bound to receive the pulsations of this vessel (Ask-Upmark). The structure of the wall of the arteries of the extremities favour the amplitude of the pulsations (contrary to the intracranial arteries, cfr Wolf 1938) and the rhythmic pressure impulses transmitted to the adjoining veins will drive the venous blood in the direction indicated by the valvulas. This physiological arrangement seems, as a matter of fact, to be of paramount importance. Any factor liable t o reduce the blood pressure or the arterial amplitude will facilitate the occurrence of venous stasis. In pneumonia the impairment of the heart on the one hand, the involvement of the peripheral vasomotor tonus on the other invite a reduction of the blood pressure, which may be noted during the course of the pneumonia (when it however also may increase) but particularly after the crisis (Reimann, 1938). Another factor, which may be of importance in this connection, is the observation of Naumann (1939) that the arterial pressure in the lower extremities, which in normal individuals is a t least as high and often higher than in the arms, during the course of infectious disorders may be lowered below the brachial level.

With regard, finally, to the condition of the heart in pneumonia it is obvious that the heart (as well as the vascular centre and the vasomotor periphery) will suffer from the toxemia, from the increased venosity of the blood and from the increased load repre-

1 In Graves’ disease, where TE is rare, this arterial amplitude is cons iderabl~ increased.

296 E R I K A S K - U P M A R K .

sented by the increased demand of the tissues for oxygen and perhaps occasionally also by the diminished arterial bed in the lungs: Reimann states that myocardial degeneration should be found in almost one half of the patients studied a t necropsy. Although the general impression of the circulatory failure to be noted in pneunio- nia is that of dcrward failure)) i t is obvious that the impairedcondi- tion of the heart may represent a contributory factor. The old experience of the greater frequency of TE in individuals with affected heart (old people, fat individuals etc.) is in line with this assump- tion. In coronary thrombosis TE is met with much more often than in pneumonia and perhaps more often than in any other internal disorder (Ask-Upmark, unpublished observations); although the importance of the vasomotor collapsc in this connection is outstanding the primary importance of the affection of the heart should not be forgotten.

Last but not least should be remembered that the mechanical conditions present in a person lying down on his back, hardly are liable to facilitate the venous circulation of the legs: on the one hand the direction of the femoral vein is by no means horizontal but rather much up-hill towards the inguinal region, and the same may be said of the pelvic veins; on the other hand the pressure of the abdoniinal organs rests upon thc cava system and the veins of the calves are liable to be compressed by the weight of the legs (cfr the observations of Berblinger about the necroses of tlie muscles of the calves in bcdriddcn individuals). If a urinary retention should I)c present (more often of course after an ahdominal operation than in pneumonia), the venous drainage of the pelvis is liable to suffer, being deprived of the pressure impulses exerted by the constantly variablc size of the bladder.

ad (2) With regard to the composition of tlie blood in pneumonia it is ohvious that several features are to be encountcred which a t least apparently will facilitate the evolution of thrombosis. ‘lhe increased venosity of thc blood (cfr Stuber and Lang 1930 and others), thc quite considerably increased fraction of fibrinogen (cfr Frey 1928, Hecht Johansen 1933, Keimann 1938), and the behaviour of the blood platelets (Reimann 1938, Heinild 1942) are such characters. It should be observed that the fraction of fibrinogen will be increased particularly about the time of crisis and for some few weeks afterwards, and that the blood platelets, reduced ns in all in-

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fections during the febrile period, surge above normal level a t the crisis and remain high for a t least a fortnight. The coincidence in time between these features on the one hand, the occurrence of TE on the other makes it tempting t o consider the matter of a t least contributory importance.

On the other hand i t should be observed that the characters just mentioned may occur without any TE, and that fibrinogen and thrombocytes only are to be considered as raw material, supplied by nature for the development of TE but by no means as the primary factor in the sequence of events resulting in TE. As Leng- genhager (1941) rightly puts the matter: ))In diesem Uberangebot von gerinnungsfahigen Substanzen . . . benotigt die Gerinnung ebenso nicht wesentlich kiirzere Zeit, wie ein Kilogramm Schiess- pulver nicht wesentlich rascher abbrennt als ein Gramm.)) In the system of clotting, however, there are two antagonistic principles to be considered: on the one side the thrombokinase (Morawitz- Mellanby = thromboplastin of Howell = thrombokinin of Leng- genhager), which invites clotting by transforming prothrombin into thrombin and which is said to he present in all tissues but particularly in lung and brain, on the other side the heparin, which prevents clotting by neutralizing thrombin 1, assisted by another substance present in circulating blood (an albumin, termed by Lenggenhager metatrombinogen). By the ingenious investigations of Jorpes and Hjalmar Holmgren i t has been established beyond reasonable doubt that heparin is produced by the ))Mast-Ztlleno of Ehrlich, which are present all over the body, mainly arranged in a perivascu- lar way. Various animals do present the bulk of oMastzellen)) in various organs (the cow in the capsule of the liver, the rats in the skin, ctc.). Already the Toronto school, however, did find out the large amounts of heparin which were to be obtained from the lungs (cfr Jorpes), and this observation has been histologically substantiated by the studies of Holmgren: the amount of Mast- zcllen in the lungs may be somewhat variable in the various species but they were always present. I t should be emphasized that the

Thi\ is tlic conception of Mellanby, most generally accepted. According t o the old aspcct of Howell the action of heparin WBF to prevent the conversion of prothrombin into thrombin; according to the recent hypothesis of Lenggen- hager the main eIfect of heparin should be con\ideretl the neutralization of thrombin although i t should also stabilize the prothrombokiriin aud block the, effect of t hrombohini t i .

298 ERIK A S K - U P M A R K

lungs assume a privileged position with regard to the blood supply in as much as every drop of blood has t o pass the pulmonary capil- laries in order to perform the circle. The involvement of the lung or part of it in a severe pathological process as pneumonia is no doubt liable on the one side to liberate quite a lot of thrombokinase in the circulation, on the other side to paralyse the activities of the Mast- zeller?, not only in the involved part of the lung but reasonably also in the rest of the body (cfr below). Just as we may encounter jaun- dice or albuminuria or cerebral symptoms during the course of a pneumonia we may of course just as well encounter a damage to the heparin-producing parenchyma. I t is possible that this aspect may enable an understanding of the occurrence of TE in pneumonia.

ad (3) As to the vascula~ endothelium several authors have tried to make alterations of this structure responsible for the development of TE. These attempts have been based mainly on two seiies of observations: on the one hand the analogy with the conditions in the arterial system, where atheromatous changes are believed to facilitate the evolution of thrombosis, on the other hand certain expeli- ments in animals, carried out especially by Ritter and by Dietrich. Ritter obtained histological changes of the vascular endothelium by intravenous injections of vital dyes, of micro-organisms and of protein substances. Dietrich by the same means allegedly sensitized the endothclium and eventually, under certain conditions, did observe thrombosis and occasionally even embolism. Valid objections have however been raised against this interpretation of an endothelial factor in the pathogenesis of TE: they have been re- viewed to some extent by Geissendorfer (1936), by Silberberg (1938) and by Lenggenhager (1941) where references and details are to be had.

Briefly summarized, the main objections are 1. that alterations of the venous endothelium may occur without any subsequent thrombosis (for example when the vein is sutured after thrombectomy or in connection with intravenous injections), 2. that no anatomical alterations of the vascular endothelium hitherto have been demonstrated in early instances of human TE (Aschoff), 3. that numerous conditions in clinical pathology invite to endothelial reactions without inducing any particular occurrence of TE, 4. that such recent instances of thrombosis, where the obliteration of the vascular lumen is only partial, are not circular but do present an adhesion to the venous wall only

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in the lower half of the lumen (following the gravity). The opinion seems warranted tha t , a t the present time, there seems to be no reason to attribute an outstanding role to the endothelial factor in the pathogenesis of TE.

On the other hand i t should be readily admitted that the question of the endothelial response is not entirely untangled. It should thus be observed that a t least when thrombophlebitis is about, an alteration of the wall is present, whether primary or secondary remains to be settled. I t should further be remembered that, to the best of my knowledge, no investigations seem t o have been carried out of the histological behaviour or that venous plexus which represents the plantar basin. That this venous system is likely to represent the source and the matrix of a t least a large part of the clinical instances of TE has already been emphasized. In this connection i t seems not out of the way to recall the rather unique physiology of the vascular system of planta pedis: Danish authors have demonstrated that the diurnal alterations of the temperature of the skin is of quite another magnitude in this region than in any other arva of the body surface and that prognostical conclusions may be drawn from the behaviour of the temperature of planta pedis in connection with narcosis and surgical interventions. It seems entirely possible that an interference with the vasomotor I egulatory mechanism here concerned (whether caused by an operation or by a severe febrile condition such as pneumonia) may represent a contributory factor in the sequence of events responsiblc for the development of thrombosis, i t may be admitted, however, that even if such be the case the vasomotor factor rather will be of haemodynamic than of endothelial character.

Briefly summarizing the discussion i t may be concluded that haemodynamic factors are likely to be of importance for the evolution and localization of thrombosis in pneumonia, that however the primary cause seems to be the affection of the clotting mechanism of the blood, and that hitherto no definite evidence is available about any importance of the vascular endothelium. The hypothesis has been marshalled that a central position in the pathogenesis of TE is rcpresentd by the presumed affection of the basophil parenchyma, the entity of heparin-producing ))Mastzelleno. Further investigations will have to demonstrate whether this aspect is to be haematologically and histologically corroborated. It should, how- 20 - Acia med. scandinav. Vol. C X I I I .

SLO E R I K A S K - U P M A R K .

ever, be emphasized, on the one hand that a functional lesion by no means always is to be anatomically substantiated (cfr those instances of diabetes mellitus with morphologically normal insular structure!), on the other hand that this aspect seems to be well compatible with our present knowledge about the clinical behaviour of TE: the occurrence in certain individuals, the possibility of prevention viz. of combating the further development by the use of heparin, and the hitherto enigmatic chronology of its appearance (vide infra). I t is perfectly obvious that the aspect here mentioned by no means does exclude the importance of other, contributory mechanisms: the salient feature seems to be the balance between, on the one side thrombin, as determined by the amount of thrombokinin liberated from the damaged or diseased tissue and by the ability of the liver to eliminate the thrombin (cfr Lenggenhagcr), on the other side antithrombin, as determined by the heparin and the metatrombinogen available. If, for example, the amount of throinbokinin should be considerable (after a major surgical operation 0r.a severe internal disease such as pneumonia) even a slight reduction of the heparin production might mean insufficient protec- tion against TE. I t should however be remembered that thrombokinin, according to Mellanby, is prone to neutralize the action of heparin.

The validity of the hypothesis thus outlined may be tested morphologically by determining the number of basophil Ehrlicli cells in connection with disorders liable to present TE (this line of research scheduled in the Medical Clinic a t Lund), cheniically by investigating the neutralization of thi ombin by antithrombin, along the lines indicated hy Lenggenhager; the demonstration by this author that the impaired inactivation of thrombin is due not to any increased amount of thrombin but to its reduced destruction seems to be entirely compatible with the aspect here marshalled.

The following are some features of the TE disorder which might become understandable by the interpretation already suggested:

1. Certain individuals do obtain TE, others not. The constitu- tional disposition seems to be substantiated by racial differences (Holm found no T E whatsoever during about 2 years in the 110s-

pital of Lambarene in equatorial Africa, where negroes were taken care of surgically and medically), by the old observation of a ))typus

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embolicusr, and by the well established familiar occurrence of T E (the author has repeatedly observed 4-6 instances of T E in the same faniily; cfr the observation of Moncani, who among 800 operations for herni had 3 instances of TE, all brothersl). I t seems entirely reasonable that the heparin-producing parenchyma of the basophil cells might be of constitutionally different resistance, just as is the case with other organs, for ex. the kidneys, the lungs, the arterial musculature (in hypertension), and the bone marrow (susceptibility to toxic agranulocytosis).

2. The treatment of TE with heparin, as performed nowadays by Lenggenhager, Bauer, and others, will appear as a feature which not only has given practical results but also, according to the opinion here maintained, should be looked upon as a substitutional therapy in much the same sense as the insulin treatment of diabetes, with the difference of course that the need of heparin is tran- sitory. I t seems logical to support this treatment by measures intended to eliminate the haemodynamic conditions favouring the evolution of TE: to increase the blood pressure, if lowered, to improve the muscular tonus (not least so by active movements) and to support the heart.

3. The appearance of TE as well after operations as according to the present study in pneumonia has a definite predilection for the second week, about 10 days after the onset of the eliciting cause. Although it may be conceived that the onset of T E may precede this date, the period mentioned is nevertheless from clinical point of view the average time in which the appearance of a T E may be expected. I t is extremely instructive to note that this period of time is approached by several other biological phenomena, such as the appearance of antibodies, the occurrence of serum sickness, the peak of experimental eosinophilia after intravenous oil-injections, the maximal response of the reticulocytes during the treatment of pernicious anemia, the occurrence of drug fever, the duration of the periods of pyrexia in numerous conditions with periodic fever, etc., all phenomena which apparently have in common the character of reaction to a challenge t o the protective mechanisms of the body. With regard to the ))Mastzellen)) parenchyma it seems likely to assume a damage to its heparin-producing function in niuch the same way as the glomerular structures are damaged in acute nephri- tis (cfr the occurrence of this disease 1-3 weeks after the eliciting

302 ERIK AS K - U P M A R K

angina). In this sense i t may even be spoken of an allergic mechanism. This, of course, is only one of several possible explanations l, other factors (e. g. of haemodynamic character) may be involved as well.

Other hitherto enigiiialic observations in connection with TE (for example the apparent predilection for abdominal operations) might be explained as well hut the examples given may be sufficient to elucidate the handiness of the theory here suggested.

Summary and conclusions.

1. Contributions to the problem of venous thrombosis and pulmonary embolism (TE) have been numerous from surgeiy, only scanty from internal medicine, owing no doubt to the fact tha t only few internal disorders, complicated by TE, allow the establishment of a definite time table between Ihe primary disease and the secondary evolution of TE. Such internal disorders are, however, pneumonia, coronary thrombosis and certain instances of pernicious anemia. The present study is concerned with the occurIence of TE in pneumonia.

2. The material was represented by 1454 cases of lobar pneumonia, observed in tlie Medical Clinic a t Lund during tlie years 1916-1941. TE was ohseived in 27 instances, i. c. in about every 50111 case. 11 cases were males (1.1 yo), 16 cases females (3.4 o/o).

Persons above 40 years wwe afflicted somewhat more often than cases below this age (males 1.5 yo versus 0.9 yo, females 3.7 yo versus 3 yo). During the last 4 years (1938-1941) more instances of TE have been taken to the records than during the preceding 22 years, owing no doubt to the introduction of specific therapy which allows cases to survive and develop TE who previously might h a w succumbed in pneumonia a t an early stage. The average time clapsed between the onset of pneumonia and the onset of TE was 13tlays, the average tinic clapsed between the crisis and the onset of TII was S days. For reasons developed in this paper this pcriod of time should be considered as sorncwliat less than the dates just indicated. The evolution of TE is particularly Lo be feared in such instances of pneumonia whcre tlie temperature does not attain nor-

1 Whcthcr lor cxatiil)lc tlie l ~ a s o ~ ~ l i i l cells should in any way be elig:iguI in I tie lysis of piicumoiii:~ rcnr:iins to be \ten.

T H E O C C U R R E N C E O F THROMBOSIS A N D P U L M O N A R Y ETC. 303

ma1 level a t the crisis resp. viz. lysis, but i t may occur even if this level is reached.

3. The observations hence recorded are discussed. Haemody- naniic factors favouring the evolution of TE are the reduction of muscular tonus, the impairment of the blood pressure and the involvement of the heart. Haematological factors are the increased venosity of the blood, the increased amoiunt of fibrinogen and the increased amount of thrombocytes but probably particularly the behaviour of thrombin. The hypothesis is marshalled that a salient featurc in the pathogenesis of TE is represented by the impairment brought about by the pneumonia of the hepai in-producing ))Mast- zellen)) parenchyma.

Bibliography.

Ask-Upmark, E.: I . 1038, Klin. Wo.schr. 2. 1938, Acta SOC. Med. Suecan. (on periodic fever). 3. unpublished observation. - Berblinger , W.: 1940, quoted by Lenggenhager. -Best and Taylor: 1937, Physiological Basis of Medical Practice, Baillibre, Tindall & Cox. London. - Budel- mann et al.: 1939, Zbl. f . inn. Med., XXIX. Tagung der Nordwestd. Gesellsch. f. inn. Med. - Frey, 11. C.: 1928, Dtsch. Arch. f . klin. Med. 162: 1 . - Genell, S.: 1936, Sv. Likartidn. och J . Obst. Gyn. Brit. Emp, 43: 1124. - Geissendorfer, R.: 1935, Thrombose und Embolie, Barth. Leipzig. - IIecht, Johansen, A.: 1934, Acta Med. Scand. 82: 276. - Heinild, S.: 1942, Undersogelsen, blodpletttalet, Reitzel, Kopenhamn, - Holm, S.: 1939, Nordisk Medicin 1: 313. - Holmgren, Iljalmar: 1938. Hygiea 100: 139. - IIultquist, G.: 1936, Act. Soc. Med. Suec. 62: 264 - Jorpes, E.: 1938, IIygiea 100: 255. - Ingvar, S.: 1939, Svenska Lakar- tidningen. - Lenggenhager, K.: 1940, Ilelvet. Med. Act. 7: 262. 1941, c h e r die Ersteliung, Erkennung und Vermeidung der postoperativen Fernthrombost?, Thiene, Leipz. - Naumann, M.: 1939, Zschr. f . Kreislauff. 3 1 : 513. - Reirnann, H. A.: 1938, The Pneumonias, Saunder Co., Phila- delphia-London. - Silberberg, M.: 1938, Physiol. Reviews 18: 197. - Stubw und Lmg: 1930: Klin. Wo.sc1ir. 1: 1113. - Wolf: 1938, in Sym- posion on Cerebral Circulation (Trans. Am. Neurol. Assoc.).

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The occurrence of thrombosis and pulmonary embolism in pneumonia

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