CARCINOMA AND VENOUS THROMBOSIS: THE FREQUENCY OF
ASSOCIATION OF CARCINOMA I N THE BODY OR TAIL OF
THE PANCREAS WITH MULTIPLE VENOUS
THROMBOSIS
E. E. SPROUL, M.D.
(Frm the Deportment of Pathology, Cohgs of Phyddwu a d Surgeons, Colvrnbh Udvsrdty)
RELATIONSHIP
BETWEEN CARCINOMA
AND THROMBOSIS
Text-books of medicine and of pathology often refer to the coincidence
of a malignant tumor of epithelial origin and venous thrombosis. One of the
earliest observers to stress this relationship was Trousseau (1) in 1865. He
was especially interested in the frequency with which thrombosis of one or
more peripheral veins was the first indication of the presence of a malignant
tumor. Since his series of patients included those with tumors arising in the
stomach, uterus, and testis, he concluded that the tendency to thrombosis was
a characteristic of carcinoma in general and not dependent upon its origin in
any particular organ. Recently Thomson @) quoted extensively from Trousseau's original article and added a description of three cases in which the
presenting disability was thrombosis of the veins of the leg. Examination
after death showed a carcinoma arising in the tail of the pancreas in one of
the patients, and of uncertain origin in another, A tumor of the stomach wall
was demonstrated by x-ray studies in the third. Again emphasis was placed
on the absence of any sign of internal disorder when the venous thrombosis
was first apparent.
In citing somewhat similar cases, James and Matheson (3) regarded
thrombosis as an incident of the advanced stages of'a variety of debilitating
diseases such as chronic infections, anemias, and malignant. tumors. They
describe two cases of carcinoma of the stomach in which there was occlusion
of the basilic and saphenous veins respectively and a carcinoma of the lung
associated with multiple thrombosis oL internal and peripheral veins.
Such individual cases, while of value, give no indication of a significant
relationship. It was of interest, therefore, to note that an analysis by Barker
(4) of the non-infectious systemic diseases complicated by thrombosis at the
Mayo Clinic revealed the presence-of a carcinoma in 27 of the 58 cases included in this group. This report was based on clinical observation alone,
necessitating limitation of the study to thrombosis of the veins of the legs
and occasionally of the upper extremities. A similar study, based on necropsy
reports, of causative factors involved in intru vitum coagulation of the blood
was presented by Haward (5). In a series of 2,903 necropsies, fatal thrombosis had occurred in 81. A list of the underlying diseases in these cases
placed cancer second in frequency, exceeded only by middle ear infection.
Further indication that a relationship may exist between cancer and coagulation of the blood was found in the numerous reports of changes in bleeding
and coagulation time in the presence of a carcinoma. Figurelli (6) reviewed
566
CARCINOMA AND VENOUS THRODOSIS
567
the literature on this subject and listed the coagulation time in 35 cases of
cancer and 20 noncancerous conditions, including several sarcomata. While
there was considerable variation, the average time was found to be several
minutes lower in the cancer group. The findings of Antonioli (7) were similar. Bock and Rausche (8) offered a method of testing the coagulative power
of the blood as an aid in the diagnosis of cancer. The method entails the
recording of the number of drops of a 2 per cent solution of magnesium
sulphate required to prevent the coagulation of plasma. Normal blood can
be kept liquid by 3 to 5 drops. In 18 cases of carcinoma, among which were
several arising in the alimentary tract, the plasma clotted unless 7 or 8 drops
of the salt solution were added. The opposite situation was encountered in
diseases complicated by jaundice, where the blood remained fluid with the
addition of as little as 1 to 3 drops. This test was examined by numerous
workers. Perlmann and qodin ( 9 ) thought it unreliable for differentiation
between carcinoma of the stomach and peptic ulcer because of the overlapping
in the two groups. Abramson (lo), on the other hand, cited many others
who found it more difficult to prevent coagulation when a carcinoma was
present, and his own series indicated that more cases of cancer were associated
with increased tendency to coagulation of the blood than cases of sarcoma,
'ulcer, or nondebilitating diseases.
Little is found concerning such an association in animal experimentation.
Mendelkff (11) first observed that the coagulation time of guinea-pig plasma
was greatly reduced when the animal bore a tumor. By extraction of the
tumor, precipitation at pH 4, and solution of the sediment in an alkaline
mcdkun, she found that the agent responsible for transmission of the tumor, as
well as the factor stimulating blood coagulation, was present in the sediment,
w'bile an agent inhibiting both tumor growth and blood coagulation had been
separated in the supernatant fluid. Her studies were continued by investigating the effect of the addition of leukocytes and red cells on the coagulation
of plasma in Vitro. The red cells of a tumor-bearing animal greatly accelerated clotting of the plasma in comparison with the effect of red cells of
normal guinea-pigs (12). When a similar test was applied to three cases of
human catdnoma, the results were comparable (13). Holf (14) followed
the changes in coagulability of chicken plasma by a variety of concentrated
salt solutions following inoculation of the Rous sarcoma No. 1. All showed
an increasing speed of clotting up to the fourth day after injection.
I t could hardly be expected that all tumors would affect blood coagulation
in the same way. Quite the opposite effect was reported by Van Allen (15),
who studied the blood of rabbits bearing the Brown-Pearce carcinoma. The
growth of the tumor paralleled a delay in clot initiation and retraction.
Kopauewski (16) carried the investigation into the field of synthetic carcinogenic chemical agents. His findings that many of these substances had the
ability to coagulate horse serum in vitro or to accelerate the action of other
coagulating substances led him to -believe that this characteristic was of
considerable importance in the production of tumors.
This study was undertaken to ascertain the incidence of carcinoma in the
cases &owing thrombosis at necropsy and to determine whether any one organ
was more commonly involved than others in such a relationship.
568
E. E. SPROUL
TABLE
I: Systamic C
Aseociated
Condition
a Associated with Thrombosis of Vmns i s Various & g h s
-
'ulmonary hdominal
Cerebral Neck
Infection
Arteriosclerotic
heart disease
Rheumatic heart
disease
Pregnancy
Carcinoma
Syphilitic heart
dime
Peptic ulcer
Hyperthyroidism
Tuberculosis
Perniciousanemia
Cause unknown
Polycythemia
Trauma
Lead poisoning
Hernia
Varicosity
Cirrhosis of liver
Leukemia
15
TOTAL
23
19
6
12
1
6
2
29
2
2
2
3
1
LOWV
UPF
Extremitiee 2xtremities
-
30
50
6
'elvic
1
26
10
2
2
4
48
1
1
1
1
1
1
1
1
2
3
3
1
1
1
1
3
5
13
I
12
101
CONDITIONS
ASSOCIATED
WITH THROMBOSIS
A review was made of 4258 consecutive necropsies performed at the Presbyterian Hospital, New York, and the presence of a thrombus in the heart,
arteries, or veins was noted in 617 or 14.4 per cent. The findings were based
on microscopic as well as gross examination of the body. The presence of 8
thrombus was therefore not necessarily of importance in causing the death of
the patient. The highest incidence occurred in the sixth decade, which is in
accordance with previous studies, but in contradistinction to most reported
series, thrombosis was found to be somewhat more common in the male than
the female, the proportion of cases being 355 to 262. In the total series of
4258 cases males constituted but 56.01 per cent.
A thrombus in either auricle or ventricle was present in 279 cases. In
recording the associated diseases a certain amount of arbitrary interpretation
was necessary. When sclerosis of the coronary arteries and tuberculosis
were present in the same patient, the former was regarded as the condition
more likely responsible for thrombus formation in the heart. In the absence
of such a local cayse, tuberculosis would have been recorded as the associated
systemic disease. The study of cardiac thrombosis showed the following
relationships: coronary sclerosis, 142 ; rheumatic heart disease, 85 ; carcinoma,
17; syphilitic heart disease, 16; general infection (Le., pneumonia, bacteremia,
peritonitis, etc.) , 7 ; tuberculosis, 5 ; polycythemia Vera, 2 ; hyperthyroidism,
2; cause unknown, 2; cirrhosis of liver, 1.
Thrombosis of the veins and arteries can best be summarized according
569
CARCINOMA AND VENOUS THROMBOSIS
TABLE11: Sydemik CorrditionsAss&
Aeaocited
Condition
--
Infection
Arteriosclerosis
Carcinoma
Cirrhosis of liver
Syphilis
Peptic ulcer
Polycythemia
Hyperthyroidism
Lead poisoning
Rheumatic heart
disease
Tuberculosis
Cause unknown
Arterial aneurysm
TOTAL
with Thvmbosis of Artcrics in Various Regions
I
Lower
Upper
Cerebral Neck Pulmonary Lbdominal Pelvic Extremities
Extremities
4
'I
4
1
1
1
12
15
23
1
1
1
14
1
2
1
1
13
2
1
1
1
1
3
1
I
l7
to the regions involved. Table I indicates the number of cases with obstruction of veins due to coagulation of the blood and the conditions thought to be
of greatest significance in the development of the process. Despite the frequency of infection in the abdominal cavity, here, as well as in the lower
extremities, the presence of a carcinoma accounted for almost half of the
instances of venous thrombosis. The incidence is somewhat less striking in
the series of pelvic vein thrombosis, while clotting in the cerebral veins was
more often dependent upon a contiguous infectious process in the brain or
meninges. The number of cases of thrombosis in neck, arm and pulmonary
veins is too limited to be of significance, but again carcinoma was the most
common associated condition except in the last named group, where it was
exceeded by cardiac insufficiency.
Table I1 was similarly prepared from an analysis of arterial thrombosis
in various portions of the body. I t will be seen that carcinoma plays a minor
r61e in all but the pulmonary group. It may be that these were actually
emboli and the source in the venous system went unnoticed.
From such a study, then, it is apparent that one must qualify observations
on coincidental lesions by specification of the region and type of vessel involved. Thrombus formation in the heart occurs most frequently when there
has been myocardial and endocardial damage due to coronary occlusion.
Thrombosis of the arteries, with the exception of those in the lung, most often
seems to be dependent upon an underlying sclerosis. On the other hand,
venous thrombosis shows a significant relationship to the presence of a carcinoma, especially when the veins of the abdomen and lower extremities are
involved.
RELATIONSHIP
OF CARCINOMA
OF VARIOUSORGANS
TO T H R O ~ O S I S
The high incidence of cancer associated with venous thrombosis in this
necropsy series stimulated our curiosity as to the types of tumor found. For
570
E. E. SPROUL
TABLE
111: Imidsncs of Thrombosis in Garcinoma of Va*iour Organs
-
Organ in which tumor arose
Total
4
5-
&sea With Multiple
Thromboses
No.
cases
Anywhere in pancreaa
Head of pancreaa
Body or tail of pancreas
Lung
Liva
Gallbladder
Stomach
Duodenum
Colon
Kidney
Prwtate
Uterus
Caaet~With
Thrornbosii
.
47
31
16
81
22
30
147
16
94
27
43
27
17
-
No. Cases
14
5
9
12
6
5
32
3
15
7
7
6
4
'er cent 01
No. Cam 'er cent of
Total
Total
29.7
16.1
56.2
14.8
27.2
16.6
21.8
18.7
15.9
25.9
16.3
22.2
23.5
8
3
5
2
0
0
2
0
0
0
17
9.7
31.3
2.5
1.3
0
0
0
this purpose the cases of the more common carcinomata were examined and
the presence of thrombosis noted. Since a single vessel might well be thrombosed without relationship to the presence of a tumor in the body, the number
of cases of each type of carcinoma accornpanied by multiple thromboses was
thought to be of greater significance. See Table 111.
It is immediately apparent that a carcinoma originating in the pancreas,
and more especially if the body or tail alone were involved, was most frequently
accompanied by thrombosis of numerous vessels. A more detailed study of
each case was conducted in the hope of determining the causative factors.
Carcinoma o j the Pancreus: The fact that a carcinoma of the pancreas
may first manifest its presence by thrombosis of peripheral veins has been
noted in several reports of individual cases. Umlauft (17) described three
cases of multiple thrombosis of which two were associated with such a tumor,
while in the third a carcinoma arising in the lung was found. In one 'instance
the veins of all four'extremities were involve& Tumor cells were not present
in the vessel walls. (In three cases reported by Thoenes ( 18) a carcinoma was
found in the pancreas and many of the peripheral veins were thrombosed.
Thoenes suggested that pancreatic ferment may have been responsible, without
further elucidation of the mechanism. In tbe single case described by Winter
( 19) invasion of veins by the pancreatic tumor accompanied widespread thrombosis of these vessels. Smith (20) found a carcinoma arising either in the
pancreas or in the alimentary tract in a case predominantly one of thrombosis
of the iliac veins and inferior vena cava. Gangrene of the intestine has been
noted following thrombosis of the portal and mesenteric veins with pancreatic
carcinoma (21). And, as would be expected, a pancreatic tumor has sufficiently invaded and obstructed the splenic artery and vein to cause infarction
of the spleen, and in one case spontaneous rupture of necrotic tissue (22).
In our series of 47 cases of carcinoma arising in any portion of the pancreas, the ages ranged from thirty-two to eighty-two years, the majority oc-
CARCINOMA A N D VENOUS THR0116BOSIS
571
cumng in the sixth and seventh decades. Thirty-four of the patients were
males, 13 females. Many races were represented, but the great majority
of patients were white and born in America.
In only 16 cases was the head of the pancreas well preserved, the remaining 31 having pronounced involvement of the head either primarily or as a
result of extension of the process from the body of the organ. These tumors
of the head, while somewhat more often accompanied by thromboses than
those arising in other organs, did not show this association with the same
frequency as did the tumors originating in the body or tail. The most obvious
result of the difference in location is the effect upon the patency of the pancreatic ducts and the activity of the remainder of the organ. As would be
expected, almost all of the carcinomata in the head of the pancreas effected a
complete closure of the excretory ducts, and in most instances a profound
atrophy and fibrosis of the body and tail of the organ had taken place. The
3 cases of carcinoma of the head of the pancreas with multiple thromboses
recorded in Table I11 presented various degrees of change. In one, the duct
curved around the tumor and was patent throughout, leaving the distal parts
of the pancreas well preserved. In another the head of the pancreas with
the tumor had been resected in part and the remaining organ suffered little
damage. The third case did show the customary extensive loss of secretory
tissue and fibrosis.
( In all of the 16 cases of carcinoma confined to the body or tail of the
pancreas well preserved parenchyma was found in the head of the organ and
the communications with the duodenum were patent. In 9 of 56.2 per cent
of this group of 16 cases there was thrombosis of some vessel, and in 5 or 31.3
per cent many thrombosed vessels were found in various parts of the body.
Obstruction of veins in the immediate neighborhood of a tumor, especially
if the latter had a tendency to invade the vessels, could readily be explained
on a mechanical basis alone. Since many of the vessels involved were at
some distance from the primary tumor site, they were studied for any histologic changes which might account for the development of a thrombus.
The pancreatic tumors were often disseminated by the blood stream and it
is conceivable that the presence of tumor cells in vessel walls could have
formed a nidus for thrombus formation. The 3 cases of carcinoma arising
in the head of the pancreas showed somewhat less widely distributed thromboses than those described later, but all were at a sufficient distance to exclude
the possibility of direct invasion or obstruction by pressure. In one case the
ovarian and iliac veins were distended with partly organized thrombus material
and the patient died, presumably following pulmonary embolism. The thrombi
in the second case were somewhat similarly located, the prostatic and iliac
veins and the inferior vena cava being completely obstructed. In the third
case thrombi were found not only in the prostatic, femoral, and iliac veins
and the inferior vena cava, but in the right external jugular vein as well.
Again emboli in the pulmonary arteries with infarction of the parenchyma
had occurred. The thrombi and emboli were all undergoing organization.
In no instance were tumor cells found in the thrombi or vessel walls, nor waa
there any inflammatory process involving the vessels or the contiguous organs.
The 5 cases of carcinoma of the pancreas arising in the body or tail of the
1
572
E. E. SPROUL
organ, in which multiple venous thromboses were described, did not present
a uniform picture. The first showed thrombi in the saphenous, femoral, iliac,
hypogastric, renal, inferior mesenteric, superior mesenteric, portal, and cephalic
veins and the inferior vena cava. The pulmonary arteries were distended by
emboli and an infarct of the lung was present. Numerous microscopic sections revealed the presence of tumor cells in the walls of several veins even
in the lower extremities. Several thrombi were organized.
In the second case there was thrombosis of the testicular, prostatic, spermatic, hepatic, and portal veins. Emboli were again found in the pulmonary
arteries. The thrombi were quite old, often undergoing organization, but in
none of the sections were tumor cells or an inflammatory process found to
account for the occluded vessels.
In the third case the veins involved were the saphenous, femoral, iliac,
prostatic, hemorrhoidal, splenic, and portal, and the inferior vena &a.
There were infarcts of the spleen and lung, the latter due to an embolus in the
pulmonary artery. Microscopically tumor tissue was found in the portal vein
alone. Those vessels at a distance from the site of origin of the tumor showed
no invasion and no inflammatory changes in the walls. In general the thrombi
were undergoing organization.
In the fourth case fewer large vessels were involved, but since the thrombi
were found in the femoral vein apart from the tumor and there were numerous
small vessels in the brain, lungs, and heart occluded by thrombotic material,
it was included in this group. The thrombus material in the leg was of more
recent formation; that elsewhere was organized in good part. No tumor cells
were found in the sections of any of these vessels.
In the last case thrombi occluded the splenic, portal, pelvic, ovarian, and
coronary veins, and there were numerous infarcts in the liver, spleen, kidneys,
and heart. Tumor cells were found within the intrahepatic branches of the
portal vein but not elsewhere.
An interesting finding was the presence of non-bacterial vegetations on
the heart valves, either the mitral, or both mitral and aortic, in 4 of the 5
cases just described. The vegetations were composed of masses of fibrin
sufficiently large to have been interpreted as bacterial endocarditis on gross
examination. Not only were cultures and smears of the vegetations negative,
but sections showed no organisms or leukocytes and the only valvular change
was the proliferation of endothelial cells and fibroblasts to invade the base of
the fibrin mass. That they did not represent a mere terminal agglutination
of platelets is attested by the degree of organization and by the positive fibrin
stain with the Gram method. I t seems probable that they were further
evidence of the increased tendency to coagulation of the blood in the presence
of a carcinoma in the tail of the pancreas.
The benign epithelial tumors arising in the pancreas were also reviewed
to see if the same association could be established. Although 9 of the 25
cases, or 36 per cent, had a single thrombus somewhere in the body, there
were no instances of multiple thrombosis. It was also considered of interest
to determine whether the presence of a tumor secondarily invading the pancreas, but not originating from pancreatic cells, could in some way alter the
function of the secreting cells and favor coaguiation of the blood. Among
CARCINOMA AND VENOUS THROMBOSIS
573
83 cases of malignant disease with metastases in the pancreas, only 11 or
13.2 per cent had any thrombus in the body, and no examples of multiple
thrombosis were noted.
Since multiple venous thrombosis in cases of carcinoma of the pancreas
could seldom be explained by the presence of tumor cells in the vessel walls,
by inflammation or by mechanical obstruction from the growth of the primary
tumor, further study of this group was directed toward the factors which
might conceivably effect the coagulation of the blood.
I t is apparent from the few studies available that the amount of pancreatic
secretion as measured by enzyme content of the duodenal juices varies greatly
in cases of pancreatic tumor. Chiray and Bolgert (23) found little constancy
in the volume of excretion following secretin injections when the head of the
pancreas was occupied by a carcinoma, but the enzyme content, especially
the amount of lipase recovered, was greatly reduced. Huguenin, Albot and
Bolgert (24) also found a greater diminution of lipase than of trypsin in a
Comparable case. Meerssemann, Blan and Perrot ( 2 5 ) , on the other hand,
arrived at somewhat different conclusions as a result of detailed studies of
the enzymes in duodenal contents and fat and protein digestion as measured
by stool analyses in a case of carcinoma of the head of the pancreas. The
volume of pancreatic secretion was reduced after secretin (8 C.C. as compared
with 100 to 150 C.C. in a normal individual), but the quality of the secretion
as far as enzymes were concerned matched the normal juice. There was
faulty metabolism, however, both of proteins and fatty foods. Bolgert and
Audpy (26) described a case in which the tumor was situated in the body of
the organ but microscopic examination of the head is said to have revealed no
normal secreting tissue. Analysis of the duodenal contents following an injection of secretin showed a diminution in both lipase and tryptic activity.
The clearest differentiation between the pancreatk ‘activity in cases in
which the head is involved and those- where the body or tail alone is occupied
by tumor was found in the report of MrClure et al (27). In the latter group
the proteolytic activity of the duodenal juice was increased by about onefourth over the normal; lipase activity was three times that in normal individuals, and only the amylase was reduced. When the tumor was present in
the head of the pancreas all enzymes were greatly diminished.) Additional
information regarding the secretory activity of pancreatic tumds was found
in the analytical studies of Sugiura, Pack, and Stewart (28). While their
material was limited to one adenocarcinoma and three normal pancreases, the
same rate of digestion of starch, degree of proteolysis, and hydrolysis of esters
were present in the tumor extract as in that of the normal organs. It is probable that the lack of uniformity can well be explained by differences in degree
of involvement of the ducts and the amount of unaltered pancreatic tissue
remaining. Maceration juice obtained from the pancreas shortly following
ligation of the ducts had no tryptic activity, although it retained the ability to
activate juice from a normal pancreas (29). No estimations of the lipase or
esterase activity were made.
With these reports in mind, an attempt was made to establish the presence
or absence of secretory activity of the pancreatic tumors by their histologic
appearance. Such a study gave little support to the physiological evidence
574
E. E. SPROUL
that the tumors were actively secreting. All but one of the 8 tumors associated with multiple thromboses showed gland formation of more or less irregular pattern, and there was usually an abundance of much within the cells
and free in the lumen of the glands. But this was also true of the cases in
which no thrombi were found. Occasionally the inner margin of the tumor
cell, approximating the lumen, stained somewhat more deeply with eosin than
the base of the cell but did not show distinct granule formation. When this
was compared with the deep eosin stain of the zymogen granules in the normal
acinar cells which were often present in the same section, the disparity was
too great to permit interpretation of the tumor stain as representing secretion.
The condition of the liver and the degree of obstruction of the biliary tract
are also of interest where changes in coagulability of the blood are concerned.
In reports describing carcinomata of the pancreas and the accompanying
lesions, jaundice has been noted in the majority of those in which the tumor
was in the head of the organ; tumors in the tail of the pancreas have rarely
caused obstruction of the bile ducts. It has long been observed that a tendency to bleeding may be present in jaundiced individuals, and more recently
this has been ascribed to a diminution in the blood prothrombin resulting
from exclusion of bile from the intestinal tract (30). Though the secretory
activity of the pancreatic tumors might tend to increase blood coagulation,
any interference with the flow of bile into the duodenum would counteract
such an effect, Extensive replacement of the liver by metastases, or considerable parenchymatous degeneration possibly following reduction of pancreatic secretion into the intestinal tract, would also tend to neutralize the
coagulative effect of excessive pancreatic secretion. Smith, Warner and
Brinkhous (31) demonstrated that the bleeding tendency accompanying at
least some liver degenerations is due to a deficiency in both plasma fibrinogen
and plasma prothrombin.
The condition of the liver and degree of jaundice werk therefore noted
in all of the cases of pancreatic carcinomata to see whether these factors could
be correlated with the extent of venous thrombosis. In the 39 cases in which
no thrombi or a single thrombus appeared, jaundice was described in 27, or
68.9 per cent. Of the remaining 12 cases without obstructive jaundice, 6 had
extensive involvement of the liver by tumor metastases, 3 showed either
necrosis or fatty metamorphosis in the liver, and only 3 of the 39 cases had
neither liver damage nor jaundice which might depress the prothrombin level
in the blood and prevent the formation of thrombi.
On the other hand, in the group of 8 patients with pancreatic carcinomata
and multiple venous thromboses, only 2 were jaundiced and in both instances
the cause of the jaundice lay in the degree of liver involvement and not in
obstruction of the extrahepatic ducts. The latter as well as the duodehum
were stained with bile. In all but one case, however, there were many tumor
nodules in the liver, fully as many as in those unaccompanied by thrombosis,
and in one instance infarcts of the liver were also conspicuous.
The only other factor amenable to investigation which might alter the
incidence of thrombosis, especially in the abdominal cavity, is the operative
procedure. Pancreatic tumors, in particular those in the tail, where recognition is difficult, are less often subjected to surgical interference than. those
CARCINOMA A N D VENOUS THROMBOSIS
575
in the stomach or colon. Only 3 of the patients with multiple thrombi had
been operated upon, and in all 3 the activity had centered about the upper
abdomen, while the thrombi were present in the pelvis, lower extremities,
or neck.
Curcinomu of the Lung: If thrombi form in the veins of patients bearing
carcinoma of the pancreas merely because of mechanical injury to the vessel
by the disseminated tumor cells, it would be expected that tumors arising in
other organs and especially prone to invade the veins would have a similar
e#fect. The lung is frequently the site of origin of a widely distributed carcinoma, presumably reaching remote parts of the body by way of the blood
stream. Despite this there are few reported cases in which thrombosis has
been a prominent feature of the disease. In a discussion of a case of thrombophlebitis migrans by Warner and Dauphinee (32) it is stated that the patient
had a bronchogenic carcinoma as well. A careful histologic study of the
peripheral veins involved failed to reveal any underlying change in the vessel
wall. Except for the report of James and Matheson (3), previously mentioned, this case seems to be unique, others showing only a more limited
thrombosis which might well be a chance occurrence. Such a one is found
in the description by Fielden (33) of a bronchogenic carcinoma with thrombophlebitis of the splenic and portal veins.
In the present series only 12 or 14.8 per cent of the cases of bronchogenic
carcinoma bad thrombosis of any part of the vascular system and but 2, or
2.5 per cent, were accompanied by multiple thrombosis (Table 111). The
sections of these cases were reviewed for possible causes of thrombosis. It
was found (see Table IV) that local invasion of the venae cavae with complete obstruction accounted for the formation of most of the thrombi. Infectious processes involving the vessels were not encountered. It is also of
interest that in many instances tumor tissue was present in the walls or lumina
of the veins without thrombus formation, indicating no especial coagulating
ability of this carcinoma. Examination of the liver and pancreas in the cases
cited yielded no features in which they differed from the cases free of thrombi.
In both, the liver frequently contained metastatic nodules. The pancreas was
usually unaltered; it rarely showed secondary invasion by tumor.
Curcinomu of the Liver: Tumors arising in this organ might reasonably
be expected to affect the coagulability of the blood either by taking part in
the pertinent functions of liver cells or by replacing normal active parenchyma. The liver is thought to be in good part responsible for the production
of fibrinogen, but it has been stated that the rate of clotting of the blood is
little influenced by its fibrinogen content (34). The liver is also a source
of the controversial anticoagulant heparin. Although many believe its action
in d u o to be inconsequential, Chargaff (35) points out that it requires such
drastic procedures to detect its presence that its r61e in inhibiting the clotting
of blood is not settled as yet. The variation of prothrombin content of the
blood with liver damage, however, and the direct parallel with clotting time
of the blood (31) remain at the present time the best established means of
association of these two factors.
Again an individual case report can be found suggesting a relationship
between a particular tumor and thrombosis. In this instance the thrombus
TABLE
IV: TbromboJisin Cases of Carcinoma not Arising in Pancreas
-
Location of
Primary.
Tumor
Lung
?lo.
1
1
1
1
3
1
1
1
Gallbladdei
-Ieart
~
~
None
None
None
None
Comprewed by primary tumor
;mall pulmonary artery
liac vein
'ulmonary artery
?ortal vein
Sclermis coronary arteries
h a l l pulmonary artery
None
Prostatic veins
Cardiac insufficiency
ienal veins and inferior vena cava Invaded by tumor
4
3eart
1
1
1
Iliac artery
lliac vein
Pampiniform plexus
Rheumatic carditis or coronary occlusion
Marked scleroeie
None
Invaded by tumor
2
2
1
1
Femoral vein
Iliac vein
Inferior vena cava
Pulmonary veins
Radiation-acar tissue
Compression by tumor
None
None
1
1
1
Iliac vein
Iliac vein and inferior vena cava
Femoral vein
None
None
Compression iliac veins by fibroids.
Tumor in vena cava
Tumor in perivaacular lymphatics
1
-
Stomach
Zomplete obstruction of vena cava by
tumor
1
1
2
Ovary
-~
3
Uterus
~
Many metastases in liver
Lobectomy
Local invasion by tumor
None
3batruction of superior vena cava
Wide dimemination of tumor in vesecl
walls
rumor in vein
'ortal vein
'ortal and mesenteric veins
rumor in vein
'ortal vein and inferior vena cava rumor in vein
nferior vena cava
rumor in vein
hart
Prostate
~
'ortal vein
'ulmonary vein
7enae cavae
liac vein
ugular vein
liac, portal, mesenteric, renal,
spermatic, and splenic veins and
inferior vena cava
iuperior vena cava, jugular, subclavian, and portal veins
1
1
1
1
1
Kidney
Factora Responsible for Thrombosis
3
3
2
Liver
Location of Thrombi
18e8
10
I
4
3
3
1
1
1
1
1
-
Iliac and femoral veins
Femoral or iliac veins or inferioi One invaded by tumor. Others no
change
vena cava
Pulmonary artery
Embolus (7) No tumor
Portal vein
Two invaded by tumor. One suppurative infection. One no change
Pulmonary vein
None
Adrenal vein
None
Renal vein
None
Prostatic vein
None
None
Hart
Subclavian, jugular, pulmonary ant None
basilic veins
Jugular, axillary and iliac veins, ant None
inferior vena cava
576
CARCINOMA AND VENOUS THROMBOSIS
577
TABLEIV-Conlinucrl
Location of Thrombi
Tumor
Duodenum
or Ampulla
of Vater
Colon
Factors Responsible for Thrombosie
1
1
1
Splenic vein
Iliac vein
Prostatic veins
None
None
None
3
1
3
1
Mesenteric and splenic veins
Aorta
Pulmonary arteries
Iliac vein
Iliac and splenic veins
Iliac vein and inferior vena cava
Mesenteric vein
Splenic vein
One periarteritis. Two none
Sclerosis
None
None
Peritoneal abscesa
None
Vein ligated at operation
One suppurative phlebitis. One
tumor approximating vessel
None
Tumor in vein
-
1
1
Portal and mesenteric veins
Adrenal vein
formation in the patient described by Stern (36) can well be ascribed to an
inflamm'atory process, since there was a true thrombophlebitis of the leg veins
with a suppuration of the portal vein. Among the 22 cases of carcinoma in
the present series, originating either from the intrahepatic bile ducts or liver
cells, 6, or 27.2 per cent, had a thrombus in some vein but there were no
examples of multiple thrombosis. The only factor of importance, as indicated in Table IV, is the invasion of regional veins by the primary tumor.
There were, in addition, several cases where tumor tissue was found in these
veins and no thrombus formed, strengthening the assumption that these cells
had no particular tendency to stimulate blood coagulation. Since, however,
so many of the cases were accompanied by cirrhosis of the liver with jaundice,
a deficiency in prothrombin may have been present, tending to inhibit clotting.
Carcinoma of the Gallbladder: The location of carcinomas of the gallbladder is also such that jaundice is a frequent finding. In our group of 30
cases it was described in half, leaving ample opportunity for a coagulant effect
to manifest itself if the tumors of this organ behaved as those of the pancreas
seem to do. There were no instances of multiple thrombosis in this group.
The individual thrombi recorded in Table IV are of little significance.
Carcinoma of the Kidney: Another tumor prone to invade the vascular
system is the so-called hypernephroma. Judd and Scholl (37) described a
case and quoted Foulds as stating in a persond communication that of 200
renal tumors seen at the Mayo Clinic 22.5 per cent had involved at least the
renal vein. Jacobson and Goodpasture (38) presented a striking case in
which the tumor filled the inferior vena cava and reached the right auricle and
ventricle, Necroses in the liver resulted from occlusion of hepatic veins.
In this series all the malignant epithelial tumors arising in the kidney were
included in one group, amounting to 27 cases, among which there were no
examples of multiple thrombosis. The causes of the individual thrombi are
listed in Table IV. Other carcinomata invaded the renal vein without complete occlusion, and thiombus had not formed about the tumor tissue.
578
E. E. SPROUL
Carcinoma of the Prostate: Although direct growth of the tumor into large
vessels is not so commonly encountered in prostatic carcinoma, the tumor cells
often travel widely through the body in the blood. In none of the 43 cases
examined did this initiate thrombosis in more than one situation. No significance could be assigned to the single thrombi recorded in Table IV.
Carcinoma of the Femde Pelvic Organs: The tumors arisingh either the
fundus or cervical portion of the uterus ordinarily receive vigorous radiotherapy, and the primary tumor in many instances had completely disappeared
at the time of post-mortem examination. The two factors which might be
expected to enhance the coagulability of the blood in the presence of a uterine
carcinoma are the amount of radiotherapy and, in untreated cases, the size
of the mass within the pelvis, providing a barrier to venous flow from the
extremities. The mechanism of the latter is obvious. The former has been
studied first by determining the effect of radiation on various organs. Saelhof
(39) demonstrated an increase in prothrombin and a diminution in clotting
time with radiation of the spleen, liver, and intestine. The platelets were
more numerous when the liver was stimulated. Pagniez et al (40) pointed
out that it mattered little what part of the body was treated, irradiation
shortened the time of blood coagulation.
Rud (41) reported a diminution in coagulation time in his study of 40
cases of uterine carcinoma. In 5 the clotting time was within normal limits
(three minutes); in 20 it was between two and three minutes and in 15 it was
one to two minutes. There was some increase in fibrinogen but no absolute
relation to the number of platelets was noted. Irradiation was not mentioned.
Despite these factors, only 6, or 22.2 per cent of the 27 cases in our records,
had a single thrombus and no example of more extensive involvement of the
veins was found. The thrombi were usually local and due to venous compression either by the primary tumor or scar tissue. The few thrombi associated with carcinoma of the ovary were close to the site of origin of the tumor.
Carcinoma of the Stomach: Gastric carcinoma proved to be of interest
second only to those arising in the body or tail of the pancreas. Moser (42)
took exception to Thoenes’ implication that a carcinoma of the pancreas should
be suspected when many veins were thrombosed and described a case presenting a similar pattern except that the primary tumor arose in the stomach.
In this series there were 32 instances of thrombosis in the 147 cases of
carcinoma of the stomach, of which 2, or 1.3 per cent, were multiple to an
extent comparable with the thromboses accompanying pancreatic tumoys.
The 30 individual thromboses appeared in a variety of situations, as indicated
in Table IV. In most instances there was no assignable cause for the formation of thrombi even in the two cases where these were more widely distributed.
The pancreas was grossly and histologically normal in one and, while the liver
included a small amount of tumor tissue and an echinococcus cyst, there was
well preserved parenchyma amounting to at least half the normal organ. In
the second case the pancreas and liver had been invaded to a slight degree
by tumor nodules but there remained a good proportion of apparently functioning tissue. No operation had been performed. There was no infection.
Carcinoma of the Intestine: Thrombi rarely occuped in association with
carcinoma of the duodenum. Carcinomas arising in the large intestine com-
CARCINOMA AND VENOUS THROMBOSIS
5 79
prise a relatively large group, yet the incidence of thrombosis, 1s of the 94
cases, or 15.9 per cent, was low and there was no tendency to multiple
thrombosis. And this was true despite the fact that the great majority of
patients had undergone one or more operations of considerable extent.
In none of the tumors of various origin could any correlation be discovered
between the histologic type of tumor and the condition of the pancreas or the
extent of liver involvement. Nor were the vessels thrombosed any more frequently in one sex than in the other. The age distribution was comparable in
those with and without thrombi.
DISCUSSION
From this study it would seem fair to conclude that the chief factors
responsible for thrombosis in the presence of a malignant tumor are direct
invasion of a large venous trunk by tumor tissue, compression by the primary
mass, or irregular invasion of the vein wall following extension of the tumor
along the perivascular lymphatics. The first was found especially when the
site of the primary tumor was the lung, liver, or kidney. Carcinomata arising
in the pelvis often formed an obstructive mass.
Not all thrombi, however, could be thus explained. When an individual
vein was involved the significance was too slight to warrant additional inquiry
into the causative factors. But the frequent occurrence of venous thrombi in
remote parts of the body in patients having carcinoma of the pancreas and,
less often, of the stomach, without morphologic changes to account for their
formation, deserved further consideration.
Previous workers have been interested in the relation between the pancreas
and clotting of the blood. In a series of studies Boldyreff (43, 44) followed
the effects of complete extirpation of the pancreas in dogs. His ‘‘ pancreatic
triad ” included a‘rise in blood sugar, decrease in coagulability of the blood,
and leukocytosis. ’ The rapidity of coagulation was diminished from a normal
level of 40 seconds to 250 seconds in nine hours, and a similar but less pronounced effect was evident when partial pancreatectomy was performed. The
fact that complete loss of coagulability was never attained and that there was
grdual restoration toward the normal state led him to believe that additional
sources of the “fibrin ferment” might exist, or that enzyme previously secreted by the pancreas was stored in other organs.
Turcatti (46) corroborated these findings. Interference with the clotting
mechanism of the blbod was noted not only with pancreatectomy but when a
pancreatic fistula was created. Turcatti believed the external secretion of
the pancreas to be the responsible factor in maintaining blood coagulability,
but stated that the effect is probably indirect through the liver.
Ferrari and Cortese (47) also studied the external secretion of the pancreas for its influence on blood coagulation. In addition to the lengthening
of clotting time they reported a reduction in thrombin when the pancreas
was resected or a fistula formed. The rise in fibrinogen they attributed to
operative trauma as it occurred in control operated animals. They assumed
that the substance responsible for these effects usually enters the intestine,
is absorbed there, and influences the formation of prothrombin by the liver.
5 80
E. E. SPBOUL
Since no changes were noted following ligation of the ducts, they suggested
that the substance, under these circumstances, passes directly into the blood.
It might be well to point out that this conclusion should be reached only if
great care has been taken to establish beyond a doubt that no accessory ducts
carrying a small quantity of pancreatic secretion into the duodenum have
escaped detection. It is well known that separation of the head of the pancreas from the intestine is required in addition to duct ligation in order to
ensure a complete interruption of the flow of secretion.
Dogs have usually been the subject for such investigations but the same
effects have been noted in rabbits. Hiruma (48) found that the prolongation of clotting time paralleled the increase in fibrinogen in the blood when
the pancreatic duct of the rabbit was ligated. Other factors of possible
influence were not measured.
Pancreatic activity might dter the coagulability of the blood in a variety
of ways, the most plausible of which are by its protease action, by the effect
of its lipases and esterases on cephalin or on the absorption of the coagulating
vitamin K,or by secondary alterations in liver functions. There is no information associating amylase activity with the phenomenon of coagulation.
Trypsin could increase the tendency to clotting of the blood either directly
or by improving digestion and absorption of proteins in the duodenum. In
1916 Douglas and Colebrook ($Q) stated that the blood clotted more rapidly
in vitro when a weak solution of trypsin was added, while its use in large
quantities delayed coagulation. Heard ($0) also found that trypsin in certain
concentrations clotted oxalated blood. He attributed this effect to a disturbance in the calcium and phosphorus in the protein molecule, bringing about
alterations in surface forces which cause the clotting. That the calcium content of the trypsin preparation used could not be the important factor seemed
probable since the dilution was such that the quantity of calcium present was
below the significant level.
Waldschmidt-Leitz ( ~ believed
)
thrombin to be a proteolytic enzyme
related to trypsin and explained the phenomenon of blood coagulation as an
enzymic hydrolysis of fibrinogen to an insoluble product. Trypsin, he stated,
accelerated clotting by hastening the hydrolysis. Other proteolytic enzymes
including papain were ineffective.
The objection to ascribing the relation of the pancreatic secretion and
blood clotting to tryptic activity in the blood itself lies in the antitryptic substances which are constantly present. It seems quite unlikely that free
trypsin would remain in the circulating blood as long as antitryptic substances
were active to a normal degree. Oelgoetz and Wittekind (52) did not succeed
in increasing the level of the pancreatic enzymes (amylase, lipase and proteases) in the blood of a normal animal, although it could be restored by oral
administration in the presence of pancreatic hypofunction. When fed in
excess the enzymes were stored in the liver and spleen rather than in the blood.
It is also stated (53) that antitryptic activity of the serum is especially increased in carcinoma as in other cachexia-producing diseases,
The only indication that enhancement of protein digestion in the intestinal
tract might influence blood coagulation was found in a discussion by Mills
(54). In order to avoid thrombosis following operations, trauma, or child-
CARCINOMA AND VENOUS THROMBOSIS
581
birth, and in febrile disease and cardiac decompensation, he suggested a low
protein diet, believing that the resulting drop in serum protein would decrease
the tendency to coagulation. Certainly the protein level of the blood falls
when pancreatic secretion fails to reach the duodenum, but whether the
reverse situation exists and a hyperproteinemia accompanies hypersecretion
of the pancreatic acini has not been established.
The possible r61e of the pancreatic lipases and esterases in maintaining
the coagulability of the blood is also of interest, but little experimental work
on this question has been reported. The two substances, probably of lipid
nature, having greatest effect on the clotting of blood are the phospholipid
cephalin and vitamin K. The former, present in all tissues but especially
in the lung and brain, presumably aids in conversion of prothrombin to
thrombin. Its identity as the coagulating lipid has been established by
Wadsworth et al. ( 5 5 ) and by Fischer and Hecht ( 5 6 ) .
There seems to be no doubt that variations in the amount of pancreatic
secretion are reflected in the level of the lipids in the blood. Chaikoff and
Kaplan ( 5 7 ) demonstrated the diminution in all lipids following pancreatectomy and were able to bring about a rise in blood lipid above normal by feeding
raw pancreas. The phospholipids were not so strikingly increased but were
elevated. The link between high blood cephalin and thrombosis is less clear.
The only work found relating these two changes was that of Rabinowitz and
Kahn (58), who reported a great increase in cephalin of the blood plasma
in thromboangiitis obliterans. They also studied the effect of injection of
an insulin-free extract of the pancreas and found that, while the lecithin
dropped, the cephalin rose above the normal level. No experimental evidence
has been found, however, for such a mechanism in venous thrombosis.
The nature, source, and mode of action of the coagulating vitamin K has
been elucidated only within the last decade. A summary of the more important facts can be found in the recent papers of Almquist ( 5 9 ) and of Dam
and Glavind ( 6 0 ) . The antihemorrhagic vitamin has not, to date, been
completely identified, but it is known to be fat-soluble and is found in the
non-sterol part of the unsaponiiiable fraction of active materials. Its absence
in the diet of chicks is followed by diminution in the prothrombin level of the
blood and the Occurrence of multiple hemorrhages. Other animals, including
dogs, rats, and guinea-pigs, do not develop these changes on a deficient diet,
indicating an ability to synthesize the vitamin. Human subjects have not
been studied extensively, but Dam found a large quantity of vitamin K in
the lipid fraction of the feces in persons limited to a K-free diet for a week,
indicating that they too may be able to manufacture the vitamin.
Interest lately has been focused on the correlation of our knowledge of
vitamin K with the changes in coagulability of the blood in obstructive
jaundice and in some degenerative diseases of the liver. Hawkins and Brinkhous (61) found a definite drop in the level of prothrombin in the blood of
bile fistula dogs, hemorrhage occurring at a certain level. Greaves and
Schmidt ( 6 2 ) reported a similar finding in rats with bile fistulae and an
excess of vitamin K in the diet was found to counteract the hemorrhagic
diathesis. Warner, Brinkhous, and Smith (30) also succeeded in restoring
the prothrombin level of the blood yith an extract of alfalfa rich in ‘‘ K ”
582
E. E. SPBOUL
mixed with bile, and found this more effective than bile alone. Recently
reports from the Mayo Clinic (63) bear out these findings in cases of obstructive jaundice.
To summarize then, vitamin K is a fat-soluble substance, probably a lipid,
absorbed from the intestinal tract in the presence of bile, and there seems
to be adequate proof that it is responsible for the level of prothrombin in the
blood. Prothrombin has been shown to vary directly with the coagulability
of the blood more consistently than any other known factor. No studies on
the relation of pancreatic secretion to the activity of the vitamin have yet
been reported, but it is possible, in view of its solubility in fats, that the
lipases and esterases elaborated by the pancreas might influence the absorption
of the vitamin or even be responsible for its apparent synthesis in the intestinal tract. An increase in pancreatic secretion such as seems to occur at
times when a carcinoma is present in the body or tail of the pancreas and
the duct is patent might be expected to increase the quantlty of prothrombin
in the blood. Such a rise would probably not, in itself, precipitate thrombosis
since we normally have more than the amount utilized in clot formation, but
an increase in prothrombin with the initiating factor of tumor cells in the
blood stream might be responsible for the many thrombi.
It is possible that the effect of the pancreas on the blood is an indirect one,
brought about by secondary changes in the liver. The fact that fat appears
In the liver cells, often in large amounts, in the absence of external pancreatic
secretion has frequently been stressed. Allan and his co-workers (64) demonstrated that the administration of insulin to depancreatized dogs led to the
disappearance of the fat which had accumulated in the liver but that the
fat returned after a long period of time. They concluded from this that the
external secretion of the pancreas was necessary for proper metabolism of
fat. Chaikoff, Connor and Biskind (65) reported the development of cirrhosis of the liver in dogs after a period of two to five years when they were
deprived of the pancreas but maintained with insulin. Aubertin et al. (66)
found large fatty livers in three dogs in which the pancreatic duct had been
resected. The degeneration of the liver cells was progressive from the
periphery of the lobule toward the center.
The functions of the liver are so complex that, even if it were known that
this organ was primarily responsible for alterations in blood coagulability in
the absence of external pancreatic secretions, the manner of production of
such a change would remain uncertain. Fluctuations in fibrinogen level of
the blood are not well correlated either with the degree of liver damage or
with clotting time of the blood. T The effect of variations in heparin production
are far too nebulous to deserve discussiom The plasma globulins in general
tend to be elevated, but their relationship to clotting time is questionable.
Trautwein (67) concluded that the globulin was more often elevated when
thrombosis was present. However, cases such as multiple myeloma from our
records showed a low incidence of thrombosis' despite a great increase in
plasma globulin. In one case the blood clotted rapidly after death, forming
an almost solid cast of the vascular system, yet thrombosis had not occurred.
The specific globulin, prothrombin, is more closely correlated with liver
activity and with the coagulability of the blood. In order to establish the
CARCINOMA AND VENOUS THROMBOSIS
583
hypothesis mentioned sometime previously-that the pancreas, independent
of the liver, may directly affect digestion and absorption of vitamin K and
thus the prothrombin level-it would be necessary to demonstrate that such a
change antedated any degenerative process in the liver. In the cases described in this study there was no morphological evidence that liver damage
was any more common in the group having thrombosis than in those without
it. While functional deviations undoubtedly occur before there is a change
in the microscopic appearance of the cell, damage sufficient to be reflected in
a significant blood dyscrasia would probably have been recognized in histologic study. I t seems likely that the liver did not play a very important r8le.
The hypotheses presented so far have assumed that the pancreatic tumor
cells may have exercised a general effect by discharge of enzymes into the
circulation or by alteiation of some process of digestion in the duodenum.
It is also possible that their effect is entirely a local one wherever metastatic
pancreatic cells chance to be in the blood stream. Coagulation of blood at
those points due to the secretory activity of a few tumor cells could initiate
the process of thrombosis and the responsible cells be missed in the sections
examined.
Since, however, carcinoma of the stomach is sometimes, though less frequently, accompanied by venous thrombosis, we have additional intimation
that the mechanism is one of disturbance in some digestive process. Achylia
gastrica, which accompanies so many gastric carcinomata, would provide a
more favorable medium for the action of pancreatic lipase and trypsin. It
has also been suggested that achylia is accompanied by a “ compensatory ”
increase in pancreatic secretion ( 6 8 ) . This mechanism probably does not
function alone, since the cases of pernicious anemia with achylia in our records,
37 in all, show a single thrombus in but 3 instances. Pernicious anemia,
however, is frequently responsible for a fatty liver, which may well have
interfered with the production’of prothrombin.
SUMMARY
( The incidence of thrombosis in any portion of the circulatory system and
the associated conditions were noted in a series of 4258 consecutive necropsies.
A carcinoma was found to be the most common cause of thrombosis of the
neck, abdominal, and pelvic veins and those of the extremities. Thrombosis
of the cerebral veins was more often accompanied by a local infectious process.
In the lung, carcinoma was second to arteriosclerotic heart disease as a precipitating factor.
Thrombosis of the arteries was usually dependent upon arteriosclerotic
chyges in the wall. Coronary sclerosis and rheumatic heart disease, as
would be expected, were found most frequently when the thrombus occurred
in the heart.
The cases of the more common carcinomata were studied and distribution
of venous thrombosis recorded. In 56.2 per cent of the cases of carcinomata
in the body or tail of the pancreas at least a single thrombus was present; in
31.3 per cent of these cases widely disseminated venous thrombosis occurred.
Inflammation or invasion of the vessels by tumor tissue could not be in-
584
E. E. SPROUL
crimhated as a cause of the thrombosis except in one case. There was no
correlation between age, sex, race, or the type of carcinoma and the formation
of thrombi.) Jaundice was usually absent in the group having extensive thrombosis, but the degree of involvement of the liver by tumor was variable.
Carcinoma arising in the head of the pancreas was associated with multiple
thrombosis in 9.7 per cent of the cases.
Bronchogenic carcinoma often penetrated the venae cavae and at times
thrombi formed distal to the invading tumor. Multiple thrombi were found
in 2, or 2.5 per cent of the cases. Invasion of the walls of the veins or
obstruction by the main tumor mass accounted for these.
Carcinoma of the stomach showed a high incidence of thrombus formation,
and in 2, or 1.3 per cent, the thrombi were widely distributed. No morphologic changes in the walls of the veins were found to actount for the formation
of thrombi. It is suggested that achlorhydria may affect the process of
digestion of the coagulating vitamin by pancreatic enzymes in the duodenum.
Carcinomata arising in the liver, gallbladder, duodenum, colon, kidney,
prostate, uterus, and ovary were not associated with multiple thrombosis. The
apparent causes of formation of the individual thrombi found are discussed.
The possible mode of interference with the blood-clotting mechanism by
pancreatic activity is discussed. It has been suggested that the pancreas
might be directly responsible by increasing the trypsin content of the circulating blood, or by an improved protein digestion and absorption. Objections
are offered to both these hypotheses.
The possible effect of alterations of pancreatic lipases on the blood cephalin
are mentioned. It is thought more likely that an increase in lipase in the
intestine may influence the coagulability of the blood by a more efficient
digestion of fats and absorption of the fat-soluble vitamin K.
The influence of changes in the liver secondary to pancreatic disease and
their presumed effect on blood clotting are discussed. They seem less significant as a factor in the production of thrombosis in this series of cases.
NOTE:Mrs.Isabel E. Malone assisted in the preparation of tables and bibliography.
BmLIoCIUPHY
1. TROUSSEAU,
A,: Clin. mbd. de 1'HBtel-Dieu de Paris 3: 80 and 739, 1877.
2. THOMSON,
A. P.: Clin. J. 47: 137, 1938.
3. JAMES, T.G.I., AND MATHESON,
N. M.: Practitioner 134: 683, 1935.
4. BARKER,
N. W.: Proc. Staff Meet. Mayo Clin. 11: 513, 1936.
5. HAWARD,
W.: Lancet 1: 650, 1906.
G.:Morgagni 73 (2): 2429, 1931.
6. FIGURELLI,
7. ANTONIOLI,G. M.: Minerva med. 9 (2): 735, 1929.
8. BOCK,H., AND RAUSCHE,C.: Deutsche med. Wchnschr. 26: 2025, 1926.
9. ~ R L M A N N I, ., AND RODIN,A.: Zentralbl. f. Chir. 54: 1995, 1927.
lo. ABRAMSON,
B. P.: Vestnik khir. 17 (No. 51): 39, 1929.
P.:
, Compt. rend. SOC.de biol. 118: 196 and 364, 1935.
11. M E N D E ~ F F
12. M E N D E ~ F F
P.:
, Compt. rend. SOC.de biol. 119: 557, 1935.
13. M E N D E ~ F FP.:
, Compt. rend. SOC.de biol. 119: 1190, 1935.
14. HoLQ, J.: Ztschr. f. Krebsforsch. 33: 133, 1931.
15. VAN ALLEN,C. M.: J. Exper. Med. 45: 87, 1927.
16. KOPACZEWSKI,
W.: Compt. rend. Acad. d. sc. 200: 974, 193s.
17. UMUUFT, W.: Miinchen. med. Wchnschr. 80: 607, 1933.
CARCINOMA AND VENOUS THROMBOSIS
585
THOENES,E.: Munchen. med. Wchnschr. 79: 1677, 1932.
WINTER,R.: Virchows Arch. f. path. Anat. 282: 99, 1931.
SMITE, R. E.: Guy’s Hosp. Rep., 82: 437, 1932.
MCFARLAND,
J.: Proc. Path. SOC.Philadelphia 2: 112, 1899.
GRAY,S. H.: Arch. Path. 6: 433, 1928.
CHIRAY,M., AND BOLGERT,
M.: Nutrition 6: 223, 1936.
HUGIJENIN,R., ALBOT,G., AND BOLGERT,
M.: Ann. d’anat. path. 12: 1098, 1935.
MEERSSEMANN,
F., BLAN,P., AND PERROT,
L.: Lyon mCd. 154: 248, 1934.
BOLGERT,
M., AND AUZEPY,P.: Bull. et mdm. SOC.rntd. d. hap. de Pans 52: 1124, 1936.
MCCLURE,C. W., ET AL.: Am. J. M. Sc. 167: 649, 1924.
Sucum, K., PACK,G., AND STEWART,
F.: Am. J. Cancer 26: 351, 1936.
ITZIOKA,F.: J. Biochem. (Tokyo) 26: 75, 1937.
WARNER,E. D., BRINKHOUS,
K. M., AND SMITH,H. P.: Proc. SOC.Exper. Biol. and
Med. 37: 628, 1938.
31. SMITH,H. P., WARNER,
E. D., AND BRINKHOUS,
K. M.:J. Exper. Med. 66: 801, 1937.
32. WARNER,W. P., AND DAUPHINEE,
J. A.: Am. Heart J. 12: 483, 1936.
33. FIELDEN,E. C.: St. Michael’s Hosp. M. Bull. 4: 74, 1930.
34. QUICK,A. J.: Am. J. Physiol. 115: 317-333, 1936.
35. CHARGAFF,E.: Science 85: 548, 1937.
36. STERN,N. S.: South. M. J. 27: 849, 1934.
37. JUDD, E. S., AND SCHOLL,
A. J.: J. A. M. A. 82: 75, 1924.
38. JACOBSON,
V., AND GOODPASTUBE,
E. W.: Arch. Int. Med. 22: 86, 1918.
39. SAELHOF,C. C.: Am. J. Roentgenol. 8: 179, 1921.
40. PAGNIEZ,
P., RAVINA,A., AND SOLOMON,
I.: Compt. rend. SOC.de biol. 90: 1227, 1924.
41. RUD,E.: Compt. rend. SOC.de biol. 96: 366, 1927.
42. MOSER,E.: Munchen. med. Wchnschr. 80: 2022, 1933.
43. BOLDYREFF,
W. N.: Am. J. M. Sc. 177: 778, 1929.
44. BOLDYREFF,
W. N. AND A. W.: Compt. rend. SOC.de biol. 95: 441, 1926.
45. LUNDBERG,
E.: Svenska Yak.-tidning. 28: 1081, 1931.
46. TURCATTI,
E. S.: Compt. rend. SOC.de biol. 100: 116, 1929.
47. FERRARI,
R., AND CORTESE,
F.: Arch. di fisiol. 31: 274, 1932.
48. HIRUMA,
K.: Biochem. Ztschr. 139: 152, 1923.
49. DOUGLAS, S. R., AND COLEBROOK,
L.: Lancet 2: 180, 1916.
50. HEARD,W. N.: J. Physiol. 51: 294, 1917.
51. WALDSCHMIDT-I$ITZ,-E.,
STADLER,
P., AND STEIGERWALDT,
F. : Naturwissenschaften 16:
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
1027. 1928.
52. OELCOETZ,
A. W., OELGOETZ,
P. A., AND WITTEKIND,J.: Am. J. Digest. Dis. & Nutrition
3: 159, 1936.
53. ROSENTHAL,
E.: Folia serologica 6: 285, 1910.
54. MILLS,C. A.: Ann. Surg. 91: 489, 1930.
55. WADSWORTH,
A,, MALTANER,
F., AND MALTANER,
E.: Am. J. Physiol. 97: 74, 1931.
56. FISCHER,
A., AND HECHT,E.: Biochem. Ztschr. 269: 115, 1934.
57. CHAIKOPF,I. L., AND KAPLAN,A: Proc. SOC.Exper. Biol. & Med. 32: 934, 1935.
58. RABINOWITZ,
H. M., AND KAHN, J.: Am. J. Surg. 31: 329, 1936.
59. ALMQUIST,H. J.: Poultry Science 16: 166, 1937.
60. DAM,H.,AND GLAVIND,1.:Lancet 1: 720, 1938.
61. HAWKINS,
W. B., AND BRINKHOUS,
K. M.: J. Exper. Med. 63: 795, 1936.
62. GREAVES,J. D., AND SCHMIDT,
C. L. A.: Proc. SOC.Exper. Biol. & Med. 37: 43, 1937.
63. MACATH,
T. B.: Proc. Staff Meet. Mayo Clin. 13: 67, 1938.
64. ALLAN,F. N., BOWIE,D.J., MACLEOD,
J. J. R., AND ROBINSON,
W. L.: Brit. J. Exper.
Path. 5: 75, 1924.
65. CHAIKOFF,
I. L., CONNOR,
C. L., AND BISKIND,G. R.: Am. J. Path. 14: 101, 1938.
66. AVBERTIN,
E., LACOSTE,
A., AND CASTAGNOU,
R.: Compt. rend. SOC.de biol. 118: 149,
A., AUBERTIN,
E.,AND CASTAGNOU,
R.: Compt. rend. SOC.de biol.
1935. LACOSTE,
118: 151,1935.
67. TBAUTWEIN,
H.: Ztsch. f. d. ges. exper. Med. 76: 236, 1931.
H., AND BERGLUND,
H.: Acta med. Scandinav. 90: 224, 1936.
68. A c m , G., LAGERL~F,