CLINICOPATHOLOGIC CONFERENCE
PULMONARY "EDEMA, CARDIOMEGALY, AND ANEMIA
WALTER 11. AKENHEAD, M.D., AND WILLIAM E. JAQUES, M.D.
Louisiana State University School of Medicine, New Orleans, Louisiana
CLINICAL SUMMARY
History. The patient was a pregnant, almost term, 34-year-old Negro housewife, who was admitted to the hospital on September 3, 1954, and expired approximately 10 hours later. She stated that she had been well until 5 days prior
to admission when she developed precordial pain and extreme shortness of breath
after having walked up a flight of stairs. The pain radiated to the left shoulder
and medial aspect of the forearm, but subsided when resting. During the ensuing
4 or 5 days she had several paroxysms of severe dyspnea, and discomfort and a
feeling of fullness in the upper abdomen became more manifest. There was no
pedal edema or hemoptysis.
Previous hospital records indicated that the patient was admitted to the hospital in August 1941, with a diagnosis of pre-eclampsia. Pertinent findings at
that time were: blood pressure 176/94; extensive edema; 4-plus albuminuria
with granular and hyaline casts; hemoglobin, 4 Gm. per 100 ml.; and marked
sickling of erythrocytes in the wet-film preparations. She was delivered of twins
and had a stormy post partum course that featured fever, pain in the left lower
region of the chest, and dyspnea. A follow-up visit to the outpatient clinic in
October 1941 revealed a normal blood pressure and urinalysis. The hemoglobin
was 9 Gm. per 100 ml., and 45 to 50 per cent sickling of red blood cells was
noted. In February 1949 an emergency left salpingectomy was done for ectopic
pregnancy. The postoperative course was uneventful.
Present admission. Physical examination revealed a well developed and well
nourished young woman in severe respiratory distress. The blood pressure was
132/80, pulse rate 142 per minute, respiratory rate 44 per minute,. and temperature 98 F. The mucous membranes were pale, there"wasmoderate cyanosis
of the nail beds, and the veins in the neclrwere - distended. The heart was moderately enlarged,"with a gallop "rhythm, but-there were no significant murmurs.
Crepitant and subcrepitant rales were present over the lower posterior lung
fields. The liver edge was palpable and tender, 4 cm. below the costal margin.
There was no pedal or sacral edema.
Pertinent laboratory data revealed a hematocrit reading of 25, and a hemoglobin of 9 Gm. per 100 ml. Many nucleated red blood cells were observed in
the peripheral blood. A sickle cell preparation had 60 to 70 per cent sickling in
2 hours. Urinalysis revealed 4-plus albuminuria, and 3 to 4 white blood cells per
high power field. X-xay films of the chest revealed enlargement of the cardiac
Received, J a m j a r 26, 1956; accepted for publication February 10.
Dr. Akenhead is Professor and Head of the Department of Medicine, and Dr. Jaques
is Associate Professor of Pathology and Acting Head of the Department.
926
Aug.
1956
CLINICOPATHOLOGIC CONFERENCE
927
shadow and a bilateral increase in the pulmonary vascular markings that was
consistent with pulmonary edema. The venous pressure measured 220 mm. of
water. The circulation time (arm to tongue) was recorded as 33 seconds.
The clinical course of the patient was progressively ingravescent to exitus,
approximately 10 hours after admission, in spite of efforts to treat the cardiac
failure and bronchopneumonia.
CLINICAL
DISCUSSION
Dr. Akenhead. Summarizing in a few words, the patient entered the hospital
and died some hours later with signs of acute pulmonary edema, cardiomegaly,
gallop rhythm, and anemia. Lack of time and the serious state of the patient
did not permit a great deal of study, so we will have to proceed on clinical
grounds, helped by the sparse laboratory data available, but not hindered by
an overabundance.
The presence of a longstanding anemia with marked sickling of erythrocytes
in a Negro patient seems to be reasonable evidence that favors a diagnosis of
sickle cell anemia. There are some who would object to such a diagnosis in a
person of this age with only a recent history of serious difficulty. They would
insist that true sickle cell disease is a clinical syndrome that begins in childhood,
and is characterized by chronic anemia, jaundice, poor development and nutritional state, periodic hemolytic crises, changes in the bones, and ulcers of the
legs. It is true that these landmarks are the usual finding, but, in our own experience through the years, we have seen several cases in which well developed,
apparently healthy Negroes have the first clinical manifestations of the disease
in their thirties and early forties. It is unfortunate that electrophoretic studies
of hemoglobin were not conducted, but it is extremely unlikely that the high
percentage of sickling manifested by this patient would be observed with any
type of defect in hemoglobin other than the homozygous SS variety. Homozygous CC and heterozygous SC defects are characterized by large numbers of
target cells in the peripheral blood, with little or no sickling present. The heterozygous SA defect (sickle cell trait) that is observed in 7 to 8 per.cent of the
Negro population does not lead to overt anemia.
Enlargement of the heart is common in longstanding severe anemias, but it is
particularly evident in sickle cell disease, often with rather striking enlargement
of the right side of the heart. This finding, together with the presence of murmurs, fever, and pain in the joints, bones, and muscles, has at times led to difficulty in distinguishing the disease from acute rheumatic fever. The right ventricular hypertrophy so often observed is probably related to multiple and
repeated small pulmonary infarctions, leading to reduction of the pulmonary
vascular bed with subsequent pulmonary arterial hypertension. A final episode
of cardiac failure (the mode of exitus in this patient) is the usual event in this
disease, oftentimes with bronchopneumonia as a "fellow traveler."
The absence of an enlarged spleen is of no great clinical significance except
that it mitigates against a diagnosis of acquired hemolytic anemia, and favors
the diagnosis of sickle cell disease, although splenomegaly is a not uncommon
928
A K E N H E A D AND
JAQUES
Vol. 26
finding early in the disease. On the other hand, in longstanding sickle cell disease,
with repeated infarcts of the spleen, the organ becomes remarkably small; in
effect, the patient splenectomizes himself. In this instance, it is reasonably safe
to assume that the pain in the left lower region of the chest and the fever experienced in 1941 were related to splenic or pulmonary infarction.
All of the manifestations of sickle cell disease have been pathogenetically related to changes in hemoglobin architecture, with changes in the shape of the
red cells, rapid destruction of erythrocytes, and thrombosis of small vessels.
These factors superficially explain the morphologic alterations observed at necropsy, but there is much that is unexplained: (1) the cause and nature of the
frequent hemolytic crises; (2) the mechanism of destruction of red blood cells;
(3) the biochemical changes, local and remote, that are related to alteration of
the physical state of the hemoglobin molecule.
PATHOLOGIC
FINDINGS
Dr. Jaques. The heart was enlarged, weighing 450 Gm. The enlargement was
the result chiefly of right ventricular hypertrophy (7 mm.). The left ventricle
measured 12 mm. in thickness. The valves were normally constituted, and the
myocardium was homogeneously red-brown. The coronary arteries had only
minimal eccentric internal thickening.
The lungs were heavy, and contained varying sized infarcts, involving all
lobes, but particularly prominent in the lower lobes. There were numerous
thrombi throughout the ramifications of the pulmonary arterial tree. Microscopic examination revealed that the thrombi were of varying ages. One could
reconstruct the sequence of events by studying various sections. There was generalized congestion, increased tortuosity, aneurysmal dilatation, and numerous
sickled erythrocytes. The sickled erythrocytes seemed to be adherent to one
another, thereby producing a large conglutinated mass (Fig. 1). There was scant
fibrin associated with these thrombi. Later, there was organization of these
masses of sickled cells, with concomitant shrinkage and eventual thickening of
the intima (Fig. 2). The infarcts were of varying ages, and the older ones contained foci of extensive squamous metaplasia (Fig. 3).
The spleen weighed 3 Gm., and it was firm, fibrosed, and without any gross
markings. Microscopic examination revealed extensive fibrosis, encrustations
of iron, and "Gamna-Gandy bodies." Only rare foci of lymphoid tissue were
observed (Fig. 4).
The liver weighed 2580 Gm., and it was mahogany brown in color and firm
in consistency. Numerous sickle cells were present in the sinusoids, and masses
of phagocytosed sickle cells were noted in the Kupffer cells. The kidneys were
enlarged, and prominent glomeruli were noted when the organs were viewed
tangentially. There was extensive sickling in the capillary loops of the glomeruli
FIG. 1 (upper). Lung. A pulmonary arteriole containing amass of conglutinated sickle
cells. The wall is thin and the vessel is dilated. There is an associated acute congestion and
edema. Hemotoxylin and eosin. X ISO.
FIG. 2 (lower). Lung. A pulmonary artery with extensive intimal thickening and narrowing of the lumen. Hematoxylin and eosin. X ISO.
Aug. 1956
CLINICOPATHOLOGIC CONFERENCE
F I G S . 1 ANMJ 2
929
930
A K E N H E A D AND
JAQUES
Vol. 26
and renal vessels. Focal tubular degeneration was apparent, but no hemosiderin
was noted in the tubular epithelium. The brain weighed 1150 Gm., and there
was moderate flattening of the gyri, narrowing of the sulci, and generalized
dilatation of the blood vessels of the central nervous system. Extensive sickling
of red blood cells was noted, and there were small focal areas of encephalomalacia, whereas other regions had small zones of gliosis.
All of the other maternal viscera revealed generalized sickling of the red blood
cells, although no additional anatomic lesions were observed.
The fetus weighed 3300 Gm., and measured 50 cm. in length. There was evidence of intrauterine asphyxia with aspiration of vernix caseosa. I t was interesting that sections through the placenta revealed extensive sickling of the erythrocytes in the intervillous sinuses, whereas the vessels of the chorionic villi were
free of this process.
CLINICOPATHOLOGIC
CORRELATION
Electrophoretic studies were not performed on this patient's blood, but it
would seem probable that sickle cell disease, rather than the trait, existed in
this patient. It is frequently difficult to distinguish the disease from the trait
on purely morphologic criteria. However, the severity of the sickling, great decrease in the size of the spleen, prominent erythrocytophagocytosis in the liver,
pulmonary vascular changes, and findings in the central nervous system seem
to justify the assumption that the patient had sickle cell disease.
This patient had extensive pulmonary vascular changes. Sickle cell disease
as a cause of pulmonary hypertension and cor pulmonale has only recently been
appreciated. 2 In an analysis of 65 cases of sicklemia in New Orleans, it was found
that 12 (18.4 per cent) had right ventricular hypertrophy. In these instances,
the right ventricle measured more than 5 mm. in thickness. In a hospital with
a large population of Negroes, sickle cell disease must be seriously considered as
a cause of cor pulmonale.
One gains the impression that the pulmonary changes occurred over a considerable period of time. The areas of organized infarcts associated with squamous metaplasia would substantiate this view. The added burden of pregnancy
with a hemolytic crisis apparently aggravated the anoxia, and led to myocardial
ischemia and symptoms that were predominantly cardiac in type.
There is apparently no deleterious effect on pregnancy by the sickle cell trait. 1
On the other hand, crises associated with sickle cell anemia are not uncommon
during pregnancy.
We would agree with Doctor Akenhead that this case does not represent the
classic picture of sickle cell anemia. However, we do see bona fide instances of
this disease in older patients without the earlier manifestations being apparent.
We are also gaining the impression that sickle trait may not always be a benign
condition. Pulmonary vascular changes associated with the trait are now being
FIG. 3 (upper). Lung. Prominent squamous metaplasia in an old organized infarct.
Hematoxylin and eosin. X ISO.
FIG. 4 (lower). Spleen. Extensive fibrosis and encrustation with iron. Hematoxylin and
eosin. X 180.
Aug. 1956
CLINICOPATHOLOGIC CONFERENCE
F I G S : 3 AND 4
931
932
A K E N H E A D AND J A Q U E S
Vol. 26
recognized. The whole question of the pathology of sickle cell disease and trait
should be restudied.
SUMMARIO I N I N T E R L I N G U A
Es presentate le caso de un 34-enne negra in stato pregnante avantiate qui
moriva 10 horas post admission al hospital con signos de acute edema pulmonar,
cardiomegalia, rhythmo galopante, e anemia. Viste le historia del patiente, le
autores conclude que le caso non representava le aspecto classic de anemia a
cellulas falciforme. Tamen, es signalate le facto que anemia a cellulas falciforme
occurrente in patientes de etates plus avantiate, sin le previe manifestationes del
morbo, non es un phenomeno inaudite. Le caso reinfortia le impression que le
tracto de cellulas falciforme non es in omne su occurrentias un condition benigne;
illo es de interesse in connexion con le question del association de alterationes
pulmono-vascular con le tracto de cellulas falciforme; e illo servi a illustrar le
necessitate de restudiar le problema del pathologia del morbo e del tracto de
cellulas falciforme.
REFERENCES
1. SWITZER, P. K., AND FOUCHE, H. H.: The sickle cell trait: Incidence and influence in
pregnant colored women. Am. J. M. Sc., 216: 330-332, 194S.
2. YATER, W. M., AND HANSMANN, G. H.: Sickle cell anemia: A new cause of cor pulmonale.
Am. J. M. S c , 191: 474-484, 1936.