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SIGNIFICANCE OF NUCLEATED RED BLOOD CELLS IN
PERIPHERAL BLOOD
ANALYSIS OF 1,496 CASES
Steven O. Schwartz, M.D.
and
Fred
Stansbury, M.D., Chicago
Under normal conditions, nucleated red blood cells
found only in the circulating blood of the fetus and
the newborn infant. Beyond that period the presence of
nucleated red blood cells in the peripheral blood indicates disorder in the blood-producing mechanism. Because nucleated red blood cells are immature cells, they
do not enter the blood normally. No totally satisfactory
explanation is available of the precise mechanism that
maintains a "barrier" that normally prevents primitive
cells of the marrow from reaching the peripheral circulation. Evidence suggests at least two mechanisms: one
chemical, primarily influenced by anoxia; the other physical, dependent at least in part on the syncytial arrangement of primitive cells. The violation of this "barrier"
and the escape of nucleated red blood cells signal the
presence of a stimulus that is allowing the release of these
cells, before they have passed through the intermediate
reticulocyte stage, to become adult red blood cells ready
for the circulation. An abnormal demand for red blood
cells produces an outpouring into the peripheral blood
of all cellular elements, because there is a certain amount
of nonspecific stimulation that will increase the white
blood cells with a concomitant increase in primitive white
blood cells. The specific stimulation will bring an increase
in young red blood cells and the reticulocytes and, in the
severe case, an increase in nucleated red blood cells,
which is the point of interest here.
Stimuli sufficient to cause nucleated red blood cells
to cross the barrier between the marrow and the general
circulation are (1) hemorrhage, (2) hemolysis, (3) per¬
are
nicious anemia, (4) marrow displacement, which may
be intrinsic or extrinsic, (5) anoxia from other causes,
and (6) a diverse miscellaneous group of conditions that
will be listed specifically later. Our interest in the signifi¬
cance of nucleated red blood cells in the peripheral blood
was aroused by the remarkably high incidence of death
that was noticed in a group of patients in whom this phe¬
nomenon had been observed. The present study, which
revealed a mortality of almost 50% among patients in
whom nucleated red blood cells appeared in the periph¬
eral
blood, confirmed
this correlation.
EARLIER OBSERVATIONS
It was not until the end of the last century that nucle¬
ated red blood cells were observed to be present in the
peripheral blood in certain diseases: Von Noorden,
quoted by Da Costa,1 in 1891 emphasized the presence
of showers of nucleated red blood cells in cases of chloro¬
sis. Da Costa interpreted these blood crises as a favorable
sign indicating regeneration of blood and therefore indi¬
cating an increase in red blood cells and the hemoglobin
level. Bramwell2 saw nucleated blood cells in the periph-
eral blood as being indicative of an excessive or imperfect
blood formation, an effort on the part of nature to com¬
pensate for increased corpuscular destruction. He cited
experimental work in which nucleated red blood cells
were made to appear in the peripheral blood of animals
by bleeding them. In 1904 Cabot8 noted that nucleated
red blood cells occur in patients with severe infections
and cited a fatal case of pneumonia with empyema in
which the patient had a red blood cell count of 4,500,000.
Cabot also noted that these nucleated cells were fre¬
quently present in cases of carcinoma even though an
adequate red blood cell count and amount of hemoglobin
were present. We now generally tend to think first of
erythroblastosis fetalis, of Mediterranean anemia, and the
other hemolytic anemias in connection with nucleated red
blood cells in the peripheral blood. Diamond4 had pointed
out, however, that infectious diseases such as syphilis
must be ruled out when erythroblastosis is suggested, be¬
fore a diagnosis is made. In 1948 Groen and Godfried 5
observed that the prognosis is poor when nucleated red
blood cells occur in the peripheral blood in congestive
heart failure. In all the cases mentioned by these men,
thrombi were found in the lungs, and cyanosis was a
prominent clinical sign. Our studies confirm Groen and
Godfried's observation with regard to prognosis.
MATERIAL AND RESULTS OF STUDY
The records of the Department of Hematology of the
Cook County Hospital, Chicago, were reviewed for a 10
year period from 1941 to 1951. There were 1,496 cases in
which nucleated red blood cells had been recorded during
that time. In each of the 1,496 cases, the records showed
whether the patient died while in the hospital or was dis¬
charged after therapy. Hemorrhage was the leading cause
of nucleated red blood cells in the peripheral blood, and
the most frequent lesion was a duodenal or gastric ulcer.
Varices due to cirrhosis were next in order of frequency,
and uterine bleeding was third. There were five cases of
genitourinary bleeding of sufficient severity to produce
From the Hematology Laboratory and the Hektoen Institute for Medical
Research of Cook County Hospital.
This study was aided by grants from the Olivia Sue Dvore and
Edward Friedman foundations.
1. Da Costa, J. C., Jr.: Clinical Hematology: Practical Guide to the
Examination of the Blood with Reference to Diagnosis, Philadelphia,
P. Blakiston's Son & Company, 1901, p. 143.
2. Bramwell, B.: Anemia and Some of the Diseases of the Blood\x=req-\
Forming Organs and Ductless Glands, Philadelphia, P. Blakiston's Son &
Company, 1899, p. 18.
3. Cabot, R. C.: Guide to the Clinical Examination of the Blood for
Diagnostic Purposes, ed. 5, revised, New York, William Wood & Company, 1904, p. 189.
4. Diamond, L. K.: Anemias of Nutritional Deficiency, in Meulengracht, E.: Symposium on the Blood and Blood-Forming Organs, Madison,
University of Wisconsin Press, 1941, p. 57.
5. Groen, J., and Godfried, E. G.: Occurrence of Normoblasts in
Peripheral Blood in Congestive Heart Failure: Indication of Unfavorable
Prognosis, Blood 3: 1445 (Dec.) 1948.
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nucleated red blood cells in the peripheral blood. Also
included in this category were several cases of thrombocytopenic purpura and one case of Rendu-Osler-Weber
disease. The gross mortality in this group was 36%. The
second largest group exhibiting nucleated red blood cells
in the peripheral blood were patients with pernicious
anemia. It is notable that in this condition for which in¬
tensive treatment was employed and specific therapeutic
agents were available, the mortality was still 29%. Pa¬
tients with carcinoma comprised the third largest group,
with an over-all mortality of 61%. This suggests that by
the time nucleated red blood cells appear in the blood the
carcinoma is well advanced, that is, it has led to either
considerable anemia or extensive involvement of the
marrow.
Among the cases of blood dyscrasias, acute and chronic
myelogenous leukemia produced by far the largest num¬
ber of nucleated red blood cells in peripheral blood. Of
the 154 cases in this group, 90 were due to myelogenous
leukemia and were equally divided between the acute and
chronic forms. There were 21 cases of chronic lymphatic
leukemia and the others were about equally distributed
among lymphosarcoma, monocytic leukemia, retículoConditions in Which Nucleated Red Blood Cells Were Found
in the Peripheral Blood
Percent-
No. of No. Who No. Who age of
Died
Deaths
Condition
Patients
Lived
231
130
Hemorrhage.
361
Pernicious anemia.
78
192
29
270
88
136
Carcinoma.
61
224
195
65
Cardiac conditions.
130
37
117
Leukemia and related conditions 154
7«
49
Infections.
66
115
67
86
17
Hemolytic anemia.
Miscellaneous (cerebral vascular
91
45
accidents, diabetes, etc.).
46
60
Total. 1,496
endotheliosis, Hodgkin's disease,
776
acute
720
lymphatic
48
leu¬
kemia, and multiple myeloma. It is hardly surprising that
the mortality in this group should have been the highest,
76%. In the group with hemolytic anemia, sickle cell
anemia was present in 64 cases out of the 86. The re¬
maining cases consisted of congenital and acquired he¬
molytic anemia and Mediterranean anemia. The mortal¬
ity rate in this group was the lowest, but even here it was
20%. The miscellaneous group contained such diverse
conditions as lead, phosphorus, arsenic, and gas poison¬
ing; diabetes; polycythemia; myxedema; hyperthyroid¬
ism; lupus erythematosus; osteitis deformans; methemoglobinemia; and cerebral vascular accidents. Cerebral
vascular accident was the largest single cause of the ap¬
pearance of nucleated red blood cells in this group, and
only one in 17 patients survived. It is of interest that in
this diverse group the mortality rate is 50%, which is
almost the average for the entire group included in this
study.
Examination of data for two groups, 195 patients who
had cardiac conditions and 115 who had infections, re¬
veals that the gross mortality in the former was 66% and
in the latter 57%. In an attempt to evaluate these cases
more particularly, all complicated cases and, in partic¬
ular, any in which the number of red blood cells of pa¬
tients was below 3,500,000 or in which hemoglobin
levels were below 10.9 gm. (70% ) were eliminated. Ex¬
cluded also from the group with cardiac conditions were
those in whom anemia was due to uremia. Even with this
critical selection the percentage of deaths remained high.
The number of nucleated red blood cells in the remaining
group of 93 patients varied from 1 to 19 per 100 white
blood cells counted; usually there were less than 4 nucle¬
ated red blood cells per 100. Two of the cardiac condi¬
tions were caused by heart disease due to syphilis, and
seven were listed as cor pulmonale. The remainder of
these cases were evenly divided among rheumatic heart
disease, arteriosclerotic coronary disease, and hyperten¬
sive heart disease. Of these patients, 41% failed to re¬
cover. After selective exclusion, 42 patients remained in
the group with infectious diseases. The number of nucle¬
ated red blood cells varied from 1 to 9 per 100 white
blood cells. Pneumonia was the diagnosis in 28 of the 42
cases, and 5 cases were diagnosed as tuberculosis. Vari¬
ous bacterial infections made up the remainder. Fortyfive per cent of these patients died.
CONCLUSIONS
The presence of nucleated red blood cells in the pe¬
is generally a sign that the prognosis is
poor, as evidenced by the appalling mortality rate of
almost 50% in the present study. Our findings would
indicate that this is also true in cases of cardiac disease
and in infectious diseases, especially when anoxia is pro¬
duced. It is worth repeating for emphasis that, of 93 pa¬
tients with cardiac conditions in the selected group, 41 %
died, and in the total group of 195 patients, 66% did not
survive when nucleated red blood cells appeared in the
peripheral blood. The relatively large number of deaths
in the infectious group, particularly from pneumonia,
was unexpected. Of 115 cases in which infections com¬
prised the principal cause of nucleated red blood cells in
the peripheral blood, 57 % were fatal, and, of the specially
selected group of 42, 45 % were fatal. Anoxia is evidently
a dominant influence here as it is in the group of patients
with cardiac conditions. Because of the nature of the un¬
derlying conditions, the prognosis is better in hemolytic
anemia, hemorrhage, and pernicious anemia. The pres¬
ence of cases in which bleeding was a consequence of
cirrhosis of the liver raised the percentage of fatalities in
the hemorrhagic group. The prognosis is least good in
carcinomatosis and leukemia.
1835 W. Harrison St. (12) (Dr. Schwartz).
ripheral blood
Boric Acid.—It is incredible that a drug with such toxic pro¬
pensities and doubtful therapeutic value should continue to
enjoy such popularity in the armamentarium of so many phy¬
sicians and occupy such a prominent place in the home medi¬
cine cabinets. Perhaps the explanation of this paradox is
that many topical agents survive as therapeutic agents, not so
much in their power to do good, but in their failure to do
harm. Apart from accidental poisoning with boric acid there
should be greater awareness on the part of the medical pro¬
fession and laity of the toxic effects of absorption of boric
acid from broken skin surfaces and mucous membranes.
Boric acid should be replaced in medical practice with more
efficient and safer medication, and pharmaceutical houses
should cooperate in an educational campaign to acquaint the
public of its potential danger.—H. G. Poncher, M.D., Boric
Acid, The Journal of Pediatrics, December, 1953.
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