THE CRISIS IN SICKLE CELL ANEMIA
HEMATOLOGIC STUDIES
L. W. DIGGS, M.D.
University
of Tennessee College of Medicine and City of Memphis
Memphis,
Tennessee
Hospitals,
The word crisis* was first used in association with sickle cell anemia in 1924
by Sydenstricker,13 who noted that abdominal pains and ". . . increase in jaundice
and in the urobilin content of the urine. . ." resembled the crises in congenital
hemolytic jaundice. Graham, 5 in the same year, observed that the recurrent
paroxysms of acute illness were characterized by "fever, prostration, pain in
extremities and joints, and evidences of marked blood destruction." Penberthy
and Cooley (in 1935)10 and Cooley (in later publications)2 described "hemolytic
crises" occurring in patients with sickle cell anemia in association with streptococcal infections. Since then the words hemolytic and crisis have been used
frequently in combination. Although no convincing proof has been presented
that there is a significant change in the rate of destruction of red blood cells
preceding, during, or following the crisis, the majority of students of sickle cell
disease have accepted the concept of "hemolytic crisis" and continue to use the
term in their publications.
A few authors have questioned the validity of the thesis that the painful and
febrile paroxysms, and other episodes of acute illness in patients with sickle
cell anemia, are necessarily associated with an exaggeration of the hemolytic
process. Leivy and Schnabel8 stated that the "hemolytic features of sickle cell
anemia are not accountable for the critical abdominal attacks." Tomlinson14
noted that the clinical symptoms are remarkably similar to the symptoms that
Received, February 20, 1956; revision received, J u n e IS; accepted for publication
.July 2.
D r . Diggs is Professor of Medicine and Director of Department of Medical Laboratories.
This work was supported in part by a grant from the Herff Foundation, Memphis,
Tennessee.
* Dictionary definitions of the word crisis (Gr., Krisis, turning point) include: (1)
" a striking change in symptoms attended by outward manifestations;" (2) " a painful
paroxysmal a t t a c k ; " (3) " a paroxysmal disturbance of function accompanied by p a i n . "
T h e crisis in sickle cell anemia is defined as a striking and sudden change in the symptoms and signs in a patient with homozygous hemoglobin S disease. A hemolytic crisis is a
significant change in the blood picture, characterized by a precipitous drop in the erythrocyte values associated with an increase in serum bilirubin, with no increase (or only a slight
increase) in t h e 1-minute bilirubin, an increase in the o u t p u t of focal urobilinogen, an
increase in the urinary urobilinogen (in the absence of bile), a hypercellular bone marrow,
and an increased number of immature cells in the peripheral blood. An aplastic crisis is a
sudden change in the findings in the blood, characterized by a decrease in the cellularity
and m a t u r i t y of the cells of the bone marrow, associated with a striking decline in the values
for erythrocytes, a low count of reticulocytes, a decrease in the concentration of serum
bilirubin, and, usually, an associated leukopenia and thrombocytopenia.
1100
a
1110
Vol. 26
MGGS
are usually associated with rapid destruction of blood, but that "there is no
evidence of extremely rapid blood destruction in these cases." Pratt-Thomas
and Switzer,11 and Henderson7 stated that the crises may be independent of
sudden and massive destruction of erythrocytes. Green, Conley, and Berthrong 6
used the term crisis to designate the characteristic episodes of pain "whether
or not there is evidence of a coincident increase in the rate of red cell destruction."
Watson17 defined the crises as "severe bouts of trouble, which often occur without
exacerbation of the hemolytic anemia."
Aplastic crises* in patients with sickle cell anemia have been reported by
Singer, Motulsky, and Wile,12 by Godfried,4 and by Chernoff and Josephson.1
Many feel that the clinical symptoms and signs are best explained on the basis
of occlusive vascular phenomena that are the result of the increased viscosity of
the blood caused by the crystallization of Hb S within the erythrocytes. The
sickled and rigid erythrocytes "log jam" the vascular channels, and this produces
stasis, hypoxia, vascular and perivascular lesions, and degenerative parenchymal
changes.3,15
Because opinions differ in regard to the nature of the critical episodes occurring
in patients with sickle cell anemia, and because there is a paucity of controlled
hematologic studies, the author believes that a presentation of his observations
is justified.
MATERIALS AND METHODS
The clinical material on which this paper is based consists of 166 patients with
classic sickle cell anemia. They were patients in the out-patient clinics and the
wards of the City of Memphis Hospitals, and each of them was examined by the
author during one or more of their hospital admissions. These patients were
admitted to the hospital in so-called "crises" on 747 occasions.
Thirty of the 166 patients were hospitalized for the purpose of studying the
fluctuations in hematologic values during the intervals between crises, as well
as at the time of the crisis. In the majority of these 30 patients, daily reticulocyte counts, determinations of hemoglobin, leukocyte counts, and examinations
of blood smears were made.
Erythrocyte counts, packed cell volumes, and 1-minute and total concentrations of serum bilirubin were determined each week (or at more frequent intervals) at the time the patients had acute symptoms or signs.
Standard hematologic procedures were used. The concentrations of serum
bilirubin were estimated by the method of Malloy and Evelyn.9 The determinations of 24-hour fecal and urinary urobilinogen were performed according to the
procedure recommended by Watson.16 The output of fecal urobilinogen per day
was calculated as a fourth of the total urobilinogen on a pooled 4-day specimen.
OBSERVATIONS AND
DISCUSSION
Patients with sickle cell anemia have an unremitting anemia and jaundice
from early infancy until the day of their death. The survival time of their defectively formed erythrocytes is significantly decreased. There are continuous signs
ISDI
20
30
40
50
60
nm^Mn^.
DAYS
70
7
80
90
^Av^w^^^A ^
10
100
FIG. 1. Hematologic changes in a 4-year-old Negro boy with sickle cell anemia (Hb S-S) in association with recurrent
crises. (Symbols used for symptoms: solid black = pains in bones and joints; solid white = systemic symptoms; di
agonal lines = abdominal pains; dots = chest pain; black-and-white parallel bars = headache; small squares = symptoms referable to the central nervous system; perpendicular lines = upper respiratory infections).
o—-o 2 • — •
mg/lOO
I MIN
TOTAL
BILIRUBIN
RBC HBG PCV
cv mm gmt ml/100
Jfea_
4-M-C I
SYMPTOMS
S. C.
F
F
F
£73
w
en
1112
Vol. 26
D1GGS
of increased destruction of erythrocytes and compensatory regeneration. The
balance between the rate of destruction of red blood cells and the ability of the
bone marrow to replace cells is established at a level that is lower than that of a
normal person.
In evaluating an increase in the severity of the anemia, or an increase in the
rate of destruction of blood, it is necessary to ascertain the "baseline" for a given
patient. It is not valid to assume that there is an increase in the rate of hemolysis,
or in the degree of anemia at the time of the crisis by comparing the laboratory
values with the values for normal persons. One must compare standard values
based upon previous observations of the individual patient with sickle cell
anemia.
Erythrocyte values in patients with uncomplicated sickle cell anemia were
not significantly affected by recurrent and febrile episodes. A true "hemolytic
crisis"* was not observed in any patient with sickle cell anemia. Representative
charts illustrating the values for erythrocytes in relation to the clinical crises
are illustrated in Figures 1 to 5.
The reticulocyte count is characteristically increased in patients with sickle
S.C. 5 C M
12
JUNE
IT
SYMPTOMS
HI
RBC
HGB
PCV
u
0--o
OMS
ML/IOO
4
3
2
12
9
6
3
36
27
18
9
RETIC
nainftim
111
IIMI r—i IB
fr;-
n
B
-=.-J::;X;^
NUC. RBC
# • - ' » / C U HH O — O
1,200,000
3,000
800,000
2,000
400,000
1,000
SERUM BILIRUBIN
MGM/IOOMl
URINE UROBILINOGEN
CU/84
MRS
10
5
FECAL UROBILINOGEN
E U
600
300
F I G . 2. Hematologic findings and total urinary and fecal urobilinogen excretion in a 5-year-old Negro boy (Hb S-S) during recurrent respiratory infections, and at the time of mild crises. There are minor variations in the values
for erythrocytes, but no significant change in the concentration of scrum bilirubin or in the excretion of urobilinogen in the urine or the feces.
Oct. 1956
CRISIS
IN S I C K L E
CELL
111
ANEMIA
T. P. 31 CM
SYMPTOMS
RBC
HGB
M
i
PCV
CMS
ML/IOO
0
3
9
27
2
6
18
1
3
9
RETIC
NUC- RBC
/CUMM
/CUMM
40,000
20,000
SERUM BILIRUBIN
MGM/KUML
I MIN.
TOTAL
2
•—•
•-CK--0
-0---0
Q
URINE UROBILINOGEN
EU / Z4 HOS
iliM
45
30
15
FECAL UROBILINOGEN
200
I 00
TREATMENT
n
TT
FIG. 3. Values for erythrocytes, concentration of
scrum bilirubin, and total urobilinogen in the urine and
the feces in a 31-year-old Negro man with sickle cell
anemia (Hb S-S). There is evidence of hemolytic jaundice at all times, but no evidence of an increase in
hemolysis in association with the crisis of abdominal
and joint pain.
cell anemia. The number of reticulocytes varies considerably during periods in
which the patients had no symptoms, as well as during the crises, but there is no
consistent change in association with the crisis (Fig. 1 to 6). Nucleated red blood
cells and Howell-Jolly bodies are usually demonstrable in the peripheral blood
during quiescent periods, as well as during the crises. There is a tendency for
reticulocytes and for nucleated red blood cells to decrease temporarily following
transfusions (Fig. 3 and 4).
The percentage of sickled cells in air-exposed smears of peripheral blood of
patients with sickle cell anemia varies considerably, but the level tends to remain
fairly constant for any one person, year after year, and it does not change significantly at the time of the crisis (Fig. ]).
The excretion of urobilinogen in the urine and feces is increased, whether the
patient is in crisis or not. Studies are inadequate to warrant final conclusions,
but there was no apparent consistent change in the output of pigment in the
urine or feces at the time of the crisis, as compared with the output during the
symptomless periods (Fig. 2 to 5).
Patients with sickle cell anemia who develop complicating diseases do not
1114
Vol. 26
DIGGS
necessarily develop clinical crises. Hematologic changes vary in different patients
as a result of their combined diseases. In the majority of patients with secondary
viral, bacterial, or protozoal infections, and with systemic diseases, there is a
decrease in erythrocyte values, and this is primarily the result of defective
regeneration rather than an increase in the hemolytic process. There is likely to be
a decrease in the number of reticulocytes and nucleated red blood cells in the
peripheral blood, and lower concentrations of serum bilirubin in these patients
as their anemia progresses.
A true aplastic crisis was observed in only 1 patient in our series of 747 crises.
This patient was a 16-year-old Negro girl who had been previously diagnosed as
having sickle cell anemia, and whose level of hemoglobin was persistent at approximately 7 to 9 Gm. per 100 ml. of blood. She had a history of gradual onset
of fever and malaise (without apparent cause) several days prior to admission.
There were associated anorexia, progressive weakness and drowsiness, dyspnea,
and cardiac discomfort. Erythrocytes numbered less than a million and the
U
I
U
* C
r
C
m.u.n. on K. r
AUOUST
-
,.
SEPTEMBER
_.
_.
.
lo
,.
OCTOBES
70
23
so
s
10
15
SYMPTOMS
RBC
H6B
PCV
• MS
HL/IOO
RETIC
NUC. RBC
/6UMM
•
•
/CUHM
O
-O
120,000
30,000
80,000
20,000
40,000
10,000
nooooo—00000—-QOQO^^O—aoooorf
SERUM BILIRUBIN
MOH/IOOML
I HIN.
1
»
URINE
TOTAL
o
I
°—°
UROBILINOGEN
CU/t4
HUB
10
5
FECAL UROBILINOGEN
c u
200
100
TREATMENT
t i t
t
T T
FIG. 4. Hematologic observations and pigmentary studies in a 36-year-old Negro
woman with severe sickle cell anemia (Hb S-S), low-grade hemolytic jaundice, and
chronic ulcers of the legs. It is possible that the slight rise and subsequent fall in
the values for erythrocytes, and the increase in nucleated red blood cells followed
by an increase in reticulocytes are the result of the transfusions.
Oct. 1956
CRISIS
INT SICKLE CELL
HAY
22
PS 20 C M
27
mmM
SYMPTOMS
RBC
H6B
M
PCV
QMS
0--0
•
1.1.15
ANEMIA
ML/100
•
X
-K
3
9
27
2
6
18
I
3
9
RETIC
NUC. RBC
/CU MM
•
•
/CU MM
O
0
600,000
3QO0O
400,000
15,000
SERUM BILIRUBIN
I MIN.
o--o
M0M/I00ML
TOTtt.
9
• m
— _-0
"°
URINE UROBILINOGEN
E U / 2 4 HRS
30
20
10
FECAL UROBILINOGEN
E u
800
600
400
200
TREATMENT
c
*ul]llL
:
t t
FIG. 5. Hematologic studies and determinations of urobilinogen on a 20year-old Negro man with severe sickle cell anemia (lib S-S). He was admitted
for treatment of chronic ulcers of the legs, and had a pronounced increase in
nucleated red cells and reticuloc\'tes at the time of admission The patient
developed abdominal pains, pain in the chest associated with hemoptysis,
headache, and systemic symptoms following the administration of typlioid
vaccine.
leukocyte count was 2600 per cu. mm. The bone marrow was hypocellular, and
there was a relative increase in immature erythrocytic cells, with a decrease in
mature forms. Many of the nucleated erythroid cells had degenerative changes.
The patient was not jaundiced. After transfusions were administered, the girl's
condition improved rapidly, and the bone marrow returned to the usual hypercellular state, with a normal distribution of cells. There was a concomitant increase in reticulocytes and nucleated red blood cells in the peripheral blood, and
the values for erythrocytes returned to their previous low levels.
A few patients had numerous nucleated red blood cells in the peripheral blood,
extremely high reticulocyte counts, and a hypercellular bone marrow when they
were admitted to the hospital. The hematologic course in these patients was
characterized by a gradual return toward normal in erythrocyte values,
without a significant change in the concentration of serum bilirubin. It is prob-
mo
Vol. 26
DIGGS
DAYS AFTER ONSET OF CRISIS
2
4
6
6
10
12
14
RETICULOCYTES
HEMOGLOBIN
GMS/IOOML
15
10
5
SERUM BILIRUBIN
| MGM/IOO ML
10
5
FIG. 6. Reticulocytes, nucleated red blood cells per 100 leukocytes, hemoglobin
determination, and total serum bilirubin in 25 consecutive, unselected patients with
classic sickle cell anemia, in crises, without demonstrable complicating disease. An
increase in serum bilirubin (indicated by dotted lines) occurred in 2 patients. In
these cases, the jaundice was of an obstructive, rather than a hemolytic, type.
able that such persons were in a recovery phase, following an aplastic or hypoplastic crisis.
In occasional patients with sickle cell anemia, there was jaundice of an obstructive type at the time of the clinical crisis. This jaundice was characterized by an
increase in 1-minute serum bilirubin, a total serum bilirubin above 5 mg. per
100 ml., and bile in the urine. In these patients an intrahepatic regurgitant (obstructive) jaundice was superimposed upon the pre-existing hemolytic jaundice.
Sections of the liver from patients with obstructive jaundice have revealed
engorgement of the vascular channels by sickled erythrocytes, degenerative
parenchymal changes, and focal hepatic necrosis.15
Oct. 1.956
CRISIS IN SICKLE CELL ANEMIA
1117
SUMMARY
1. Clinical and hematologic studies of 166 patients with classic sickle cell
anemia were made during 747 clinical crises. These patients had chronic anemia,
continuous jaundice of a hemolytic type, and signs of increased regenerative
activity of the bone marrow during their quiescent intervals, as well as during
their clinical crises. There was no evidence of the development of a more severe
anemia during or following the crisis, as compared with the values for erythrocytes and bilirubin previous to the crisis. Similarly, there was no significant or
consistent alteration of the reticulocyte count, the number of nucleated red
blood cells, the percentage of sickled cells, or the excretion of urobilinogen in the
urine and feces in association with the crisis.
2. A true aplastic crisis (with hypocellularity of the bone marrow, an absence
of jaundice, and a decrease in reticulocytes and nucleated red blood cells in the
peripheral blood) was observed in only 1 patient.
3. The concept of "hemolytic crises" in sickle cell anemia is a myth that should
not be perpetuated in the light of present knowledge.
SUMMAUIO I N I N T E R L I N G U A
1. Studios clinic e hematologic de 166 patientes con classic anemia a cellulas
falciforme esseva facite durante 747 crises clinic. Iste patientes habeva anemia
chronic, continue jalnessa del typo hemolytic, e signos de augmentate activitate
regenerative del medulla ossee durante lor periodos de quiescentia como etiam
durante lor crises clinic. Esseva notate nulle signo del disveloppamento de un
plus sever forma de anemia durante o post le crises in comparation con le valores
pro erythrocytes e bilirubina obtenite ante le crises. Similemente il non habeva
un regular o significative alteration del numeration de reticulocytes, del numero
de nucleate cellulas rubie, del procentage de cellulas falciforme, o del quantitate
de urobilinogeno excernite in le urina e le feces in association con le crises.
2. Un ver crise aplastic (con hypocellularitate del medulla ossee, absentia de
jalnessa, e un reduction del reticulocytes e del nucleate cellulas rubie in le sanguine peripheric) esseva observate in solmente 1 patiente.
3. Le concepto de "crises hemolytic" in anemia a cellulas falciforme es un
mytho que non deberea esser perpetuate in le lumine de nostre presente cognoscentias.
REFERENCES
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and infectious mononucleosis. Am. J . D i s . Child., 82: 310-322, 1951.
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Practice of Pediatrics, Vol. 3, ed. by I. McQuarrie. Hagerstown, M d . : W. F . Prior
Co., Inc., p p . 1-87 (Revised 1946).
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cell disease. J . N a t . M . A., 46: 46-49, 1954.
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DIGGS
Vol. 26
8. LEIVV, F . E . , AND SCHNABLE, T . G.: Abdominal crises in sickle cell anemia. Am. J. M.
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estimation of urobilinogen in urine and feces. Am. J. Clin. Path., 6: 458-475, 1936.
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